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264 Cards in this Set
- Front
- Back
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What is a hormone?
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Chemical messenger released by an endocrine gland, tranported in low concentrations to a target cell
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What is the difference between a hormone and a neurohormone?
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A neurohormone is secreted by neurons; hormone is secreted by any endocrine cell
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What is the overall endocrine role of the thyroid?
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Metabolism
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What is the overall endocrine role of the parathyroid?
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Calcium metabolism
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What is the overall endocrine role of the adrenal glands?
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Salt, water metabolism, stress response
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What is the overall endocrine role of the kidneys?
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Vitamin D conversion
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What is the overall endocrine role of the gonads?
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Puberty, reproduction
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What is the overall endocrine role of the pituitary gland?
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Master regulator, controls many peripheral endocrine orgas
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What is the overall endocrine role of the hypothalamus?
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Important for releasing factors that control pituitary
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What is an example of positive feedback?
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Oxytocin and uterine contractions
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Where are hormone receptors located?
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On the cell surface OR inside the cytoplasm/nucleus
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What type of signalling amplifies cell surface receptor action?
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Secondary messenger signaling (G-protein for example)
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What is the difference between primary and secondary hypothyroidism?
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Primary: no thyroid gland; Secondary: no TSH
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What happens in Grave's disease?
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Antibody mimics TSH and binds to TSH receptor; stimulates extra production of T3 and T4, which then negatively feedback to lower TSH secretion; therefore very low TSH levels but very high T3/T4 - hyperthyroidism Sx
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What is an example of a nonspecific protein carrier to which hormones are bound?
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Albumin
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What is the benefit of having bound hormone in our system?
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Bound hormone provides a reservoir and extends the half life for stable hormone action
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The amount of binding protein affects: Total, Bound or Free?
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Total and Bound, not free.
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What are the stimulatory and inhibitor releasing factors from the hypothalamus for GH?
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Stimulatory: GHRH (growth hormone relasing hormone); Inhibitory: Somatostatin
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How does GH affect bone metabolism?
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Increased osteoclast differentiation and activity; increased osteoblast activity; increase in bone mass by endochondral bone formation; increased epiphyseal growth
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What releasing factor stimulates release of LH and FSH?
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GnRH (Gonadotropin releasing hormone)
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What are the releasing factors/hormones involved in the adrenal glands?
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Corticotropin Releasing Hormone (CRH) stimulates release of Corticotropin (ACTH) from pituitary, which stimulates release of cortisol in adrenal glands
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What hormones are produced by the zonas: glomerulosa, fasciculata, reticularis, and medulla of the adrenal gland?
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ZG: aldosterone; ZF: cortisol; ZR: androgens; Medulla: Catecholamines (eg. epinephrine=adrenaline)
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What is the releasing/inhibiting factor for thyroid hormones?
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TRH (Thyrotropin releasing hormone) stimulates release of TSH; Somatostatin inhibits release of TSH
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How is T3 and T4 produced in the thyroid then released?
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Iodine, thyroglobulin, and thyroid peroxidase (TPO) form thyroglobulun+Iodine - colloid is reabsorbed, proteolysis generates T3 and T4, then secreted into blood bound to Thyroxine-binding globulin (TBG)
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Is there more T4 or T3 in the blood?
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More T4
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Is the pancreas controlled by the pituitary gland?
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No - it reacts directly to blood glucose
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What is the basic mechanism by which insulin is secreted, after glucose sensing?
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Glucose -> ATP -> closes ATP sensitive K+ chanel -> depolarises nearby Ca2+ channel -> stimulates insulin secretion
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High levels of blood calcium cause the thyroid to release what?
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Calcitonin
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Low levels of blood calcium cause the parathyroid to release what?
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PTH
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How does PTH affect the kidneys?
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PTH stimulates kidneys to release calcitriol which stimulates increased absorption of calcium from food
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When you are hypotensive, is renin secreted or inhibited?
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Renin is secreted with low blood pressure/volume
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What does ACE do?
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Converts angiotensin I to angiotensin II
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What does renin do?
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Converts angiotensinogen to angiotensin I
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What cells of the pancreas produce insulin?
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Beta cells
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What are three effects of insulin?
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Decrease lipolysis in fat, decrease glucose production in liver, increase glucose uptake in muscle
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What is the difference between Type I and Type II Diabetes?
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Type I: absolute deficiency of insulin, beta cells are destroyed; Type 2: insulin resistance with beta cell secretory defect
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Does obesity cause Type II Diabetes?
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No; it causes insulin resistance, which can have similar effects - but Type II DM is distinct. Having one does not necessitate having the other.
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What are three types of animal steroids?
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Sterols (cholesterol), bile acids, and steroid hormones
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Are steroids hydrophobic or hydrophilic?
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Hydrophobic; they are lipid like
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______ is the basis for most steroid hormones in the body.
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Cholesterol
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What kinds of tissues is cholesterol synthesised in?
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All tissues, particularly high in liver, adrenal cortex and gonads
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Where does cholesterol synthesis occur in the cell?
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Cytoplasm and smooth ER
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What is the rate limiting enzyme in cholesterol synthesis?
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HMG CoA reductase
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Is cholesterol a precursour for Vitamin D?
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No; it is the precursour for all other steroid hormones though.
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How is cholesterol metabolised?
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It canNOT be metabolised! it is excreted in the feces as bile salts/acids.
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Steroid hormone biosynthesis is catalysed by what types of enzymes?
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P450 enzymes
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What are the steps of making cholesterol into pregnenolone?
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Cholesterol synthesised in sER/cyto; transpoted to mito for side chain cleavage, pregnenolone made, goes to sER for further steps
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How are sex steroids made from pregnenolone?
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Pregnenolone goes to sER, then synthesised into specific androgens, estrogns progestins
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How are glucoorticoids and mineralicorticoids made from pregnenolone?
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Pregnenolone goes to sER and then back to mitochondria
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What organelles would you expect to find an abundance of in steroid producing cells?
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Mitochondria and smooth endoplasmic reticulum
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What is the most common reaction catalysed by P450 enzyme?
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Monooxgenase reaction; insertion of one atom of O into an organic substrate
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What pituitary hormones regulate activity of P450scc?
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LH in the gonads, ACTH in adrenal cortex (P450scc converts cholesterol to progestrone)
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What does the StAR protein do?
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Transports cholesterol through mito membranes so conversion to pregnenolone can occur
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What defect occurs in Lipoidal Congenital Adrenal Hyperplasia?
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Defect in StAR protein; loss of steroidogenesis; cellular damage from accumulated choletserol esters and then further loss of steroidogenesis; no steroid hormones synthesised
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What is the phenotype of someone with Lipoidal Congenital Adreal Hyperplasia?
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Phenotypic females (absence of androgen during development) + severe salt-losing (absence of mineralocorticoids)
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What defect occurs in Smith-Lemli-Opitz Syndrome?
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C7 reductase problem; less cholesterol production, accumulation of precursour; impaired development of genitalia because of lack of testosterone in foetal life
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What is the phenotype of someone with Smith-Lemli-Opitz Syndrome?
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Ambiguous genitalia in males; mental retardation
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What defect occurs in Congenital Adrenal Hyperplasia?
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21-hydroxylase deficiency; can't produce cortisol/aldosterone from progesterone, so all progesterone is redirected to making sex steroids
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What is the phenotype of someone with Congenital Adrenal Hyperplasia?
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Virilisation of female infants - abnormal/ambiguous genitalia for females; salt-wasting crises.
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What defect occurs in 5α-reductase deficiency?
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Testosterone cannot be converted to 5αdihydrotestosterone; mutation in 5α-reductase-2
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What is the phenotype of someone with 5α-Reductase deficiency?
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Males are undervirilised, but they virilise at puberty; normal male internal genitalia, ambiguous genitalia at birth; absent internal female genitalia; grow up usually as girl but then at puberty virilise
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Steroid hormone receptors typically involve what 3 elements?
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Heat shock proteins, coactivators, speciic DNA binding element.
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What part of a steroid hormone receptor determines the specificity of action?
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The DNA binding domain
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What defect occurs in Complete Androgen Insensitivity?
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Mutation in androgen receptor gene, X-linked recessive expressed in 46,XY only
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What is the phenotype of someone with Complete Androgen Insensitivity?
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Breast development, female habitus at puberty; female genitalia and hair; female with blind vaginal pouch genitalia; no wolfian derivatives, no mullerian derivatives; testes as gonads
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How do anabolic steroids work in adults?
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1) fully saturate and activate androgen receptors, thus increasing muscle mass; 2) inhibit function of glucocorticoid receptor in muscle, by inhibiting action of cortisol in muscle and thus increasing muscle mass (cortisol usually stimulates protein breakdown)
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How is cAMP synthesised from ATP?
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By adenylyl cyclase, from Mg2+ - ATP
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How is cAMP degraded into AMP?
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Phosphodiesterase
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What energy molecule causes dissociation of the hormone:receptor complex?
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GTP (hence, "G"-protein)
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What are some characteristics of G-proteins?
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1) interact with beta-adrenergic receptor and cause it to dissociate from its ligand epinephrine; 2) they bind GTP; 3) they activate adeylyl cyclase in GTP dependent manner; 4) they turn themselves off by hydrolysing GTP
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What is the first step in signal transduction?
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Hormone binds to receptor, induces exchange in which G protein binds GDP and then GTP
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Once the G-protein is binding GTP, what happens?
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GTP-bound G protein activates adenylyl cyclase resulting in cAMP generation (signal output)
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What is the "on" signal for a G protein?
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Nucleotide exchange (GDP to GTP)
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What is the "off" signal for a G protein?
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GTP-ase (GTP to GDP)
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What is the typical structure of a G protein?
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Heterotrimeric (alpha, beta, gamma subunits)
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How many subtypes of the α subunit of the G protein are there?
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2: Gsα = stimulates adenylyl cyclase; Giα = inhibits adenylyl cyclase
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Do Gsα and Giα interact directly with adenylyl cyclase?
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Yes
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What is the cycle of action of Gsα?
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1) receptor binds hormone; 2) GDP bound to α is replaced by GTP; 3) GTP-bound Gα releases from beta-gamma and activates an effector; 4) Gα hydrolyses GTP and returns to GDP-bound state.
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Does cholera exert a systemic effect?
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No; it never gets past the gut mucosa
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Does pertussis exert a systemic effect?
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Yes; toxin circulates in blood
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What type of molecule is the cholera toxin?
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Enzyme
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How does the cholera toxin act?
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Catalyses ADP-ribosylation of Gsα; inhibits GTPase activity; Gsα is irreversibly turned on; adenylyl cyclase stimulation
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How does the pertussis toxin work?
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Catalyses ADP-ribosylation of Giα; locks ability to exchange GTP for GDP; loss of inhibition of adenylyl cyclase
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What subunit does cholera affect?
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Gsα (stimulatory)
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What subunit does pertussis affect?
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Giα (inhibitory)
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What are the analogues of the G-protein system in light reception?
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Rhodopsin=receptor; Transducin=G protein; Phosphodiesterase=effector
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Which toxins affect transducin?
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Cholera and pertussis
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What is the effector action in olfaction?
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cAMP leads to opening of sodium channels which results in signal propagation down an axon
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What is special about the olfaction-specific adenylyl cyclase?
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It has a much more pronounced "on" vs. "off"
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Is adenylyl cyclase directly activated by GTP?
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No; it is indirectly activated because it forms an active complex with Gsα
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Through what enzyme does cAMP exert its biological action?
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cAMP-dependent protein kinase (PKA) ; serine-threonine kinase
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Levels of what molecule regulate PKA activity?
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cAMP levels
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What is the structure of PKA (cAMP-dependent protein kinase?)
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2 regulatory, 2 catalytic subunits; cAMP binds to 2R and releases it rom the 2C, allowing for activity
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Can cAMP affect transcription factors?
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Yes; several response elements have been located on promoters
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How does cAMP affect transcription?
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Phosphorylation by PKA in response to cAMP activates DNA binding.
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How do mutations in Ras cause cancer?
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Ras mutations cause loss of GTPase activity; Ras stays active all the time; uncontrolled growth = cancer
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What happens in pseudohypoparathyroidism?
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Resistance to cAMP mediated hormones (PTH, TSH, LH) because of problem with the Gs activity; problem with receptor, so even though excess hormones are produced, they are not exerting their effect. Therefore, it resembles hyPOparathyroidism even though they have elevated hormone levels in blood.
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What are some of the effects of cell transformation (ex. after infection by RSV?)
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Loss of contact inhibition; indefinite proliferation; lose need for serum; anchorage dependence lost; glycolysis and glucose transport increase
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What proteine in RSV allows for transformation?
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v-Src = tyrosine protein kinase
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What are the three aa's on which phosphorylation occurs in protein kinases?
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Threonine, Serine, Tyrosine (Tyrosine is the most rare)
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How many autophosphorylation sites does v-src have? c-src?
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v-src: 1, activating. c-src: 2, activating and inhibiting.
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Where is the primary autophosphorylation site in c-src? What does it do?
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Near carboxyl tail; inhibits kinase activity.
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Does c-src cause normal cellular transformation?
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No.
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What is a proto-oncogene?
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The normal cellular gene that gives rise to an oncogene
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What type of kinase is the EGF receptor?
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Receptor tyrosine kinase
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What are the typical features of a receptor tyrosine kinase?
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Extracellular ligand binding domain; transmembrane region; tyrosine kinase domain with ATP and substrate binding regions; intracellular domain with Tyr autophosphorylation and Ser/Thr phosphorylation sites
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Is tyrosine kinase activity required for biological activity of the receptor?
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Yes
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What are the first steps for EGF signalling?
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Dimerisation, followed by trans-phosphorylation of the tyr kinase domain
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In the EGF receptor, autophosphorylation on ___ activates the kinase, and ___ phosphorylation shuts it off.
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Tyrosine; Threonine
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How are erb-b and EGF-R related?
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erb b oncogene is a truncated (non-regulated) EGFr; it has the intact tyrosine kinase function but does not require EGF for activity
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EGF receptor is a prototype of ______ whereas Sarc is a prototype of _______.
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Receptor Tyrosine Kinases; Non-Receptor Tyr Kinase
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How is Tyr kinase activity modulated in RTKs?
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Ser/Thr phosphorylation
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Do RTK receptors interact directly with signaling molecules?
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Yes
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What is the first mechanism of action of receptor Tyr kinase?
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Phosphorylates enzyme on tyrosine, conformational change results in catalysing a reaction that causes an effect
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What is an alternate mechanism of action for RTK signaling?
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A conformational change of an enzyme's regulatory subunit leads to localisation and activation of the catalytic subunit
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What is a third mechanism of action for RTK signaling?
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Formation of multisubunit signaling particles that activate small G proteins; ultimately phosphorylates MAPK that outputs a signal
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What is an important structural motif in the c-Src protein?
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SH2 domain interacts with Tyr phosphorylated proteins; SH3 domains interact with cytoskeletal proteins
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What is a fourth mechanism of action of RTK signaling?
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JAK/STAT system
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MAP kinase pathways are characterised by what kind of signal initiation?
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Initiation by small G proteins
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MAP kinase pathways involve a cascade of how many protein kinases?
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three
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MAP kinase pathways involve a terminal kinase that is activated upon dual phosphorylation of what residues?
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Thr and Tyr
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Big Picture: tyrosine phosphorylation is central to what important body/cell processes?
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Growth regulation.
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What pathway causes direct activation of transcription factors?
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JAK/STAT system
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What pathway causes direct activation of signaling enzymes?
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Phospholipase C
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What pathway involves formation of signaling complexes that activate signaling enzymes?
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PI 3-kinase
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What pathway involves formation of signaling complexes that activate kinase cascades?
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MAP kinase pathways
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A defect in the STAT5b gene was found to be associated with what symptoms?
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Short stature and impaired immune function
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What is the structure of the insulin receptor?
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2 alpha, 2 beta subunits; alpha and beta have extracellular, glycosylated domains; only beta spans membrane
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Where is the tyrosine kinase domain located in the insulin receptor?
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Beta subunit, intracellular
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Which subunit binds insulin in the insulin receptor?
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Alpha subunit is cystein rich for insulin binding (extracellular)
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What is the main protein that is phosphorylated on tyrosine in response to insulin?
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IRS-1 (insulin receptor substrate-1)
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What types of domaines would you expect to find on IRS-1 (insulin receptor substrate-1)?
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SH domains; since insulin binding domain is Cys rich
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How does insulin affect serum glucose concentration?
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Decreasing hepatic gluconeogenesis; stimulating uptake into skeletal muscle
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Is increase in skeletal muscle gluc disposal in response to transporter activity or number?
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Transporter number; Vmax changes but Km stays the same
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How are glucose transporter numbers increased?
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Translocation of transporters from intracellular membranes to cell surface membranes
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Which glucose transporter is most potently translocated in response to insulin?
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GLUT4
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Are brain glucose transporters translocated in response to insulin?
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No; they are not insulin responsive.
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What is the primary reason for hyperglycemia in Type 2 DM?
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Impaired skeletal muscle glucose transport in response to insulin
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The insulin receptor is a ____ kinase
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tyrosine
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What is IRS-1's role?
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It is a docking protein; binds effector proteins such as PI-3 kinase, which then transmit an insulin signal
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What is the order of phases in the cell cycle?
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G1, S, G2, M, G0
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Is the M phase regulated?
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No
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Where are the two checkpoints in the cell cycle?
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After G1 and G2
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Which phases in the cell cycle vary most in duration?
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G1 and G2 phases
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What three classes of proteins control progression through the cell cycle?
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Cyclins; Cyclin-dependent kinases; cyclin-dependent kinase inhibitors
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What does a cyclin do?
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Regulate activity of CDK to 'activate' kinase activity
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Does binding of a cyclin activate or inhibit the CDK?
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Activates it
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Once a CDK is activated, how does it exert its action?
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Phosphorylating other proteins
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Are cyclins specific to CDKs?
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Yes
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What aa residues are on cyclin dependent kinases?
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Serine/Threonine - very few Tyrosine
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What do CKI's bind to?
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Cyclin/CDK complex
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What are the two major classes of CKIs?
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KIP (Kinase Inhibitor Protein) and INK (Inhibitor for Kinase)
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What cell cycle phase does KIP affect?
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G1, G2, some M
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What cell cycle phase does INK affect?
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Only G1
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Mutations in certain CKIs have what clinical significance?
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Cause of many cancers/mutated in human tumours
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Can cyclins/CDK/CKI undergo post-translational modification?
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Yes, through phosphorylation
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What is required for the formation of active cyclin/CDK complexes?
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1) cyclins at adequate levels; 2) CDKs; 3) CKI at sufficient level to assist assembly but low enough to permit it; 4) ability of CDK-Activating-Kinase/other kinase to phosphorylate the complex while suppressing activity of relevant phosphatase
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What is required for the forward phosphorylation reaction of the cyclin-CDK complex?
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CDK-activating kinase
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What is required for the backward reaction of phosphorylated Cyclin-CDK to the non-phosphorylated form?
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Phosphatase
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Is cyclin content regulated at the level of transcription? Is CKI content?
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Yes
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Is cyclin content regulated at the level of translation? Is CKI content?
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Cyclin - yes. CKI - no.
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Do cyclin/CDK mechanisms occur before, after, or during growth factor signaling/other regulatory mechanisms?
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After; cyclin/CDK factors are downstream from other intrinsic cell mechanisms.
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What are the two fates of a cell at the restriction point?
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If it passes the restriction point it is committed to DNA synthesis/cell division; if not it goes into G0
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What protein partly regulates the restriction point?
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Retinoblastoma (Rb)
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How does Rb protein work?
|
It binds to transcription factor E2F, inactivating it; once G1 cyclin/CDK complex is activated through mitogenic stimulation, it phosphorylates Rb which then releases E2F; E2F induces transcription of genes and passage through restriction point.
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Since Rb inhibits progression through the cell cycle it is referred to as ______
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Tumour suppresor
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What is terminal differentiation?
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When cells are unable to divide
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What is an example of a terminally differentiated cell?
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Neuron; skeletal muscle
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What is an example of a cell capable of continuous cell division?
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Skin cells; gut epithelium
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For cell types that undergo terminal differentiation, what are the two options for their fate?
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Proliferation, or terminal differentiation
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What are some examples of factors that affect the cell cycle?
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Growth factors; nutrients; UV light; osmotic stress; oxidative stress...
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What are the options a cell has after going through the cell cycle?
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Proliferation; differentiation; quiescence; senescence; apoptosis
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How is "size" measured in terms of cell growth?
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Ribosome number
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In breast cancer there is an overexpression of cyclins D and E; how does this cause cancer?
|
Cell is pushed past G1 restriction point and keeps on going
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In retinoblastoma, cancer is caused by mutational inactivation of Rb; how does this lead to cancer?
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Rb is an inhibitor, and if Rb is inactivated, the cell passes the G1/S checkpoint more easily
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How does HPV cause cervical cancer?
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Sequestration of Rb by E7 protein in HPV
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Are cancer cells generally small or large?
|
Small; they have not doubled in size before passing G1/S; fewer ribosomes/proteins
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How do cancer cells acquire more nutrients?
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Upregulate amino acid transporters
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Obese girls go through puberty sooner, and end up being shorter overall. Why does this happen?
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Estrogen promotes senescence of growth plate chondrocytes; more estrogen early on, premature stop of chondrocytes and thus shorter bone length.
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What phase of mitosis are chromosomes best seen in?
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Metaphase
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The short arm of a chromosome is the __ arm and the long arm is the __ arm.
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P = short (petite), Q = long
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What does "46, XX, t(4,7)(p13,q20)" mean?
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female with translocation of gene 13 on p arm of chromosome 4 with gene 20 on q arm of chromosome 7
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What is a barr body?
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An inactive X chromosome
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How many Barr bodies does a normal male have? Klinefelter male? Turner syndrome woman?
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Normal male: 0; Klinefelter male: 1; Turner syndrome woman: 0
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What happens (genetically) in Incontinentia Pigmenti?
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X-linked; IKBKG gene affected; because of X inactivation, male foetuses usually die; Sx = blistering in 0-4m, swirling hyperpigmentation at 6m, linear hypopigmentation in adult
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What is the difference between somatic and germline cells?
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Somatic cells undergo mitosis; germline cells undergo meiosis
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What is the main difference between mitosis and meiosis?
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Meiosis involves a reduction division (n goes from 46 to 23); chiasmata prior to first division
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When does crossing over occur?
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Prophase I
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What is non-disjunction?
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Both homologous chromosomes end up in the same daughter cell
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What are the n and c numbers normally, just before meiosis, after meiosis I, after meiosis 2?
|
Normally: 2n, 2c; Just before meiosis: 2n, 4c; After M1: n, 2c; After M2: n, c
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What is the chromosomal distribution in the four daughter cells after a nondisjunction meiosis?
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2 daughter cells with n+1, 2 daughter cells with n-1
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What are the consequences of meiotic nondisjunction, after fertilisation?
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Monosomy or trisomy
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What three trisomes are compatible with live birth?
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Trisomy 13, 18, 21
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What is trisomy rescue?
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When a cell loses a chromosome of which it has 3; can lead to uniparental disomy
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Why is uniparental disomy dangerous?
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In trisomy rescue, if a cell is left with two chromosomes from the same parent, it increases the risk of an autosomal recessive disorder
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What is an example of monosomy?
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Turner syndrome
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What is triploidy?
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3 sets of all chromosomes (69 chromosomes in total)
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What is "47,XX+21"?
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Down syndrome baby girl
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Mosaicism occurs after (mitotic/meiotic) nondisjunction.
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Mitotic
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How does mitotic non-disjunction lead to mosaicism?
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In the zygote, nondisjunction occurs early in cell division, so part of the cells are affected and others are not
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The karyotype designation 47,XY,+18 designates what?
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Male with trisomy 18
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The karyotype 46XX, del(1)(q21.1q21.2) means what?
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A female with deletion on chromosome 1
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Will the karyotype 46XYt(7,9)(q31;q22) lead to a normal child or one with intellectual disability?
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Normal; there is no loss of genetic material, just translocation.
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The symptoms: floppy, heart murmur, single transverse palmar crease, nuchal skin fold suggest what condition?
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Trisomy 21
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The symptoms: brachycephaly, epicanthal folds, flat nasal bridge, small ears, suggest what condition?
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Trisomy 21
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Elevated nuchal translucency is most likely associated with?
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Trisomy 21
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What is the most common congenital heart defect in a Down syndrome child?
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Endocardial cushion defect (AV canal defects)
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Why are women above 35 suggested an amniocentesis?
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The risk of amniocentesis < risk of Down syndrome baby after 35yo; therefore it is recommended
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How does non-invasive prenatal testing work?
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Utilises cell free foetal DNA in maternal circulation
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The symptoms rocker bottom feet, clenched fingers, small size are indicative of what?
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Trisomy 18
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The symptoms microcephaly, malformed ears, short sternum, cardiac defects are indicative of what?
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Trisomy 18
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Ultrasound findings show intrauterine growth restriction, cleft lip, 6 fingers on left hand - this suggests?
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Trisomy 13
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What are the craniofacial clinical features of Trisomy 13?
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Sloping forehead, deep set eyes, bulbous nose, cleft lip/palate, malformed ears
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What are clinical features of Klinefelter syndrome?
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Tall, long limbs, reduced facial and body hair, small genitalia, gynecomastia
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Short stature and webbed neck are indicative of what?
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Turner syndrome
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In Turner syndrome, which parent's X chromosome is usually lost?
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Paternal
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What are some clinical features of Turner syndrome?
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Failure to achieve menarche, lack of 2ary sex characteristics, infertility, cardiac abnormalities
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How many megabses is the entire human genome?
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3000 megabases
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Methylation turns DNA (on/off)
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Off.
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What are the five categories of genetic disorders?
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Chromosomal; Microdeletion/duplication; Single Gene; Epigenetic; Multifactorial
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What is FISH?
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Technique used to detect and localise presence or absence of specific DNA sequences, using fluorescence
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What test would you use if you suspected Williams syndrome?
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FISH; microdeletion syndrome
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What percentage of the total genome is the exome?
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1-2%
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Are genes distributed evenly across the genome?
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No
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What is microarray used for?
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Deletion or duplication
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Microarray is also known as:
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array comparitive genomic hybridisation (aCGH)
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What are the four possibilities of results of aCGH?
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1) diagnostic (pathological); 2) uncertain (benign copy vs. significant); 3) benign polymorphisms (well known in gen population); 4) normal
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What type of disorder would you use a karyotype/chromosome test on?
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Major chromosomal abnormality (trisomy)
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Single gene disorder test is used for what types of disorders?
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Disorders where there is a change in the sequence of one individual gene; ex. Marfan syndrome
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What type of test would you use for a disorder where there is a change in expression/sequence of DNA?
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Methylation study
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If a woman has many miscarriages, what genetic test would you give her?
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Karyotype, to rule out balanced translocations
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What test is indicated in children with congenital abnormalities, global developmental delay, autism who do not fit a known syndrome?
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aCGH
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Which two genetic tests are best for kids with developmental delay?
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Karyotype and aCGH
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Which of the genetic tests we have learned are indicated for a child without developmental delay but hypertrophic cardiomyopathy?
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None; Karyotype and aCGH are for developmental delay; FISH is for particular disorder; whole genoms is not the first step for any condition.
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Little girl has very friendly personality, high calcium, supravalvular aortic stenosis, hypertension. What is the diagnosis, and what test do you order?
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Williams syndrome; FISH or aCGH
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Baby is born with cleft palate, major heart defect, low calcium, recurrent infections, low T cell count. What is the diagnosis, what test would you order?
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DiGeorge (=22q11 deletion); aCGH or FISH
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A child is born with a cleft lip/palate, parents want to know genetic origin; what test do you offer?
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None, since cleft lip/palate is probably multifactorial, testing will probably not be helpful.
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Is someone with a balanced translocation phenotypically normal or abnormal?
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Normal
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Can a chromosome translocation occur between homologous chromosomes?
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No; only non-homologous (otherwise it is just crossing over)
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What are the two main types of translocations?
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1) Reciprocal; 2) Robertsonian
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What is the difference between a balanced and an unbalanced translocation?
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Balanced there is no genetic material missing; unbalanced there are duplications/deletions and unequal chromosomal material
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What is the name of the arm of the chromosome that includes translocated material?
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Derivative
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What are the three possible pairings of translocated chromatids in meiosis?
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Adjacent 1, Adjacent 2, Alternate Segregation
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Does Adjacent 1 segregation lead to a balanced or unbalanced gamete?
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Unbalanced; each daughter cell will receive 1 normal and 1 translocated chromosome
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Does Adjacent 2 segregation lead to a balanced or unbalanced gamete?
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Unbalanced; each daughter cell will receive 1 normal and 1 translocated chromosome
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Is there more loss of genetic information in Adjacent 1 or 2 segregation?
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Adjacent 2; you lose almost an entire chromosome's worth of material, except for what got translocated; and you duplicate almost an entire chromosome
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Are gametes viable in alternate segregation?
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Yes! 50% chance it is totally normal, 50% chance of balanced translocation but viable
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What are the acrocentric chromosomes?
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13, 14, 15, 21, 22
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What happens in Robertsonian translocation?
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Long arms of acrocentric chromosomes fuse at the centromere, with loss or partial loss of the two p arms
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What is the genotype of a person with a Robertsonian translocation?
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45XX/45XY ; eg 45XXder(13,14)(q10,q10)
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Are Robertsonian translocation carriers phenotypically normal or abnormal?
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Normal; the information lost on the small p arm is non-critical
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What are the risks to the offspring of a person with a Robertsonian translocation?
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Trisomy or monosomy
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Do all babies with translocation Down's have a parent who is a Robertsonian carrier?
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No; both parents can be normal, and the Robertsonian translocation may have appeared de novo
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For a parent with Robertsonian translocation, are all the zygote probabilities equally likely?
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No; unknown reason why, but a mother with a Robertsonian translocation involving ch21 has a 10-15% chance of having a baby with translocation Down's
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What are the two main mechanisms that cause chromosomal duplications?
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1) unequal crossing over; 2) crossing over in inversion loop
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A patient appears with peripheral neuropathy, progressive atrophy of distal muscles and progressive weakness. You suspect a chromosomal duplication disease - which one?
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Charcot-Marie-Tooth Disease
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What are the two types of chromosomal inversions?
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1) Paracentric, 2) Pericentric
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Between paracentric and pericentric inversions, which includes the centromere?
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Pericentric (per"i"centric "i"ncludes the centromere)
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What are the two clinical consequences of inversions?
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1) inherited "as is" then no consequence; 2) if crossing over within inversion area occurs, then gametes will have unbalanced karyotype
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Are gametes with paracentric inversions viable?
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No; because with crossing over results in gametes that are either dicentric or acentric and neither is viable
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In inversions, how do the chromosomes line up?
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In a loop formation
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Do paracentric inversions result in abnormal birth outcomes?
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NO, because the gametes themselves are not even viable
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What can occur in gametes with crossing over in pericentric inversions?
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Duplications AND deletions
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Do pericentric inversions result in abnormal birth outcomes?
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Yes. Gametes are viable but abnormal.
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