Define allelic heterogeneity
Different mutations on same gene cause same disease (different mutations at same locus cause similar phenotype)
Which of these organ systems is not effected in CF? a) intestine b) male genital tract c) female genital tract d) hepatobiliary system e) exocrine sweat glands
In CF, what are the 5 molecular consequences that cause the disorder at the CFTR level? Which allele is most common?
- no synthesis, block in processing, block in regulation, altered conductance, reduced synthesis - delta F508 is in 70% of cases- block in processing
What is the difference between dominant and recessive forms of FIGHD (familial isolated growth hormone deficiency)? What happens in dominant negative form?
- dominant: mutations yield altered GH proteins - recessive: reduced GH expression - dominant negative - mutant binds to normal form and inactivates it
Type II Osteogenesis Imperfecta is a dominant negative, perinatal lethal disease that expresses locus heterogeneity. What two mutations at different loci/genes cause this disease?
- COL1A1 on chromosome 17 - COL1A2 on chromosome 7 Alpha 1/Alpha 2 proteins are mutant and lead to protein suicide
Type I Osteogenesis Imperfecta is a less severe, more common form that affects 1/5000 individuals. What mutation causes this disease?
COL1A1 on chromosome 17 that causes loss of expression or rapid degradation of mutant alpha-1; normal collagen formed but only 50% of normal level
Hemophilia A and Hemophilia B express locus heterogeneity. WHy is it important to know the type?
clinically indistinguishable, type affects treatment
In congenital deafness pedigree, why were all children of affected individuals not affected?
They were double heterozygotes - inherited two different mutations that cause same disease (locus heterogeneity)
What is the difference between achondroplasia and diastrophic dwarfism in regards to inheritance pattern?
Achondroplasia - auto dominant, 7/8 cases sporadic Diastrophic dwarfism - autosomal recessive
Charcot-Marie Tooth DZ: CMT1A is autosomal _________ while CMTX is X-linked.
Difference in modes of inheritance in male pattern baldness?
X-linked recessive OR Autosomal dominant (male sex influenced)
when a genetic trait present in a genotype does not manifest the phenotype
Retinoblastoma is an autosomal dominant disorder where 40% of cases are familial. Explain the "two hit" process in RB and why 10% of obligate heterozygotes are non-penetrant
Two hits - need two hits in same cell to cause disease In familial, inherit one of the hits, only need 2nd hit. 10% of carriers never get second hit.
Describe how to incorporate penetrance into probability calculations
Multiple proportion of penetrance (or non-penetrance) by probability of passing gene down in each applicable step
True or false: A disease cannot have both non-penetrance and variable expressivity
False, totally can
While penetrance is ___________, variable expressivity refers to __________
Neurofibromatosis type I (NF1) is autosomal dominant and an example of a disease that shows variable expressivity. Describe symptoms and occurrence/recurrence.
- 1/2 of NF1 are due to spontaneous new mutations - affects 1/3K - most (2/3) only have mild cutaneous involvement - sx include cafe-au-lait spots, lisch nodules, few neurofibromas - mildly affected parent can have a severely affected child - severe: 100s of fibromas, optic gliomas, learning disabilities, HTN, scoliosis, malignancies
Marfan Syndrome is an autosomal dominant connective tissue disease affecting 1/10K-1/20K that exhibits variable expressivity and pleiotropy. Explain.
- all affected individuals in one family have identical mutation in fibrillin gene, but will have different manifestations - Severe: aortic dilatation, pectus scoliosis, ectopia lentis - Mild - mitral valve prolapse, joint laxity, arachnodactyly, myopia - affects skeletal muscle, eye, heart
Diverse effects of a single gene on several organ systems and functions
In Osteogenesis Imperfecta II, all mutations are new mutations. What may be an exception in terms of inheritance?
If homozygous dominant, achondroplasia is _____________
In DMD, rate of loss of alleles in each generation is _____. In achondroplasia this number is ____
Why is the rate of loss for alleles low in Tay Sachs and Cystic fibrosis?
autosomal recessive, affected make up small portion of compared to carriers
In germline mosaicism, a new somatic mutation occurs during embryogenesis in germline progenitor cells of one of parents. The recurrence risk in a family is equal to what?
the proportion of germ cells in parent that carries the mutation
Germline mosaicism plays an important role in recurrence risk in DMD. Describe.
in de novo cases, RR is 1-5% due to possible germline mosaicism. in DMD and hemophilia, spontaneous new mutations cause 10-20% of disease
Huntington's disease is an autosomal dominant disease that is 100% penetrant and affects 1/20K people of European descent. Describe.
Loss of motor control, dementia between 30-50 Delayed age of onset
DNA cleavage by restriction enzymes facilitates isolation and manipulation of genes. The phosphodiester backbone is digested and produces palindromic type based on overhangs: ___, ___, ___
3', 5', blunt end
Nucleic acid hybridization identifies DNA/RNA on basis of binding to complimentary sequences. It is very sensitive, selective, and specific. Probes must be _________
Describe in-situ hybridization
Reveals position of or location of gene on a chromosome, reveals distribution, can be done with intact cell/chrom/tissue
Describe the differences between Southern Blot and Northern Blot
Both are hybridization techniques - Southern Blot - DNA, requires restriction enzyme digestion, can be used for DNA library screening, identification of methylation sites, RFLP genetic analysis, detecting SNPs - Northern Blot - RNA, NOT Quantitative, used to observe gene expression, determine transcript size, map intro/exon positions, identify isoforms