Autosomal Dominant Disorders Flashcards
Know the characteristic features of autosomal dominant inheritance.
- Disorder is expressed in heterozygote
- Only a single mutant gene is necessary to produce the disorder
- Offspring have a 50% chance of inheriting the disorder
- The disorder appears in every generation –> vertical pedigree
- occurrence and transmission are not gender specific
- Typically late onset disorders
- Less lethal than autosomal recessive disorders
- Often involve structural protein defects
- Show wide variations in phenotypes (even within families) due to interactions between the affected gene and both the rest of the genome and the environment
Lethal autosomal dominant disorders would _______ the fitness of those affected and as a result, _______ be passed onto future generations. In contrast, lethal autosomal recessive disorders _______ in which fitness is not affected.
decrease
would not
can be passed onto future generations through heterozygotic carriers
Structural proteins are often _______ and produce a _______ when only one allele is defective
nonfunctional
mutant phenotype
Autosomal dominant disorders demonstrate variability in phenotype due to
unknown interactions between the mutant allele and the genome and environment even when the genotype of individuals is the same. Both the penetrance and expressivity vary from person to person, even among the same family.
With incomplete dominant inheritance, the severity of disease increases in _______ versus _______An example of this is _______.
homozygotes (AA)
heterozygotes Aa
achrondroplasia (Heterozygotes for the disorder can lead relatively normal, healthy lives, while a homozygote genotype is often incompatible with life early on)
Diagnosing autosomal dominant disorders on the basis of clinical presentation and pedigree presents several complications:
- new mutation rates for autosomal dominant disorders are high
- the phenotypic expression of the disorder may be mild and difficult to detect clinically
- Phenocopies may exist
- genocopies may exist
- differences in penetrance and expressivity
- germline mosaicism
Phenocopies
individuals with environmentally-influenced, non-hereditary disorders have phenotypes that mimic the phenotype of the genetic disorder
genocopies may exist
expression of similar phenotypes resulting from mutation at a different locus
Germline mosaicism
some or all of the cells of a parent’s germline carry the diseased mutation but their somatic cells do not
(a random mutation occurs in the parent’s germline and can be passed onto offspring. Because the mutation does not exist in the parent’s normal somatic cells, there is no increased recurrence risk for passing the mutation onto future offspring (beyond that of random mutation). The offspring, however, now have the mutated gene as part of the genome and can pass it onto subsequent generations.)
Achondroplasia: Molecular basis
• Substitution of a guanine at position 1138 in the FGFR3 gene resulting in the substitution of an arginine residue for glycine
o 80% of cases are de novo in the paternal germline
ofrequency of de novo cases increase with paternal age
• FGFR3 function
o transmembrane tyrosine kinase receptor that binds fibroblast growth factors
o normally activated to inhibit chondrocyte proliferation to coordinate differentiation
• Effects of position 1138 mutation on FGFR3
o Gain-of-function mutation
o Ligand-independent activation of FGFR3 inhibits chondrocyte proliferation and leads to abnormal differentiation and shortening of bones
Achondroplasia: Phenotype
Dwarfism, hypoplasia, normal intelligence, delayed motor development, hydrocephalus, brainstem compression and death in 3-7% of patients
Achondroplasia: Other details
- Increased likelihood of individuals homozygous for Achondroplasia due to increased mating between individuals with the disorder
- Homozygous genotype is incompatible with life
Marfan Syndrome: Molecular basis
Result of two common genotypes
1) Mutation of FBNI gene on chromosome 15 coding for fibrillin 1
- –Mutation leads to defective synthesis of microfibrils, inhibition of normal microfibril synthesis, and/or proteolysis of extracellular microfibrils
2) Mutations in TGF-beta R2
- –Leads to decrease in fibrillin and elastin deposition
- –Patients lack ocular defects, but have increased cardio abnormalities
Marfan Syndrome: Phenotype
- Multisystem disorder
- Musculoskeletal defects: tall stature and abnormally long extremities
- Ocular abnormalities: flat corneas, increased globe length, etc.
- Cardiovascular abnormalities: mitral valve prolapse, aortic regurgitation, dilation of the ascending aorta
- Major cause of death in patients with the disorder is heart failure from regurgitation or aortic rupture (improved with surgical intervention)
- Pulmonary defects: pneumothorax
- Skin abnormalities
- Expressivity and penetrance in patients with Marfan syndrome vary and many of the symptoms develop with age.
Neurofibromatosis-I: Molecular Basis
- Mutations in neurofibromin gene (NF1)
- –commonly deletion within gene
- –more than 500 mutations identified
- 50% are de novo mutations and 80% of those are paternal in origin
- neurofibromin is a protein that activates GTPase activating protein, thus regulating cellular proliferation as a tumor suppressor
- mutation results in loss of function of the gene
