18. Molecular and cytological consequences of some monogenic disorders (p11)

Question 1

Extensions of Mendelian inheritance

Answer 1

• Lethality
• Penetrance
• Expressivity
• Pleiotropy
• Heterogeneity
• Epistasis
• Phenocopy
• X inactivation
• Epigenetics

Question 2

Frequency polycystic kidney disease, albinism, fragile X

Answer 2

Polycystic kidney disease (AD) 1:800
Albinism (AR) 1:1000-10000
Fragile X (XD) 1:3500-4000

Question 3

Dominant and recessive…

Answer 3

…phenotype (not “genes” or “alleles”)

Question 4

Autosomal dominant inherited disorders - usually

Answer 4

• Structural proteins
• Regulatory proteins
• Receptors
• Protooncogene products

Question 5

Polycystic kidney disease

Answer 5

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

Question 6

ADPKD

Answer 6

AD polycystic kidney disease

• 95% inherit mutant from parents (5% de novo)
  
  • Disease is usually manifested in adult
• Heterozygotes (homozygote lethal in embryo)

Question 7

Genes in ADPKD

Answer 7

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

Question 8

Role of polycystin protein complex

Answer 8

Development of kidney is normal, polycystin is involved in the regulation of renal cell proliferation only later
=> manifested in late childhood or in adults

Question 9

Role of infections in polycystic kidney disease

Answer 9

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

Question 10

Role of modifier genes in PKD

Answer 10

eNOS gene polymorphism => decreased NO => decreased endothel functions => high blood presure => destroys kidney

Question 11

Autosomal recessive inherited diseases usually…

Answer 11

• Enzymes

- Hemoglobin

Question 12

Albinism genetic cause

Answer 12

1) Faulty melanin synthesis - classical albinism

2) Faulty melanin transport - other disorders

Question 13

Albinism other symptoms

Answer 13

• Photophobia
• Nystagmus
• Blindness
• Strabismus

Question 14

Albinism prognosis

Answer 14

Does not influence lifespan - unless Hermansky-Pudlack syndrome

Question 15

Albinism possible complications

Answer 15

• Visual impairment
• Blindness
• Skin cancer

Question 16

Genes classical albinism

Answer 16

• Tyrosinase
• P gene
• Tyrp 1 gene

Question 17

Genes albino phenotype associated syndromes

Answer 17

• LYST gene
• HPS gene
• Rab27a gene
• MYO5a gene

Question 18

Hermansky Pudlak syndrome symptoms

Answer 18

• Oculocutaneous albinism
• Platelet dysfuntion
• Progressive pulmonary fibrosis
• IBS
• Kidney disease

Question 19

Hermansky Pudlak syndrome mutation

Answer 19

Classical mutation: 16bp duplication in 15th exon

Non-classical mutation: does not change the length

Question 20

Duchenne muscular dystrophy special symptom

Answer 20

Gower’s sign

Question 21

Usual cause of death in Duchenne

Answer 21

Pneumonia due to respiratory muscle weakness or heart muscle weakness

Question 22

Lab tests Duchenne

Answer 22

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