Atypical Inheritance Flashcards
(49 cards)
Patterns of Pseudoautosomal inheritance
Inheritance pattern for genes located in the pseudoautosomal region of the X and Y chromosomes that can undergo homologous recomb.
DYSCHONDROSTEOSIS-skeletal dysplasia with disproportionate short stature and deformity of the forearm. Gene codes for a transcription factor and escapes X-inactivation. (pattern looks x-linked, but we don’t know for sure)
Mosaicism
Presence of at least 2 cell lines in an individual the differ genetically but originate from a single zygote. Can be somatic, germ line or both.
Ex: X chrome inactivation
Somatic mosaicism
Mutation occurs during embryogenesis and affects morphogenesis, may manifest in patchy abnormality. NF-1 sometimes SEGMENTAL->only certain body part affected
Urea cycle enzyme OTC,Hemophilia A, DMD
Germline mosaicism
parent phenotypically normal and can have affected children as a result of a NEW mutation. 30 mitotic divisions prior to meiosis in females and hundreds in males->opportunities for mutation.
Ex: 6% of osteogenesis imperfecta, hemophilia A and B, DMD.
*Mutation will be missed b/c we analyze somatic cells(i.e. lymphs)-often see the condition in offspring which is how we find out.
What are diseases due to unstable repeat expansions?
CHARACTERISED BY AN EXPANSION OF REPEATING UNITS OF 3 OR MORE NUCLEOTIDES IN TANDEM W/IN THE AFFECTED GENE. Often 3 nucleotide repeat, but 4/5 also seen.
WILD TYPE ALLELES THAT ARE POLYMORPHIC.
DYNAMIC MUTATIONS of micro satellite repeats usually seen in vicinity of genes.
What are the general features of diseases with unstable repeat expansions?
ANTICIPATION-all gene expansion cases show anticipation. Appearance of the disease at an earlier age as it is transmitted through a family-Increase in severity as the disease is passed on.
PARENTAL TRANSMISSION BIAS: Friedrich’s ataxia, myotonic dystrophy, fragile X syndrome are unstable when maternally transmitted.
Huntington’s disease repeats expand when paternally transmitted.
PRIMARILY NEUROLOGICAL:ataxia, cognitive defects, dementia, nystagmus, parkinsonism, spasticity.
What is the likely mechanism to which unstable repeat expansions occur?
Slipped mispairing: Replication is started->replicating strand detaches inappropriately from template strand->replicating stand slips from proper alignment by 1 repeat (R) length->mismatched 2 repeat lengths (2R) out. Newly synthesised strand contains an extra repeat.
Expanded region continues in DNA
What is an example of a disease due to tetra nucleotide repeat expansion?
Myotonic dystrophy 2(close genocopy of myotonic dystrophy). Repeat of “CCTG”
What is an example of a disease due to a pentanucleotide repeat expansion?
Spinocerebellar atrophy 10-> repeat of “A T T C T”
Unstable repeat expansions: Huntington disease
AD, CAG, HD gene, coding region. >40 repeats are affected
Unstable repeat expansions: Fragile X
X-linked Dom. CGG. FMR1 gene, 5’ untranslated region. >200 affected
Unstable repeat expansions: Myotonic Dystrophy
AD, CTG, DMPK gene. 3’ untranslated region. 80-2000 affected.
Unstable repeat expansions: Friedreich ataxia
AR, AAG repeat. FRDA gene, Intron regions. >100 affected
Fragile X Syndrome
XD.Expansion of triplet CGG, 5’ UT region of the 1st exon of FMR1 gene.
2nd most common cause of moderate retardation.
Xq27.3 is fragile site
What is the mechanism of inactivation of FMR1 gene?
CGG repeats in 5’ UT UP TO 60->NORMAL
60-200 REPEATS->PREMUTATION
>200 FULL MUTATION->HYPERMETHYLATION OF 5’ UTR AND PROMOTER->SHUTS DOWN TRANSCRIPTION.
What are the clinical features of males with Fragile X?
delayed dev milestones, retardation, abn temprament:tantrums, autism. Abnormal craniofacies: long face, coarse facial features.
Macro-orchidism, Strabismus, joint hyperextensibility, mitral valve prolapse, pesplanus
Fragile X syndrome premutation is unstable and expands when?
What can carriers of permutation develop?
When transmitted by mother!
Carriers can develop ADULT-ONSET DISORDER FRAGILE X-ASSOCIATED TREMOR/ATAXIA SYNDROME.
2-5x increase in FMR1 mRNA->gain of function->formation of intranuclear neuronal inclusions.
1/4 of female carriers will have ovarian failure by 40 yrs.
Huntington Disease?
CAG repeat in coding region/exon->codes for glu->poly-glutamination of protein. AD neurodegen disorder.
Shows PATERNAL TRANSMISSION BIAS. almost always inherited from affected father.
What is the mutation for Huntingtons disease?
Abn INCREASE IN # OF CAG REPEATS IN THE CODING REGIONS.
Normal:9-35 repeatss
Premutation: 29-35 repeats
Borderline repeats: 36-39-> assoc. w/ HD at advanced age.
Full mutation:≥ 40 repeats
70-121 repeats: severe juvenile onset HD.
What are the clinical features of Huntingtons disease?
AGE DEPENDENT CORRELATION-age of onset correlated to number of repeats. Mean age is 40. Early on, minor motor abns: clumsiness, hyperreflexia, eye movement->evolve to involuntary movements (CHOREA), progressive dementia and psychological disturbances.
What is Friedreich Ataxia?
AR, Expansion of GAA repeats in 1st intron of FRDA gene.Normal=5-34, Path >100-200.
LOF from both alleles is required to produce the disease
What are some clinical features of Friedreich Ataxia?
Diagnostic triad: Progressive ataxia, Cardiomyopathy, Absent/diminshed tendon reflexes. . . Spino-cerebellar ataxia, difficulty w/speech, scoliosis, foot deformities, type 2 diabetes.
Clinical onset before adolescence.
What is Myotonic Dystrophy?
AD,CTG repeat, Progressive muscle weakness/wasting, with myotonia.
Myotonia=delayed relaxation and muscle stiffness.
What is the mutated gene in Myotonic Dystrophy?
DMPK gene, (Myotonic Dystrophy Protein Kinase)/Myotonin. chrome 19
