ANO5 – Autosomal Recessive Limb-Girdle Muscular Dystrophy

Biallelic mutations in ANO5 are established as a cause of autosomal recessive limb-girdle muscular dystrophy type 2L (LGMD2L) and Miyoshi myopathy type 3 (MMD3). In a retrospective Dutch cohort of 244 AR-LGMD/MMD patients, 64 individuals (26% of the cohort) harbored two ANO5 mutations, representing one of the most frequent genetic subtypes of recessive LGMD (PMID:30919934). The minimum prevalence of ANO5-related LGMD in the Netherlands was estimated at 14.4 × 10⁻⁶ (PMID:30919934).

Inheritance is autosomal recessive, with affected individuals typically carrying homozygous or compound heterozygous ANO5 variants. A recurrent founder allele, c.191dup (p.Met543AsnfsTer11), was identified in both French-Canadian and Dutch families, accounting for a significant fraction of cases (PMID:20096397). To date, at least 64 probands with confirmed biallelic ANO5 variants have been reported across unrelated families, with no additional segregation data published.

The variant spectrum comprises at least 27 distinct alleles, including 15 frameshift and 12 missense changes, as well as splice-site mutations. The recurrent c.191dup frameshift allele illustrates a founder effect in multiple populations. Patients display a wide phenotypic spectrum: onset ranges from infancy to the seventh decade, with loss of ambulation between ages 5 and 74 years, cardiac abnormalities in 17% of cases, and non-invasive ventilation required in 14% (PMID:30919934).

In vitro studies demonstrate that ANO5 deficiency impairs sarcolemmal membrane repair, as shown by delayed resealing assays in patient fibroblasts and myoblasts (PMID:20096397, PMID:33934044). An Ano5−/− mouse model with targeted deletion recapitulates key LGMD2L features, including progressive muscle weakness, myofiber regeneration without chronic inflammation, and functional deficits in vivo (PMID:34633328).

However, an earlier Ano5 knockout in C57BL/6J mice did not develop overt muscle pathology up to 18 months, suggesting species-specific compensatory mechanisms or the need for truncated peptides to drive disease (PMID:26693275). This discrepancy highlights the complexity of modeling ANO5-deficient muscular dystrophy in rodents.

Collectively, robust genetic evidence from large cohorts, recurrent founder alleles, and concordant functional data support a strong gene–disease association. ANO5 should be included in diagnostic AR-LGMD panels, enabling accurate molecular diagnosis, carrier screening, and informing future membrane-targeted therapeutic strategies.

References

• Clinical Genetics • 2019 • Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients. PMID:30919934
• 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
• Cell Calcium • 2021 • ANO5 in membrane repair - Status: "It's complicated". PMID:33934044
• 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

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