SELENON – Congenital Fiber-Type Disproportion Myopathy

SELENON encodes selenoprotein N, and biallelic SELENON mutations cause autosomal recessive congenital fiber-type disproportion myopathy (MONDO:0009711), formerly classified under SEPN1-related myopathies. ClinGen classification is Moderate based on multiple unrelated probands, familial segregation, and concordant functional studies.

Autosomal recessive inheritance is supported by sequencing in five unrelated CFTD patients with scoliosis and respiratory muscle weakness, identifying homozygous or compound heterozygous SELENON variants in two sisters and three additional probands (5 probands) (PMID:16365872). One recurrent missense variant, c.943G>A (p.Gly315Ser), segregates with disease in a sibship (2 affected relatives) and was absent in controls.

Functional assays demonstrate a loss-of-function mechanism: a homozygous SECIS element mutation in the 3′ UTR significantly reduces SELENON mRNA and protein in patient fibroblasts and abolishes SBP2 binding, preventing selenocysteine incorporation (PMID:16498447). This finding confirms that impaired SelN synthesis underlies muscle pathology.

Clinically, SELENON-CFTD presents with early-onset axial weakness, rigid spine, scoliosis (HP:0002650), and progressive respiratory insufficiency due to muscle weakness (HP:0002747). Insulin resistance was also observed in SEPN1-related cases, suggesting metabolic monitoring in affected patients.

Genetic testing for SELENON should be pursued in infants and children with CFTD histology and contractures. Identification of biallelic loss-of-function variants enables accurate diagnosis, family counseling, and tailored management, including respiratory support and metabolic assessment.

Key Take-home: Biallelic SELENON mutations define an autosomal recessive congenital fiber-type disproportion myopathy with early scoliosis and respiratory failure; genetic diagnosis guides clinical care and metabolic surveillance.

References

• Annals of neurology • 2006 • SEPN1: associated with congenital fiber-type disproportion and insulin resistance. PMID:16365872
• EMBO reports • 2006 • A single homozygous point mutation in a 3'untranslated region motif of selenoprotein N mRNA causes SEPN1-related myopathy. PMID:16498447

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