X-linked severe combined immunodeficiency (X-SCID) is caused by mutation in the gene encoding the common gamma chain (γc, CD132) shared by multiple cytokine receptors. The absence of which signal transducer downstream of γc leads to impaired T-cell development?

• A ZAP-70 (zeta-associated protein 70)
• B JAK3 (Janus kinase 3)
• C STAT5 (when deficient, no IL-2 proliferative signal)
• D Both B and C are correct components of this signaling pathway ✓

Explanation

X-SCID results from γc chain deficiency, which is shared by IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors. γc signals through JAK3, which phosphorylates STAT5 (for IL-2/IL-15) and other STATs (for IL-4, IL-7). Absence of IL-7 signaling (via JAK3-STAT5) critically impairs thymic T-cell development, and absence of IL-15 signaling impairs NK cell development. JAK3 mutations cause an autosomal recessive SCID phenotype identical to X-SCID. ZAP-70 deficiency causes selective CD8+ T-cell deficiency, not SCID.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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