Truncating SLC12A6 variants cause different clinical phenotypes in humans and dogs

Clinical, pathological, and genetic findings of a primary hereditary ataxia found in a Malinois dog family are described andcompared with its human counterpart. Based on the family history and the phenotype/genotype relationships alreadydescribed in humans and dogs, a causal variant was expected to be found in KCNJ10. Rather surprisingly, whole-exomesequencing 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 familyin an autosomal recessive way and was not found in 562 additional reference dogs from 18 different breeds, includingMalinois. In humans, SLC12A6 variants cause “agenesis of the corpus callosum with peripheral neuropathy” (ACCPN, aliasAndermann syndrome), owing to a dysfunction of this K+–Cl−cotransporter. However, depending on the variant (includin gtruncating variants), different clinical features are observed within ACCPN. The variant in dogs encodes the shortest isoformdescribed so far and its resultant phenotype is quite different from humans, as no signs of peripheral neuropathy, agenesis ofthe corpus callosum nor obvious mental retardation have been observ ed in dogs. On the other hand, progressivespinocerebellar ataxia, which is the most important feature of the canine phenotype, hindlimb paresis, and myokymia -likemuscle contractions have not been descri bed in humans with ACCPN so far. As this is the first report of a naturally occurringdisease-causing SLC12A6 variant in a non-human species, the canine model will be highly valuable to better understand thecomplex molecular pathophysio logy of SLC12A6-related neurological disorders and to evaluate novel treatment strategies.

Publication year:2019

BOF-keylabel:yes

IOF-keylabel:yes

BOF-publication weight:0.1

Authors:National

Authors from:Private

Accessibility:Open