Question

Which gene is associated with congenital nephrotic syndrome?

• A. NPHS2
• B. P53
• C. RET
• D. NOTCH

Hint:

Glomerular Podocyte Genetics:
$\bullet$ NPHS1 $\rightarrow$ Nephrin (Finnish Congenital Nephrotic Syndrome)
$\bullet$ NPHS2 $\rightarrow$ Podocin (Steroid-Resistant Nephrotic Syndrome FSGS)
$\bullet$ WT1 $\rightarrow$ Denys-Drash Frasier Syndrome
$\bullet$ LAMB2 $\rightarrow$ Pierson Syndrome.

Answer 1

The Correct Option is A

Concept:
Congenital Nephrotic Syndrome (CNS) is defined as nephrotic syndrome manifesting in utero or within the first 3 months of life.
It is overwhelmingly genetic in etiology, caused by autosomal recessive mutations in key structural genes encoding the slit diaphragm and podocyte foot process proteins of the glomerular filtration barrier.
Explanation:
• The podocyte slit diaphragm is the critical size- and charge-selective filtration barrier in the glomerulus.

• NPHS2 (located on chromosome 1q25--q31) encodes podocin, a hairpin-like integral membrane protein localized to the insertion site of the slit diaphragm that interacts directly with nephrin and CD2AP.

• Mutations in NPHS2 are the most common genetic cause of steroid-resistant nephrotic syndrome (SRNS) and familial focal segmental glomerulosclerosis (FSGS), as well as congenital/infantile nephrotic syndrome.

• NPHS1 (on chromosome 19q13.1) encodes nephrin, mutations in which cause Congenital Nephrotic Syndrome of the Finnish type (CNSF).

• TP53 is a classic tumor suppressor gene involved in cell-cycle arrest (mutated in Li-Fraumeni syndrome).

• RET proto-oncogene is associated with Hirschsprung disease and MEN 2.

• NOTCH2 mutations are associated with Alagille syndrome.
Final Answer:
NPHS2 (encoding podocin) is a key gene fundamentally associated with congenital and early-onset steroid-resistant nephrotic syndrome.