Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
34 Cards in this Set
- Front
- Back
|
Phenylketonuria (PKU)
Chromosome 12 |
Deficiency: Phenyalanine hydroxylase deficiency
(PAH) BH4-tetrahydrobioptrin Causes a build up of Phenyalanine Characteristics: MR, organ damage, unusual posture-maternal PKU damages fetus. Musky smelling diaper, developmental delays, microcephaly, seizures. Phenylalanine to tyrosine conversion is deficient. Phen + BH4-->CO2 + H2O Hyperphenylalaninemia: (milder PKU) Try + BH4-->NE/E Tyr + BH4-->secotonin Control phenylalanine (<1mM plasma) in diet to avoid neurological damage, which starts a month after birth. (Phenyl-free foods) |
|
|
Tay-Sachs Disease
|
Deficiency: HexA enzyme
Effects: GM2 ganglioside synthesis is impaired; brain Enzyme (3): HEXA (a) and HEXB (b) + activator + N-acetyl-b-galactosamine (cleavage pt) Frame shift mutation: TATC [causes premature stop codon] Characteristics: Cherry-red macula, neurological defects Infants normal till 6 months>progressive neurological deficits until age 2-4 death. Later onset; if some residual activity of HEXA present > spinocerebellar degeneration, psychosis in 1/3. |
|
|
Hurlers
Chr. 4; AR Lysosomal Storage Disorder |
Deficiency: a-L-iduronidase
Dermatan and heparin sulphate in urine Characteristics: CORNEAL CLOUDING, MR, skeletal abnormalities, hepatosplenomegaly, cease linear growth after 3 yrs, death by cardiorespiratory failure (1-10 yrs) Protein Trafficking Defect |
|
|
Protein Trafficking Defect
|
Proteins that are post-translationally modified by the
addition of various sugars and end up in the lysosome are targeted by the addition of mannose subunits that get phosphorylated. If the enzyme that adds the mannose subunit to the protein is lacking, no enzyme ends up in the lysosome and they tend to accumulate in the bodily fluids. |
|
|
I-Cell Disease
AR; Chrom. 10; LOF Lysosomal Storage Disease |
Deficiency: N-acetylglucosamine-1-transferase (GNPTAB)
Addition of phosphate is defective to mannose. Characteristics: Inclusion bodies accumulate in lysosomes. Acid hydrolases end up in blood. MR, unusual facies, skeletal changes, severe GR. Survival till age 5-7yrs |
|
|
Homocystinuria
AR Aminoacidopathy |
Deficiency: cystathionine b-synthase (cofactor B6)
methionine synthase (cofactors: folate+B12) Mechanism: Occurs due to buildup of cysteine. Characteristics: MR Like Marfans: S-osteoporosis; long bones; TIGHT joints H- thrombo-embolism of veins/arteries E- Dislocated lens Any deficieny in the cofactors reqd for the enzyme’s function will lead to this disease as well. B12=cobalamin (methyl cobal.) |
|
|
a1-Antitrypsin (a1AT) Deficiency
Glu342Lys Chrom. 14; AR |
Deficiency: Protease Inhibitor
Mechanism: Reqd to inhibit elastases (neutrophils release). Chronic obstructive lung disease (emphysema-constant coughing). Expressed in liver and goes to lungs for its function. Elastin in ECM of alveoli is lost>elasticity of lungs is lost. Z proteins aggregate in rER of liver>neonatal jaundice/cirrhosis(15%) Z/Z homos have decd life expentency, w smokn its worse (ecogenetics)-due to oxidantn of methionine 358 in a1AT > lowered activity Characteristics: cirrhosis, emphysema |
|
|
Acute Intermittent Porphyria
Chrom. 11; AD |
Deficiency: Porphobilinogen deaminase (PBGD)
mutatn (inv in heme synthesis pathway) Mechanism: When heme conc lowers in response to drugs (p450 reqd.), the ALA synthetase activity incs to make more heme. As PBG deaminase activity is abt half of the normal, the intermediates buildup > ALA and PBG > toxic. Pharmacogenetic dis: acute episodes when intake of drugs/ toxins. Characteristics: neurological dysfunction and gastrointestinal symptoms>vomiting, abdom pain. Paraesthesia (tingling skin feelings) |
|
|
Familial Hypercholesterolemia
Chrom. 19; AD |
Deficiency: LDL receptor mutation
(Homo is severe than the heterozygotes) -leads to elevated LDL in blood > high blood cholesterol levels Mutations: 1. LDL receptor-loss of functn (LOF)-most common mutn-null allele-no receptor synthesis. 2. Apoprotein B100- LOF. 3. ARH adaptor protein(forms vesicle)- LOF. 4. PCSK9 protease (cleaves receptor)- GOF. Characteristics: Premature heart dis due to atheromas (coronary arteries clogged up w cholesterol). Arcus cornea. Xanthomas. Mechanism: Alu sequences lead to deletions due to misalignment n unequal crossing over. |
|
|
Cystic Fibrosis
Chr. 7q31 Auto rec (fatal childhood dis. half of patients survive till 33 years of age) -1/25 white carriers |
Mutation: CFTR gene mutated
(Cl ion channel on apical side epithelial); (deltaF508); inhibits the Ca pump in rER > reduces Ca in ER. Gentamycin/tolurine; ribosome bypasses premature stop codon Mutation: Delta F508 (most common mutatn which removes phe 508, a 3bp deletn) is in NBD1 (nucleotide binding domain)>abnormal foldn of protein (gets caught in ER). (normal gene is very large 190kb-27 exons) Tx; pancreatic enzyme supplementation Characteristics: -Chronic obstructive lung dis. Due to thick mucus>recurrent resp infection > inflamatns>hard to breath>incessant coughn, incd phlegm>pneumonia. -Pancreatic enzyme secretns are deficient (pancreatitis)>abnormal digestion> malnutritn, large greasy stools which smell bad n lighter in color. Incd salty sweat (incd Na/Cl in sweat). -Mucous plugs in lungs+purulent secretions. -95% males infertile= congenital bilateral absence of vas deferens (CBAVD). Fewer females infertile. |
|
|
Duchenne Muscular Dystrophy
Frameshift mutation |
No dystrophin
Elevated CK Characteristics: muscle weakness starts, awkward gait, running and climbn stairs is hard, pseudohypertrophy of the calves (has fat+fibrous connective tissue). Gower maneuver, proximal muscles of trunk+limbs weaken, IQ lowers by 20points. Onset: 2 yrs age; wheelchair bound by 12, death at 18 cardioresp failure. Females carriers-varying degree of problems depend on X-inactivatn (more or less)-cardiomyopathies. 1/3 DMD patients are denovo mutants, 2/3 from carrier moms. Males: 0 fitness |
|
|
Becker's Muscular Dystrophy
|
No frameshift mutation
Reading frame is maintained despite deletion Functioning Dystrophin-truncated Later onset at 11, an still walk till 16 yrs or later. Life expectancy slightly lower than normal. 46% of mutn in spectrin-repeat region. Closer to the N terminus, milder the BMD. Closer to the C terminus, harsher the phenotype (DMD) Point mutants occur usually in males spermatogenesis. |
|
|
Ehlers-Danlos Syndrome
Chrom. 10 heterogenous diseases |
Mutation: COL51 and COL52
Characteristics: Collagen structure, synthesis, secretion or degradation is abnormal. Joint hypermobility, cutaneous fragility, ‘cigarette paper’ skin, hyperextensiblty, easy bleedn. Skin, joints and blood vessels affected in all types of EDS. Classical EDS is Type I n II; COL5A1/2 mutatn>codes for a-chains of type V collagen, reqd for stabilizn type I collagen. |
|
|
Osteogenesis Imperfecta (4 types)
Auto dom. |
Type I collagen
Chr. 17 (alpha1 chain) Chr. 7 (alpha 2 chain) Mutation closer to the C-terminus results in severe phenotype, compared to mutants near N-terminus ( as collagen posttranslational synthesis begins from the C-terminus). Also if mutation substitution is with a bulkier aa or a charged aa then mutatn severe |
|
|
OI Type 1
|
Null mut in alpha1 or missense glycine substitution
Lower amnt of collagen I produced (one of the proalpha 1 alleles). Mildest form. Almost normal stature. Predisposition to brittle/breakn bones by puberty. Loose joints, low muscle tone, blue sclera, triangular face. No bone deformity. |
|
|
OI Type II
|
Improper formatn of collagen-gly missense mutation
Most severe. Small stature, numerous fractures, lethal (death in utero or a few months after birth), usually new dominant mutatn so recurrence in family is low. Unmineralized bones > enlarged soft skull. Long bones of arms and legs are short/deformed. |
|
|
OI Type III
|
Improper formatn of collagen-gly missense
Progressive deforming. Fractures present at birth, w some healed fractures. Blue sclera. Loose joints, poor muscle development. Barrel-shaped ribcage, respiratory problems, spinal curvature |
|
|
OI Type IV
|
Improper formatn of collagen-gly missense mutation
Normal sclera, deforming. Severity bet type I and III. Bones fractures easily before puberty. Short stature. Sclera is white. Milk bone deformity. Spinal curvature, barrel shaped rib cage |
|
|
Alzheimer disease
Chr. 21 (Cortex & Hippocampal degeneration) |
Beta amyloid precursor protein (Beta APP) mutated
Neurodegenerative (50% of >70yrs olds that have dementia=ALZ). Down syndrome patients will have earlier onset at age 40. Progressive memory loss and inability to recognize friends/family in later stages. 90% manifests in 6th-9th decade of life (complex dis w various genes inv+env), 10% monogenic form starts earlier on . Develop rigidity, mutism and incontinence > bedridden and socially withdrawn, hallucinations n seizures > death by malnutrition, infection or heart disease. Familial AD; PSEN1 (presenilin 1-50% 0f the cases); PM spanning protein which cleaves and produces A-beta-42 (prod in brain n outside). Overproduction of A-beta-42 n Tau leads to AD; alpha secretase is good. While if cleaved with beta and gamma then A-beta-42 toxic peptide forms (mutations at cleavage sites of beta-APP can lead to inhibition of good sites and this will lead to inc in certain bad cleavage sites). Neuronal dystrophy and loss. ECM amyloid plaques containing Ab42 and apolipoprotein E. Neurofibullary tangles in cytoplasm made up of hyperphosphorylated Tau. Mutatns in PSEN1/2; gain of function > inc in A-beta-42. PSEN 1 reqd for gamma secretase activity. Dominant mutn will lower age of onset. Early age of onset AD will have 10% mutatn in PSEN1. While PSEN2 mutatns are late onset. APOE; for VLDL bindn to its receptor. Component in senile plaques n binds A-beta. Epsilon 4 allele incs risk factor for AD. Homozygotes will be earlier onset |
|
|
MELAS
|
Point mutation in tRNA for leucine
(3243 A to G mutn) Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. Signs appear in childhood after normal development > muscle weakness n pain, recurrent headaches, loss of appetite, vomiting n seizures. Stroke like spisodes after age 40 eg hemiparesis > repeated episodes cause brain damage, vision loss, mvmnt problems + dementia. Lactic acidosis > fatigue, difficulty breathn. Some patients > myoclonus, ataxia, hearning loss, heart n kidney problems, diabetes n deafness. Or chronic ophthalmoplegia (CPEO-eye muscle paralysis) |
|
|
MERRF
|
Lys tRNA is mutated in 80% of cases (point mutatn; A to G transition)
Myoclonic Epilepsy with Ragged-Red Fibers (seen in muscle biopsy) 1-myoclonus 2-generalized epilepsy 3-ataxia 4-weakness and dementia Onset in childhood; hearn loss, short stature, opticatrophy and cardiomyopathy w Wolff-Parkinson-White (WPW) syndrome. |
|
|
Leber hereditary optic neuropathy (LHON)
|
Homoplasmic mutantn in mito DNA (maternal)
Spontaneous blindness. Only affected females transfer disease to their progeny |
|
|
Huntingtons
AD |
CAG repeats; n>40
Mechanism: polyglutamine interaction wtih TF-->can't regulate expression Chorea, neurological disease |
|
|
Myotonic Dystrophy 1 DM1
AD |
DMPK (ch.19) CTG repeats in 3`UTR > 50 is mild, >2000 is severe.
(DM protein-kinase) Onset; 20-30s. Distal muscle weakness/wasting, facial and eye muscle weakness. Myotonia (Prolonged muscle contractions and stiffness). Cataracts, heart, GI, resp. muscles, MR, diabetes and hypogonadism. Maternal inheritance gives rise to large repeats (like Fragile X). juvenile/congential form is severe-cant suck/swallow. (Anticipation behaviour seen in all repeat diseases, gets severe as we move down the generations) |
|
|
Friedreich Ataxia (FRDA)
AR |
Frataxin (ch.9) repeats GAA/AAG in 1st intron > 100 (inhibits transcriptn)
Normally; 7-34 repeats. Spinocerebellar ataxia (in preadolescence). Nervous system deficiency→Limb mvmnts are uncoordinated, speech difficulty, no tendon reflexes, position and vibratory senses impaired. Cardiomyopathy, scoliosis & foot myopathy |
|
|
Li-Fraumeni Syndrome
AD |
Tp53 mutn (p53)
Chr. 17p13.1 Cancer families. Cancer at early age, various types of cancers eg breast, bone + soft tissue sarcomas, etc. Its a transcription factor for cell cycle n DNA repair genes. Extensively damaged DNA is inhibited from replicating by p53-so mutn in p53 will not arrest damaged DNA cells form replicating. During cell stress/damage; p53 incs in cells (Mdm2 regulator protein binds to p53 and keeps it in low amnts during normal cell function). During damage > p53 is pho n separated from Mdm2 > active p53 inc gene expression of p21 > Cdk inhibitor protein > cell arrest in G1. -2ndly; excessive myc activation > hyperproliferative signal > p53 activates and counters its action by cell arrest and apoptosis |
|
|
Breast cancer
|
BRCA1 (17q21)
BRCA2 (13q12.3) TSGs. Germline mutn > women chance of breast cancer inc by 40-85% (ovarion; 10-40%) |
|
|
Familial Adenomatous Polyposis (FAP)
|
APC germline mutn. (5q21-q22)
Gatekeeper TSG Adenomatous polyposis coli gene mutn (TSG). Leads to accelerated tumour initiation-waiting for 2nd somatic APC allele mutn. Numerous polyps on colon. Internal bleedn and anemia. Surgically colon is removed by age 25 as cancer by age 40. Normally APC phosphorylates B-catenin and degrades it, otherwise B-catenin transcribes myc (oncogene). |
|
|
Hereditary Nonpolyposis Colon Cancer (HNPCC)
|
MLH1, MSH2 or MSH6 mutn (AD)
Caretaker TSGs. 2ndry mutns in APC or TGFB receptor II Mutn in tumour suppressor genes. Defect in Mismatch Repair mechanism (MMR). Secondary mutn in TGFBR2 or APC genes. Early onset. A few colon polyps present. Replication Eror Positive (RER+) > incd mutn freq in point mutns n instability of simple repeat sequences (As eg unstable microsatellites-loose As or add some leadn to frame shift) |
|
|
Fragile X Syndrome
XR |
CGG repeat in 5` UTR → inactivation of FMR1 gene
CGG exceeds 200 → excessive methylation of cytosines in promoter → silencing transcription FXTAX → permutation b/t 60-200 repeats. • Gain of Function → 5x ↑ in FMR1 protein • LATE ONSET Characteristics: • Macroorcidism • big jaws • Big ears • MR -Progressive cerebellar ataxia & intention treamor due to the formation of intranuclear neuronal inclusions -Later Onset: 1st problems w/ movement, awkward gait, memory & ANS |
|
|
Gaucher
1q21; AR Lysosomal Storage |
Deficiency: glucocerebrosidase
Disease results from accumulation of the complex lipid glucocerebroside in the lysosomes of macrophages leading to gross enlargement of the liver and spleen and replacement of the bone marrow by lipid-laden macrophages (“Gaucher cells”). The production of RBCs and platelets is compromised leading to anemia and thrombocytopenia. |
|
|
Krabbe Disease
|
Deficiency: galactocerebrosidase
Early onset: 1st months of life Late onset: 6 months – 3 years • Relentless degeneration of central and peripheral myeline • Spasticity • Dementia • Peripheral neuropathy |
|
|
Retinoblastoma
|
A rare malignant tumor of the retina in infants
Rb regulates G1 to S Transition-Dephosphorylated Rb interacts with transcription factor E2F and prevents E2F from stimulating transcription. G1 Cdk-cyclin phosphorylates Rb causing it to be released from E2F and allowing E2F to stimulate transcription. |
|
|
p53
|
Both alleles of p53 (17p13.1) are frequently found mutated in a
wide range of sporadic human tumors The p53 protein functions as a transcription factor that regulates cell-cycle and DNA repair genes UV irradiation causes cell-cycle arrest in G1 that is dependent on p53; cells that contain a mutated p53 cannot arrest and enter into S phase and replicate damaged DNA p53 loss-of-function mutations result in cells replicating with damaged DNA which leads to further accumulation of other mutations in oncogenes and tumor suppressor genes and to an increased likelihood of cancer |
