Molecular Genetics of Kidney Diseases

Question 1

Genetics of Kidney Disease

Answer 1

• Most are monogenic
• Increased incidence due to inbreeding
• If polygenic alleles→Adult onset commonly

Question 2

Classification of Cystic Kidney Disease

Answer 2

A. Dominant

1. ​Autosomal Dominant Polycystic Kidney Disease
2. Medullary Cystic Kidney Disease

B. Recessive

1. ​Autosomal Recessive Polycystic Kidney Disease
2. Nephronophthisis (NPHP)

Question 3

Extrarenal manifestations are seen in

Answer 3

Nephronophthisis

Question 4

ADPKD frequency

Answer 4

MOST common lethal dominnat disease in humans and only one mutation is needed for the disease to occur in all subsequent generations

Question 5

ADPKD genes implicated

Answer 5

1. PKD1→Polycystin 1 (master gene; structural desmosomal junctions and adherens junctions. If mutated disrupt DJ, AJ NOT tight junctions. ALSO N cadherin )
2. PKD2→Polycystin 2 (structural protein that acts as a Ca channel)

Question 6

ADPKD pathogenesis

Answer 6

TWO HIT MODEL

1. Germline mutation of PKD1 or PKD2 in all chromosomes which is usually inherited
2. You need a Somatic mutation for renal cysts to arise ie only some nephrons develop disease based on the presence of the somatic mutatiom

NOTE: Deviation from mendelian disorder cuz need TWO hits, unless PKD1 mutation in whichcase disease will DEFINETELY develop.

Question 7

Role of Cilia as Mechanosensor

Answer 7

Senses mechanical flow of urine

PC1→Adherense (focal), desmosomal junctions and ciliary membrane.

PC2→ in ciliary membrane and its function depends on PC1 therefore if PC1 is mutaed, PC2 is also nonfunctional.

Question 8

Autosomal Recessive Polycystic Kidney Disease

Characterized by

Answer 8

Bilateral renal cystic enlargment of kidney

Question 9

ARPKD and progression of disease

Answer 9

Depends on severity of the two mutations in the causative gene. may start after birth or in childhood or in adolescence.

30→die perinatally or reach ESRD in infancy or early childhood.

45% of infants→ liver also affected

OLDER PATIENTS→hepatic fibrosis

Question 10

ARPKD

Genes implicated

Answer 10

POLYCYSTIC KIDNEY AND HEPATIC DISEASE GENE 1; PKHD1

Encodes Fibrocystin/polyductin (FPC)

Parents must be carriers ie HETROZYGOUS for the disease

Child→compound heterozygous or homozygous

Question 11

FPC properties

Answer 11

• Single membrane spanning protein with multiple isoforms
• Expressed predominantly in kidneys (CD), liver (bile duct epithelium) and pancreas
• Localizes in apical membranes of renal tubules ie the PRIMRY CILIA?BASAL BODY and mitotic spindle
• Interacts with POLYCYSTIN 2 and 1→signalling pathways

Question 12

Hepatic involvement in Recessive/Dominant forms

Answer 12

• DOMINANT→hepatic cysts and enlargement appears in late stage
• Reessive→ They appear in early stage

Question 13

Nephronophthisis

Overview

Answer 13

• Most frequent cause of RF in children
• Mostly in corticomedullary junctions
• Kidneys are normal in size or slightly smaller
  
  • EXCEPT type 2: moderate kidney enlargement
• Cysts develop by loss of normal tissue
• Mutations in different genes → extrarenal manifrstations

Question 14

NPHP vs MCKD

Answer 14

BOTH:

• Corticomedullary cysts
• Normal or slighly decreased kidney size

MCKD:

• Autosomal dominnat
• UMOD gene→UROMODULIN
• Less severe→ESRD in 4^th decade
• NO extrarenal involvement except hyperurecemia and gout

Question 15

NPHP2 gene aka

Answer 15

INVERSIN

Question 16

NPHP2 gene

Answer 16

• Mutated→INFANTILE NPHP
• Slightly enlarged kidney ≈PKD
• Involved in Wnt signalling pathway (canonical and non canonical pathway)
• Situs invertus and Cardiac ventricular, septal defects
• Defective→Planar cell polarity disupted→cell dilation→cyst
• OVEREXPRESS B-catenin (eq. to canonical)

Question 17

NPHP5/IQCB1

gene

Answer 17

• NPHP5→ IQCB1 protein/nephrocystin5
• Nephrocystin 5 contains calmodulin binding portein IQ domain 1 to interact with calmodulin adn localize cilia
• Intracts with RPGR (GTPase regulator) which is mutated in most cases of X linked retinitis pigmentosa
• BOTH Nephorcysin 5 and RPGR products are in connecting cilia of photoreceptors and in primary cilia of renal cell

Question 18

NPHP5/IQCB1

Mutation

Answer 18

Early onset retinal renal syndrome Senior Loken syndrome

Question 19

NPHP7/GLIS2 gene

Answer 19

• Encodes transcription fator
• Component of hedgehog pathway for embryogeneiss
• Loss of GLIS2 promotes Epithelial to Mesenchymal transition→CYST
• Defective cilia→Hedgehog not function

Question 20

NPHP9/NEK8 gene

Answer 20

• NPHP9→Never in mitosis kinase 8
• regulates phosphorylation of Polycystin 1 and 2
• activate JAK/STAT→cell cycle arrest in G0/G1
• mutated→constant cell proliferaton