KCC3 (K+-Cl- cotransporter) encoded by SLC12A6 mediate electroneutral K+ and Cl- efflux from cells and regulate the intracellular milieu in response to osmotic changes and cell volume. Changes in SLC12A6 gene may lead to dysregulation of Cl- concentrations in neurons and disrupt the neural activity and their response to GABA.
Autosomal recessive disorder (HMSN/ACC):
Mostly predicted loss-of-function variants (nonsense, splice and frameshift) have been associated with the recessive disorder. Two missense variants (p.Gly539Asp, p.Arg207Cys) have been identified in a compound-heterozygous state with a truncating variant or in a homozygous state in patients with HMSN/ACC as well. All heterozygous carrier parents were reported to be healthy.
Autosomal dominant disorder (CMT):
The exact pathophysiologic mechanism for this disorder is yet unclear. So far, only missense variants, including a recurrent missense variant (p.Arg207His) have been associated with the autosomal dominant CMT. Most cases were sporadic where the mutation arose de novo in affected individuals.
Diagnostic testing:
Diagnosis can be made by comprehensive genomic testing (single-gene testing, gene panel, exome sequencing, genome sequencing). Molecular genetic testing excluding other possible genetic causes for HSMN, ACC and CMT should be considered.
SLC12A6