ANO10 mutations cause ataxia and coenzyme Q₁₀ deficiency

Abstract

Inherited ataxias are heterogeneous disorders affecting both children and adults, with over 40 different causative genes, making molecular genetic diagnosis challenging. Although recent advances in next-generation sequencing have significantly improved mutation detection, few treatments exist for patients with inherited ataxia. In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10, which encodes anoctamin 10, a member of a family of putative calcium-activated chloride channels, and the causative gene for autosomal recessive spinocerebellar ataxia-10 (SCAR10). Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade. Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other. The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation.

Fig. 1

Detection of heterozygous ANO10 variants in genomic DNA of patient 1 (a). cDNA analysis of patient 1 detected the c.1843G>A, p.Asp615Asn mutation in hemizygous form, confirming compound heterozygosity (b), Compound heterozygous mutations were detected in patient 2 (c), Q-RT-PCR showed significantly decreased ANO10 mRNA levels in patient 2’s fibroblast, compared with controls (d). Values are expressed as mean ± SD of patient and controls (N = 3)

Fig. 2

Schematic representation of ANO10. In green: putative intra-cytoplasmic region, in blue: putative transmembrane domains, in orange: putative extracellular domains. Text in red: previously reported mutations; in bold italic: mutations found in our patients