Truncating SLC12A6 variants cause different clinical phenotypes in humans and dogs

• Published in: European journal of human genetics : EJHG 2019-10, Vol.27 (10), p.1561-1568
• Main Authors: Van Poucke, Mario, Stee, Kimberley, Sonck, Laurien, Stock, Emmelie, Bosseler, Leslie, Van Dorpe, Jo, Van Nieuwerburgh, Filip, Deforce, Dieter, Peelman, Luc J, Van Ham, Luc, Bhatti, Sofie F M, Broeckx, Bart J G
• Format: Article
• Language: English
• Subjects: Animals; Ataxia; Biomarkers; Corpus callosum; Dogs; Electromyography; Female; Genetic Association Studies - methods; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; Genotype & phenotype; Genotypes; Humans; INDEL Mutation; Male; Muscle contraction; Neural Conduction; Neurological diseases; Paresis; Peripheral neuropathy; Phenotype; Phenotypes; Spinocerebellar Degenerations - diagnosis; Spinocerebellar Degenerations - genetics; Spinocerebellar Degenerations - metabolism; Symporters - genetics
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/s41431-019-0432-3

Clinical, pathological, and genetic findings of a primary hereditary ataxia found in a Malinois dog family are described and compared with its human counterpart. Based on the family history and the phenotype/genotype relationships already described in humans and dogs, a causal variant was expected to be found in KCNJ10. Rather surprisingly, whole-exome sequencing identified the SLC12A6 NC_006612.3(XM_014109414.2): c.178_181delinsCATCTCACTCAT (p.(Met60Hisfs*14)) truncating variant. This loss-of-function variant perfectly segregated within the affected Malinois family in an autosomal recessive way and was not found in 562 additional reference dogs from 18 different breeds, including Malinois. In humans, SLC12A6 variants cause "agenesis of the corpus callosum with peripheral neuropathy" (ACCPN, alias Andermann syndrome), owing to a dysfunction of this K -Cl cotransporter. However, depending on the variant (including truncating variants), different clinical features are observed within ACCPN. The variant in dogs encodes the shortest isoform described so far and its resultant phenotype is quite different from humans, as no signs of peripheral neuropathy, agenesis of the corpus callosum nor obvious mental retardation have been observed in dogs. On the other hand, progressive spinocerebellar ataxia, which is the most important feature of the canine phenotype, hindlimb paresis, and myokymia-like muscle contractions have not been described in humans with ACCPN so far. As this is the first report of a naturally occurring disease-causing SLC12A6 variant in a non-human species, the canine model will be highly valuable to better understand the complex molecular pathophysiology of SLC12A6-related neurological disorders and to evaluate novel treatment strategies.