18. Molecular and cytological consequences of some monogenic disorders (p11) Flashcards
Extensions of Mendelian inheritance
- Lethality
- Penetrance
- Expressivity
- Pleiotropy
- Heterogeneity
- Epistasis
- Phenocopy
- X inactivation
- Epigenetics
Frequency polycystic kidney disease, albinism, fragile X
Polycystic kidney disease (AD) 1:800
Albinism (AR) 1:1000-10000
Fragile X (XD) 1:3500-4000
Dominant and recessive…
…phenotype (not “genes” or “alleles”)
Autosomal dominant inherited disorders - usually
- Structural proteins
- Regulatory proteins
- Receptors
- Protooncogene products
Polycystic kidney disease
Monogenic inherited disease - typically in both kidneys
2 main forms:
- AD (PKD1 or PKD2 genes encoding polycystin) - 1:800
*Many smaller cysts
- AR (PKHD1 gene encoding fibrocystin) - 1:20000
*Larger cysts
Main symptoms:
- Apoptosis of renal parenchyma
- Overproduction of epithelial cells
- Accumulation of fluid
ADPKD
AD polycystic kidney disease
- 95% inherit mutant from parents (5% de novo)
- Disease is usually manifested in adult
- Heterozygotes (homozygote lethal in embryo)
Genes in ADPKD
PKD1 gene (16p13.3)
- 46 exon - 47000 bp - 4300 AAs
- 85 % of cases
- Polycystin 1 (PC1)
PKD2 gene (4q21-q23)
- 15 exon - 70000 bp - 968 AAs
- 15 % of cases
- Polycystin 2 (PC2)
Receptor ion channel complex - Ca2+ and other signal transduction pathways
Role of polycystin protein complex
Development of kidney is normal, polycystin is involved in the regulation of renal cell proliferation only later
=> manifested in late childhood or in adults
Role of infections in polycystic kidney disease
Infections => inflammation => TNF-alpha increase
- Increases expression of a scaffold protein (FIP2), which disturbs polycystin => cyst formation
- Effected people should avoid infections
- *Etanercept: TNFalpha inhibitor may help
Role of modifier genes in PKD
eNOS gene polymorphism => decreased NO => decreased endothel functions => high blood presure => destroys kidney
Autosomal recessive inherited diseases usually…
- Enzymes
- Hemoglobin
Albinism genetic cause
1) Faulty melanin synthesis - classical albinism
2) Faulty melanin transport - other disorders
Albinism other symptoms
- Photophobia
- Nystagmus
- Blindness
- Strabismus
Albinism prognosis
Does not influence lifespan - unless Hermansky-Pudlack syndrome
Albinism possible complications
- Visual impairment
- Blindness
- Skin cancer
Genes classical albinism
- Tyrosinase
- P gene
- Tyrp 1 gene
Genes albino phenotype associated syndromes
- LYST gene
- HPS gene
- Rab27a gene
- MYO5a gene
Hermansky Pudlak syndrome symptoms
- Oculocutaneous albinism
- Platelet dysfuntion
- Progressive pulmonary fibrosis
- IBS
- Kidney disease
Hermansky Pudlak syndrome mutation
Classical mutation: 16bp duplication in 15th exon
Non-classical mutation: does not change the length
Duchenne muscular dystrophy special symptom
Gower’s sign
Usual cause of death in Duchenne
Pneumonia due to respiratory muscle weakness or heart muscle weakness
Lab tests Duchenne
Increased serum creatine-kinase
Electromyography: show peripheral muscle weakness
Muscle biopsy: fat replaced a lot of muscle
*Can see pseudohypertrophia of calves due to this
Molecular genetic study: Dystrophin gene mutation
