Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Lichtenstein-Knorr syndrome is an autosomal recessive neurodegenerative disorder characterized by early-onset sensorineural hearing impairment and progressive cerebellar ataxia. Affected individuals typically present in childhood with bilateral hearing loss and gait instability. The syndrome has been linked to loss-of-function of the Na(+)/H(+) exchanger 1 (NHE1) encoded by SLC9A1, underscoring the role of pH regulation in neuronal and auditory function. Genetic testing for SLC9A1 variants is thus warranted in patients with this clinical triad.
By homozygosity mapping and whole-exome sequencing in a large consanguineous kindred, a homozygous missense variant c.913G>C (p.Gly305Arg) was identified that segregates with disease (PMID:25205112). Glycine at position 305 is highly conserved in the eighth transmembrane segment of NHE1. Unaffected family members were heterozygous carriers, consistent with autosomal recessive inheritance. No additional unrelated probands have been reported to date for Lichtenstein-Knorr syndrome.
Functional assays demonstrated that the p.Gly305Arg mutation causes near-complete loss of NHE1 glycosylation, mis-targeting from the plasma membrane, and abolished proton exchange activity in cell-based systems (PMID:25205112). Spontaneous and knockout Slc9a1 murine models recapitulate the combined ataxia and hearing loss phenotype, confirming the pathogenic mechanism of NHE1 deficiency.
Collectively, the genetic and experimental data provide a strong gene-disease association for SLC9A1 and Lichtenstein-Knorr syndrome. Clinical sequencing of SLC9A1 should be considered in patients with early cerebellar ataxia and sensorineural deafness. Establishing this diagnosis informs prognosis, genetic counseling, and potential future therapeutic strategies targeting pH homeostasis.
Gene–Disease AssociationStrongOne homozygous SLC9A1 variant segregating in a large consanguineous family and concordant murine model data (PMID:25205112) Genetic EvidenceModerateHomozygous c.913G>C (p.Gly305Arg) in a single family with autosomal recessive inheritance (PMID:25205112) Functional EvidenceStrongIn vitro assays show loss of glycosylation, mis-targeting, and abolished proton pumping; murine Slc9a1 knockout recapitulates phenotype (PMID:25205112) |