Autosomal Dominant Disorders

Question 1

Notation

Answer 1

AA = affected
Aa (heterozygous) = affected
aa = unaffected/normal

Question 2

Neurofibramatosis Type 1

Answer 2

“Curly LOF 17q NF1”

Neurofibroma
Cafe-au-lait spots 
Scoliosis
Lisch Nodules 
Optic Glioma 
Learning disability 

LOF in NF1 gene in 17q; NF1 gene –> neurofibrin protein that activates RAS GTPase, so neurofibrin acts as a tumour suppressor

Question 3

Achondroplasia

Answer 3

"GOF 4 FGFR3" 
A skeletal disorder, 80-55% new mutants 
Mutation in small arm of chromosome 4
GOF mutation of FGF receptor 3 (FGFR3) 
   Exaggerated inhibition of chondrocyte proliferation --> shortening of long bones 

Glycine replaced by arginine

Question 4

Familial Hypercholesterolemia

Answer 4

Elevated levels of LDL and cholesterol
Increased risk of CAD and atherosclerosis
Xanthoma and atheroma
Arcus corneae

4 Associated genes 
LOF of LDL receptor gene (Chrm 19p, 6 classes found from mutations)
LOF of Apo B-100 gene 
LOF of ARH adaptor protein gene
GOF of PCSK09 protease gene

Read up more on this

Question 5

Marfan Syndrome

Answer 5

“FBN1 gene, Chrm 15Q”
Missense
Dominant negative fashion:abnormal protein (usually prematurely terminated) blocks the formation of normal microfibrils

Connective tissue disorder
Excessive stretchy connective tissues 
Defect in 
Ocular: ectopia lentis (up and out)
Skeletal: long and slender limbs
Cardiovascular: Mitral regurg

Question 6

Osteogenesis Imperfecta (collagen)

Answer 6

Brittle Bone Syndrome
Skeletal Deformities
Blue Sclera

Cause: due to mutation of genes coding for Collagen Type I (mainly skeletal structures)

3 Chains
2 Pro-alpha1 (Col 1 A1 gene)
1 pro- alpha2 (Col A2 gene)

Glycine-X-Y-Glycine-X-Y-
X occupied by propline
Y occupied by hydroxyproline/hydroxylysine

OI Type I: decreased type I collagen
Type 2-4: substitution of glycine by other AA residies

Question 7

Spit Hand Deformity

Answer 7

Best example of reduced pentrance (picture)
Phenotypic expression skips a generation
Defect in 6th/7th week of development

Question 8

Familial Testotoxicosis (*Sex based phenotype in autosomal dominant disorders)

Answer 8

ONLY MALES AFFECTED, this disease example for sex based phenotype in AD disease

Mutation of LH Receptor (LCGR)
Early secondary sex characterstics as age 4

Transmission to male child either via affected dad or unaffected mom with mutant gene

Question 9

Huntington’s disease

Answer 9

HuntingTIN gene, CAG repeat (class 3), degeneration of striatum and cortex

Question 10

Myotonic dystrophy

Answer 10

DMPK gene, 3’UTR, CTG repeat expansion, mRNA instability

Question 11

Acute intermittent porphyria

Answer 11

Hydroxymethylbilane synthase