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33 Cards in this Set
- Front
- Back
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what are these?
Autosomal Dominant Autosomal Recessive X-linked Dominant X-linked Recessive Mitochondrial |
Mendelian or unifactorial inheritance patterns
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Diseases Due to Unstable Repeat (...) Expansions
-almost twenty disorders in total -three different classes of expansions Class1: Expansion of noncoding repeats that cause loss of protein function -impair ... of primary RNA -Fragile X (... inheritance) and Fredriech ataxia (... recessive) Class II: Expansion of noncoding repeats that confer novel protein function or ... -Myotonic dystrophy I/II (autosomal dominant) and Fragile X-associated tremor/ataxia syndrome (X-linked Class III: Expansion of ... of a codon -confers novel properties on the affected protein -Huntington disease (... dominant) |
Microsatellite
transcription X-linked autosomal RNA interference repeat autosomal |
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Slipped Mispairing Mechanism: proposed biochemical mechanism that underlies expansion of unstable repeat units
1. An insertion occurs when a newly synthesized strand aberrantly ... from the template strand during replication 2. New strand ... with template, the new strand may potentially slip back out of alignment with an incorrect repeat copy 3. DNA synthesis is resumed and the ... molecule will contain one or more copies of the repeat |
dissociates
reassociates misaligned |
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Phenomena associated with unstable repeat expansion
...- the size of the inherited expansion (size of the STRP) correlates to the age of onset or severity of disease; NOT an absolute predictor ...- progressively early onset and increased severity of certain diseases in successive generations; caused by expansion of unstable repeats (microsatellites) within the gene responsible for the disease |
Late Age of Onset
Anticipation |
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Huntington Disease an inherited, progressive ... disease
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neurodegenerative
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Huntington Disease major phenotypic features:
Age of onset: late childhood to late adulthood -patient disease onset is ... proportional to number of HD CAG repeats -Adult-onset disease ~40-55 repeats -Juvenile onset > 60 repeats Movement abnormalities -voluntary and involuntary movement -most common ... (involuntary movement characterized by nonrepetitive nonperiodic jerks that cannot be repressed voluntarily) Cognitive abnormalities -all aspects of ... affected -language usually affected later Psychiatric abnormalities -behavioral disturbances -personality change including psychosis and ... |
inversely
chorea cognition schizophrenia |
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Huntington Disease characteristics:
... dominant -mutation result from an unstable repeat expansion in the HD gene that encodes huntingtin protein (function unknown) Unstable repeat expansion -disease causing mutation in HD result from expansion of a polyglutamine-encoding CAG repeats in exon 1 -normal alleles have 10-26 repeats, mutant alleles have > 36 repeats Novel property mutation -expansion of the polyglutamine tract confers a deleterious novel property that induces the HD-like phenotype Anticipation Incomplete penetrance Variable expression -direct relationship between ... of repeat and disease expression; see juvenile case when there are expansions greater than 55 repeats. |
Autosomal
length |
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what disease is this?
-an inherited disorder of muscle function Major phenotypic features -Age of onset: birth to adulthood -Myotonia -Muscular dystrophy -Cataracts -Hypogonadism Characteristics -Autosomal dominant -Unstable repeat expansion -Gain of function -Anticipation -Incomplete penetrance -Variable Expression -Pleiotropy |
myotonic dystrophy I
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... - an individual does not express a phenotype even when they have the genotype for the trait; “skipping of a generation”
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Incomplete penetrance
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... - trait may vary in expression from mild to severe, but is never completely unexpressed in individuals who have the corresponding genotype
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Variable Expression
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what is this?
-Multiple phenotypic effects, seemingly unrelated, that are caused by a single allele or pair of alleles -About the total number of phenotypic features produced by mutation of an allele NOT the extent to which a phenotypic feature is expressed |
pleiotropy
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... - an inherited genetic disorder characterized by the growth of tumor along nerve tissue causing skin and bone abnormalities
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Neurofibromatosis
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Neurofibromatosis: Major phenotypic features
An individual is diagnosed with NF1 if two or more of the following criteria are met: (an example of ...) 1. Six or more café au lait spots (≥5mm prepubertal, ≥15mm postpubertal) 2. Two or more neurofibromas and any type -firm, benign encapsulate tumor resulting from proliferation of Schwann cells and fibroblasts that include portions of nerve fibers 3. One plexiform neurofibroma -neurofibroma that manifest as diffuse overgrowth of subcutaneous tissue, progress along nerve roots involving spinal roots and spinal cord 4. Axillary or inguinal freckling 5. Optic glioma -benign and malignant CNS neoplasms derived from glial cells 6. Two or more Lisch nodules 7. Distinctive osseous phenotype -sphenoid dysplasia and thinning of the long bone cortex with or without pseudoarthrosis 8. First degree relative with NF1 |
pleiotropy
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Neurofibromatosis Characteristics:
... dominant -loss-of-function mutation in the NF1 gene that encodes neurofibromin -neurofibromin regulates several intracellular processes including the activation of the G protein Ras, controlling cell proliferation and acting as a tumor suppressor gene -more than 500 identified mutations in the NF1 gene (allelic heterogeneity) Extreme ... - multiple phenotypic effects, seemingly unrelated, that are caused by a single allele or pair of alleles -manifestations are extremely variable -... mutations -alteration in a gene that is present for the first time in one family member as a result of a mutation in a germ cell of a parent of in the fertilized egg itself |
Autosomal
pleiotropy De novo |
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... - a disorder of bone growth; most common form of short-limbed stature or dwarfism
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Achondroplasia
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achondroplasia: major phenotypic features
... onset Rhizomelic short stature -... is the shortening of the proximal segments of the extremities Megalencephaly (accompanied by macrocephaly) - megalencephaly is an abnormally large, heavy and usually ... brain -most individuals are of normal intelligent, but experience delayed motor development Spinal cord compression |
Prenatal
rhizomelia malfunctioning |
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Achondroplasia Characteristics:
Autosomal dominant disorder -mutations in the FGFR3 gene that result in a gain-of function mutations that lead to ligand-independent activation of FGFR3 -FGFR3 is a transmembrane tyrosine kinase receptor that normally binds fibroblast growth factors; binding leads to activation of the intracellular tyrosine kinase domain and initiates an intracellular cascade -a mutation of guanine at position 1138 in the FGFR3 gene causes almost 100% of cases of achondroplasia -80% of cases are de novo mutations, 20% are inherited -de novo mutations occur almost exclusively in the ... germline and increase in frequency with advanced paternal age (>35 years). |
father’s
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Remember only #% of cases of achondroplasia are inherited.
Also, there is an increased frequency in affected individuals that marry one another and have offspring. ... - homozygous dominant (AA) individuals and heterozygous dominant (Aa) individuals are affected similarly in nature and severity of disease symptoms. ... (...)- a trait inherited in a dominant manner but is more severe in a homozygote dominant (AA) individual than in a heterozygote dominant (Aa) individual |
20
Pure dominance Incomplete dominance semidominant |
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... mutation- mutation associated with an increase in one or more of the normal functions of a protein
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Gain-of-function
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... mutation- a mutation associated with a reduction or complete loss of one or more of the normal functions of a protein
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Loss-of-function
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... - an inherited disease of the exocrine glands (pancreas, respiratory system and sweat glands); characterized by lung congestion and infection an malabsorption of nutrients by the pancreas
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Cystic Fibrosis
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Major Phenotypic Features of cystic fibrosis
Age of onset: neonatal to adulthood Progressive pulmonary disease -chief determinant of morbidity and mortality -most patients die of ... disease Exocrine pancreatic insufficiency -maldigestion and malabsorption resulting from the failure of secretion of the pancreatic enzymes necessary for the normal digestion of food Elevated sweat ... concentration -used as a diagnostic measure |
respiratory
chloride |
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cystic fibrosis Characteristics:
Autosomal ... -mutations (>1000 different mutations) in the CF transmembrane conductance regulator (...) gene -... gene encodes for a cAMP-regulated chloride channel -maintains hydration of secretions within airways and ducts through transport of chloride and inhibition of sodium uptake -dysfunction of CFTR affects primarily organs that secrete mucus (URT/LRT, pancreas, etc.) -dehydrated and viscous secretions Tissue-specific expression of mutations -certain mutations cause disease manifestation in certain tissues Variable expression -extent to which normal protein level is reduced correlates well with its clinical phenotype Environmental modifiers -certain factors, such as smoking, worsen severity of lung disease among patients |
recessive
CFTR CFTR |
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... - an inherited disorder of blood coagulation characterized by a permanent tendency to hemorrhage
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Hemophilia
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Major Phenotypic Features of hemophilia
Age of Onset: infancy to adulthood Bleeding ...-uncontrolled bleeding ...-bleeding into joints ...-bleeding into soft tissues, muscles and weight bearing points |
diathesis
Hemarthroses Hematomas |
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Hemophilia Characteristics
... recessive -classic ... disorder; rare ... affected due to skewed X-inactivation -mutations in the F8 and F9 genes in Hemophilia A and B, respectively -... gene encodes for clotting factor VIII; cofactor -... gene encodes for clotting factor IX; protease -Factors VIII and IX are essential components of the clotting cascade that balance clot formation and inhibition -Deficiencies or dysregulation of either Factors VIII and IX lead to hemophilia Variable expression -clinical severity based on % activity of Factor VIII or IX |
X-linked
male female F8 F9 |
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... - a neurodevelopmental disorder that affect females almost exclusively
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Rett syndrome
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Major phenotypic features of Rett Syndrome:
Age of onset: neonatal to early childhood -normal development until 6-18 months Neurodevelopmental regression -short period of developmental slowing and stagnation -deceleration in head growth -breathing irregularities -... = gross incoordination of muscle movements -seizures -pseudostabilization in school years -finally deterioration to severe mental retardation -progressive spasticity, rigidity and scoliosis Repetitive stereotypic ... movements |
ataxia
hand |
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Rett Syndrome Characteristics:
X-linked ... -loss-of-function mutations in the ... gene -... encodes a nuclear protein that binds methylated DNA and recruits histone deacetylases to regions of methylated DNA -hypothesized that ... mediates transcriptional silencing and epigenetic regulation of genes in region of methylated DNA Loss-of-function mutation Incomplete penetrance |
Dominant
MECP2 MECP2 MECP2 |
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... -clumps of diseased mitochondria clumped in subsacrolemmal region of muscle fibers appearing as “ragged red fibers” when stained with Gomori trichrome stain
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Myoclonic Epilepsy with Ragged Red Fibers (MERRF)
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Major phenotypic features of MERRF
Age of onset: childhood through adulthood ... -muscle weakness due to failure of mitochondria to produce energy ...-decline in reasoning, memory and cognitive functions ... seizures -characterized by brief jerking movement involving both sides of body (subtle to dramatic ... -gross incoordination of muscle movements Deafness |
Myopathy
Dementia Myoclonic Ataxia |
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Characteristics of MERRF:
Mitochondrial inheritance -inherited maternally mutations in the tRNA(lys) gene -greatly decreases translation efficiency in the mitochondria -impacts production of the complexes of the ... pathway, in particular complex ... and ... -Reduction in capacity of oxidative phosphorylation, decrease in overall ... output Replicative segregation - ... distribution of replicated mitochondria into daughter cells Expression threshold -threshold for expression of deleterious phenotype depends on balance between oxidative supply and depend -tissues/organs with greater oxidative depend will reach threshold ... High mutation rate -mtDNA has 10X higher mutation rate than nuclear DNA, possibly due to the high level of high concentrations of oxygen free radical produced by oxidative phosphorylation Heteroplasmy -patient are almost completely ... for the mutant mtDNA -presence of more than one type (combination of normal and mutant) of mitochondrial DNA in the mitochondria of a single individual |
oxidative phosphorylation
I IV energy random faster heteroplasmic |
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Which type of inheritance displays a pattern where children of an affected female are all affected and children of an affected male are all unaffected?
Choices: autosomal dominant X-linked dominant mitochondrial |
mitochondrial
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