According to the National Centre for Biotechnology Information (NCBI), the cytogenetic location of ANO10 is 3p22.1-p21.33, and its genomic coordinates are chr3:43,365,848-43,6915,94 (GRCh38). The primary transcript variant (NM_018075.5) has a length of 3155 bp containing 13 exons, 12 of which are coding. The encoded protein has a length of 660 amino acids.
Vermeer et al. (2010), were the first to map the ANO10 gene to a locus spanning approximately 10.5 Mb. Concurrently, they identified four distinct variants across three families from different ethnic backgrounds. A substitution variant (c.1529T>G [p.Leu510Arg]) was identified in a remote consanguineous Dutch family with three affected siblings, in the DUF590 domain of the ANO10 transmembrane protein. Two compound heterozygous siblings were identified in a French family with a splice site variant (c.1476+1G>T) and a frameshift variant (c.1604del [p.Leu535*]), resulting in premature termination. Finally, in the same study, a 2-bp deletion was identified in three affected siblings from a consanguineous family of Romani ethnic origin from Serbia, resulting in a frameshift variant (c.1150_1151del [p.Leu384fs]). The same variant was also identified in three siblings from a second family of a Roma/Gypsie ethnicity.
The c.132dupA [p.Asp45Argfs*9] variant is the most frequent ANO10 variant causing SCAR10, though it is usually not found in a homozygous state. The most frequent homozygous variant is postulated to be the c.1150_1151del [p.Leu384fs]. Other less common pathogenic variants include the splice site variant c.337+1G>A and the nonsense variant c.306C>A [p.Tyr102*]. Maruyama et al. (2014), reported the first non-European patient from Japan born to consanguineous parents. This patient was homozygous for a nonsense variant c.609C>G [p.Tyr203*].
Additional frameshift, nonsense, splice site, and missense pathogenic or likely pathogenic variants have been reported. Currently, the ClinVar database includes 30 variants classified as pathogenic, 20 as likely pathogenic and many others classified as benign or of uncertain significance.
Diagnostic testing for possible variants in the ANO10 gene should include a sequence analysis technique. Sanger sequencing targeting the coding regions could be performed if there is strong clinical suspicion for variants in this gene. Otherwise, a next-generation sequencing (NGS) approach could be performed, such as a targeted ataxia gene panel analysis or whole exome sequencing (WES) followed by a gene-targeted in silico analysis.
Regarding the ANO10 gene expression, in adult tissues, it has the highest expression in the brain, specifically in the cerebellum, the occipital cortex, and the frontal cortex. A moderate expression was detected in the retina and heart. ANO10 is postulated to have a specific function in the adult brain since expression levels are lower in the foetal brain. However, a role of ANO10 in brain development cannot be excluded, which is consistent with the onset of ataxia in adolescence or early adulthood.
The pathophysiological mechanism of the disease has yet to be fully elucidated. Several hypotheses have been studied and suggested thus far. The anoctamin protein family comprises transmembrane calcium-regulated lipid scramblases and calcium-activated chloride channels. A derangement of the calcium signalling in Purkinje cells caused by ANO10 pathogenic variants, is proposed as a mechanism leading to SCAR10. ANO10 resides mainly in the endoplasmic reticulum (ER) membrane and acts as a lipid scramblase that depends on short-chain lipids and calcium ions for optimal activity. Furthermore, ANO10 was also found to function with a non-selective ion channel activity in liposomes. It is hypothesised that the underlying cause of this disease could be the incorrect lipid distributions in ER and other membranes. Additionally, ANO10 also acts as an interorganelle regulator of endosomal sorting. Loss of this function could lead to the impairment of endosomal retrograde trafficking and dysfunction in the endolysosomal pathway. Dysfunctions in endosomal sorting accumulate over the patient’s lifetime, a common mechanism shared with other neurodegenerative diseases.
ANO10