**Question:** In familial Mediterranean fever, the following protein undergoes mutation-

A. MEFV
B. NOS2A
C. CFTR
D. SOD1

**Correct Answer:** A. MEFV

**Core Concept:** Familial Mediterranean fever (FMF) is an autoinflammatory disorder characterized by recurrent episodes of fever, pleurisy, peritonitis, and arthritis. It is primarily caused by mutations in the MEFV (Mincle-like Ectonucleotide Pyrophosphatase/Phosphodiesterase) gene, which encodes the protein pyrin.

**Why the Correct Answer is Right:** MEFV mutations lead to the production of a non-functional pyrin protein, causing uncontrolled inflammation and the characteristic symptoms of FMF. Pyrin normally acts as a negative regulator of the inflammasome, a complex involved in the activation of the immune response. In the absence of functional pyrin, the inflammasome remains activated, leading to the release of pro-inflammatory cytokines and the clinical manifestations of FMF.

**Why Each Wrong Option is Incorrect:**

B. NOS2A (Nitric Oxide Synthase 2): This option refers to a different gene (i.e., NOS2A) and protein (i.e., inducible nitric oxide synthase or iNOS), which is involved in nitric oxide production, not related to FMF.

C. CFTR (Cystic Fibrosis Transmembrane Conductance Regulator): This option refers to the CFTR gene and protein, which is linked to cystic fibrosis rather than FMF. FMF and cystic fibrosis are distinct genetic disorders with different pathophysiology and associated proteins.

D. SOD1 (Superoxide Dismutase 1): This option refers to the SOD1 gene and protein, which is linked to amyotrophic lateral sclerosis (ALS) and not to FMF. FMF and ALS are unrelated disorders caused by different genetic mutations and proteins.

**Clinical Pearl:** Familial Mediterranean fever is a prime example of a monogenic autoinflammatory disorder caused by mutations in a specific gene product (pyrin) that leads to unchecked inflammation and the characteristic symptoms of FMF. Understanding the pathophysiology of FMF helps differentiate it from related disorders like cystic fibrosis and amyotrophic lateral sclerosis, which involve distinct genetic mutations and proteins.