The SLC12A6 gene encodes the potassium chloride cotransporter KCC3 that is predominantly expressed in the central and the peripheral nervous system. Potassium chloride cotransporters regulate the intracellular milieu and play an important role in the neural excitability and regulation of cell volume.
Clinical features:
Biallelic pathogenic mutations in the SLC12A6 gene have been reported to cause the autosomal recessive disorder, hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), also known as Andermann syndrome. It is a complex neurodevelopmental and neurodegenerative disorder involving both the central and peripheral nervous system characterized by severe progressive sensorimotor neuropathy with areflexia, variable degrees of agenesis of corpus callosum, developmental delay with or without seizures, scoliosis, contractures, tremor, hypotonia and dysmorphic features.
Monoallelic pathogenic mutations in the SLC12A6 gene have been described to cause an autosomal dominant Charcot-Marie-Tooth (CMT) disease, characterized by sensory and / or motor neuropathy with or without spasticity. The prognosis of the disease is unclear, since only young patients with this disorder have been reported so far.
Prevalence:
The autosomal recessive disorder, HMSN/ACC, is mainly found in the French-Canadian population in the regions of Quebec. The founder mutation c.2436delG is estimated to be in 1 of 23 inhabitants of this population and the incidence of HMSN/ACC was 1 in 2,117 live births. The disease has been reported in other countries as well. Worldwide, HMSN/ACC is considered to be very rare.
The prevalence of CMT patients due to heterozygous SLC12A6 mutations cannot be estimated since there are only few reported cases so far.
Inheritance:
SLC12A6-related disorders can be inherited in an autosomal recessive and autosomal dominant manner.
The more severe disorder, HMSN/ACC, is inherited in an autosomal recessive manner. Most reported mutations were predicted loss-of-function mutations. The parents and further family members who were heterozygous carriers were reportedly healthy.
Various heterozygous missense mutations in the SLC12A6 gene have been associated with the autosomal dominant CMT. The affected patients mostly had de novo mutations and a much milder clinical presentation than the patients with HMSN/ACC.
SLC12A6