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GNE (HGNC:23657) encodes UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, a bifunctional enzyme essential for sialic acid biosynthesis. Autosomal recessive GNE myopathy (MONDO:0011603) presents in early adulthood with slowly progressive distal muscle weakness—particularly of the tibialis anterior—while sparing the quadriceps, and muscle biopsy reveals rimmed vacuoles. Clinical onset typically occurs in the second to third decade, with gait disturbance and atrophy of distal lower-limb muscles. Diagnosis is confirmed by identification of biallelic pathogenic GNE variants in affected individuals, with carriers remaining asymptomatic. Family segregation studies demonstrate classical autosomal recessive inheritance, as shown in two affected siblings with compound heterozygous variants (PMID:11916006).
Genetic analyses across diverse populations have identified over 167 distinct GNE variants—including missense, nonsense, splice-site, frameshift, and deep intronic mutations that activate pseudoexons—underscoring extensive allelic heterogeneity. A compound heterozygous c.2044G>C (p.Val682Leu) was reported in Japanese Nonaka myopathy patients, segregating with disease in two siblings (PMID:11916006). Large cohort studies in Japan found homozygous or compound heterozygous common mutations (e.g., c.1714G>C p.Val572Leu and c.1892C>T p.Ala631Val) in 27 unrelated patients (PMID:12473753). Founder alleles such as c.2135T>C (p.Met712Thr) in Middle Eastern Jews and c.527A>T (p.Asp176Val) in Japanese and Thai cohorts highlight population-specific prevalence.
Functional studies demonstrate that GNE mutations reduce both epimerase and kinase activities, leading to 25–75% of normal enzymatic function and resulting hyposialylation of muscle glycoproteins. In vitro expression assays of patient-derived cells and Lec3 CHO mutants reveal markedly decreased UDP-GlcNAc 2-epimerase activity, which can be rescued by ManNAc supplementation (PMID:12409274). Muscle tissue and primary cell analyses show a 60–75% reduction in sialic acid content and abnormal lectin staining patterns, linking enzyme deficiency to rimmed vacuole formation (PMID:14707127). Gene therapy using GNE lipoplex demonstrates local sialic acid induction and improved muscle function in compassionate-use cases.
No significant conflicting evidence has been reported. Phenotypic variability—such as late-onset or asymmetric presentations—appears influenced by residual enzyme activity, environmental factors, and potential modifier genes. Rare asymptomatic homozygotes for hypomorphic alleles (e.g., c.620A>T) suggest incomplete penetrance and complex genotype–phenotype relationships (PMID:36526893).
Integration & Clinical Utility: GNE myopathy has a definitive gene-disease association. AR inheritance of biallelic GNE variants leads to hyposialylation and rimmed vacuolar myopathy. Comprehensive genetic testing combined with functional assays provides robust diagnostic confirmation. Emerging therapies, including substrate supplementation and gene delivery, show promise for targeted treatment.
Key Take-home: Biallelic GNE mutations cause definitive autosomal recessive myopathy characterized by enzyme deficiency and hyposialylation; diagnosis relies on genetic and functional confirmation, guiding therapeutic interventions.
Gene–Disease AssociationDefinitiveOver 1000 patients with GNE myopathy across >100 unrelated families, extensive segregation & functional concordance Genetic EvidenceStrongBiallelic pathogenic variants identified in >200 probands across diverse populations; AR segregation in multiple families Functional EvidenceModerateReduced GNE enzymatic activity and hyposialylation demonstrated in patient cells and in vivo models |