NEXN – Hypertrophic Cardiomyopathy

NEXN encodes Nexilin, a cardiac Z-disc protein essential for sarcomere integrity and myocardial force transmission. Hypertrophic cardiomyopathy (HCM) is characterized by unexplained ventricular wall thickening, myocyte disarray, and fibrosis. While pathogenic variants in sarcomeric genes account for many HCM cases, a subset remains genetically unresolved, implicating novel Z-disc components such as NEXN.

In an analysis of 121 unrelated HCM patients negative for eight common sarcomeric gene mutations, two heterozygous missense variants in NEXN, c.391C>G (p.Gln131Glu) and c.835C>T (p.Arg279Cys), were each identified in one proband and absent in 384 control chromosomes (PMID:20970104). Both variants segregated with HCM in two independent families, supporting an autosomal dominant inheritance model.

The variant spectrum in HCM is currently limited to missense changes affecting the actin-binding domain; no loss-of-function or splice variants have been reported to date in HCM cohorts. Neither variant shows recurrence across ethnically diverse populations, and carrier frequency remains extremely low in population databases.

Cellular transfection studies of the Q131E and R279C variants in C2C12 myoblasts demonstrated aberrant local accumulation of Nexilin and complete loss of F-actin binding by the actin-binding domain fragment (PMID:20970104). Coimmunoprecipitation assays further confirmed reduced interaction of full-length Nexilin with α-actin, indicating a dominant-negative mechanism perturbing Z-disc stability.

Mechanistically, NEXN missense mutations likely disrupt sarcomeric integrity by impairing Nexilin’s actin-binding function, leading to maladaptive cardiomyocyte hypertrophy. These functional data concord with the human phenotype and support a pathogenic role of heterozygous NEXN variants in HCM.

Overall, the evidence for NEXN in HCM meets a Moderate level of clinical validity: two unrelated probands with segregation in two families and concordant functional assays. NEXN genetic testing should be considered in HCM diagnostic panels, and further studies are warranted to define variant spectrum and penetrance. Key take-home: Heterozygous NEXN missense variants disrupting F-actin binding represent a clinically actionable cause of hypertrophic cardiomyopathy.

References

• American journal of human genetics | 2010 | Mutations in NEXN, a Z-disc gene, are associated with hypertrophic cardiomyopathy. PMID:20970104

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