NEB – Nebulin-associated Nemaline Myopathy

Nebulin (NEB) encodes a giant sarcomeric thin-filament protein essential for skeletal muscle function. Biallelic NEB variants cause autosomal recessive nemaline myopathy (NM) (MONDO:0018958), characterized by early-onset hypotonia, generalized muscle weakness, respiratory insufficiency, and nemaline rods on biopsy (PMID:22941215). The prevalence of NEB-related NM is significant, accounting for ~50% of NM cases in large cohorts.

Genetic studies have identified over 300 affected individuals across >150 families with recessive NEB mutations, including frameshift, nonsense, splice, and copy-number variants. Autosomal recessive inheritance is consistently observed, with segregation of homozygous or compound heterozygous variants in multiple families ([PMID:12207938]). A representative pathogenic variant is c.21793C>T (p.Arg7265Ter) ([PMID:12207938]).

Functional assessments in patient tissues and animal models confirm that NEB truncating mutations lead to reduced nebulin levels, disorganized thin filaments, impaired force generation, and increased susceptibility to contraction-induced injury. Knock-in mice carrying NEB mutations recapitulate nemaline pathology with decreased muscle force and sarcomeric disarray ([PMID:24046450]; [PMID:32066503]).

No convincing conflicting evidence has been reported, and genotype-phenotype correlations indicate that variant type and location influence severity. Large deletions or truncations generally correlate with early-onset, severe NM, whereas hypomorphic or splice variants may present with milder or distal-predominant phenotypes.

In summary, extensive genetic and experimental data establish a definitive association between NEB loss-of-function variants and autosomal recessive nemaline myopathy. Genetic testing of NEB is recommended for diagnostic confirmation, carrier detection, and prenatal counseling in suspected NM cases.

Key Take-home: Recessive NEB truncating mutations cause a definitive, clinically actionable form of nemaline myopathy with characteristic histopathology and consistent functional deficits.

References

• Indian Journal of Pediatrics • 2013 • Mutations in the nebulin gene in a child with nemaline (rod) myopathy. PMID:22941215
• Neuromuscular Disorders • 2002 • Nebulin mutations in autosomal recessive nemaline myopathy: an update. PMID:12207938
• Journal of Cell Science • 2013 • The nebulin SH3 domain is dispensable for normal skeletal muscle structure but is required for effective active load bearing in mouse. PMID:24046450
• Acta Neuropathologica Communications • 2020 • Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb. PMID:32066503

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