ANO5 – Limb-Girdle Muscular Dystrophy Type 2L

Biallelic mutations in ANO5 cause autosomal recessive Limb-Girdle Muscular Dystrophy Type 2L, characterised by adult-onset proximal muscle weakness, quadriceps atrophy, exercise intolerance, hyperCKemia, and rhabdomyolysis (PMID:20096397).

The seminal study identified recessive splice site (c.1120-1G>A), frameshift (c.191dup (p.Met543AsnfsTer11)), and missense (c.1295C>G (p.Ala432Gly)) variants in three French Canadian families and in Dutch and Finnish cohorts, establishing a loss-of-function mechanism via nonsense-mediated decay (PMID:20096397).

A subsequent French survey of 38 ANO5-mutation carriers, including 20 without muscle weakness, delineated a phenotypic spectrum from isolated hyperCKemia (median CK 200–40 000 U/L) and exercise intolerance to frank LGMD and Miyoshi myopathy. Median onset was 23 years, with myopathic EMG changes and calf muscle involvement on imaging (PMID:28187523).

Analysis of five unrelated Polish patients (age 22–38 years) by whole exome sequencing identified nine ANO5 variants – including novel missense c.395A>T (p.Lys132Met) and nonsense c.1203G>A (p.Trp401Ter) – in compound heterozygosity with the recurrent c.191dup (p.Met543AsnfsTer11), confirming pathogenic structural disruption by molecular modelling (PMID:31395899).

Biallelic variants co-segregated with disease in three LGMD2L families comprising at least six affected relatives, consistent with autosomal recessive inheritance (ClinGen PP1_Strong).

In silico analyses predict ANO5 variant–induced conformational instability. Patient fibroblasts and myotubes exhibit defective sarcolemmal repair, and Ano5–/– mice on a mixed background recapitulate mild dystrophic pathology with persistent regeneration, supporting a loss-of-function mechanism (PMID:20096397; PMID:34633328).

Contrastingly, Ano5 knockout in C57BL/6J mice failed to exhibit overt muscle deficits at rest, suggesting strain-specific modifiers (PMID:26693275). However, expression of truncated Ano5 peptides leads to aggregation and impaired membrane dynamics, indicating variant-specific dominant-negative effects in vitro (PMID:29665321).

Overall, strong genetic data from >40 unrelated probands with biallelic ANO5 variants, concordant segregation, and moderate functional evidence establish a loss-of-function mechanism in LGMD2L. Clinical testing of ANO5 is recommended for patients with unexplained hyperCKemia, exercise intolerance, or proximal muscle weakness to enable accurate diagnosis, carrier screening, and therapeutic development.

References

• American Journal of Human Genetics • 2010 • Recessive mutations in the putative calcium-activated chloride channel Anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies. PMID:20096397
• Muscle & Nerve • 2017 • Hyperckemia and myalgia are common presentations of anoctamin-5-related myopathy in French patients. PMID:28187523
• Scientific Reports • 2019 • ANO5 mutations in the Polish limb girdle muscular dystrophy patients: Effects on the protein structure. PMID:31395899
• Journal of Neuromuscular Diseases • 2021 • Anoctamin 5 Knockout Mouse Model Recapitulates LGMD2L Muscle Pathology and Offers Insight Into in vivo Functional Deficits. PMID:34633328
• Skeletal Muscle • 2015 • Genetic disruption of Ano5 in mice does not recapitulate human ANO5-deficient muscular dystrophy. PMID:26693275
• The Journal of Pathology: Clinical Research • 2018 • A novel ANO5 splicing variant in a LGMD2L patient leads to production of a truncated aggregation-prone Ano5 peptide. PMID:29665321

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