SLC12A2 – Schizophrenia

The solute carrier family 12 member 2 (SLC12A2) encodes the Na⁺–K⁺–2Cl⁻ cotransporter NKCC1, a bumetanide-sensitive transporter widely expressed in the central nervous system. NKCC1 activity helps maintain intracellular Cl⁻ levels, thereby modulating GABAergic signaling during neurodevelopment and in mature neurons.

Schizophrenia (SCZ; MONDO:0005090) has been linked to altered GABA neurotransmission in the prefrontal cortex. NKCC1-mediated Cl⁻ import sustains depolarizing GABA responses in immature neurons and may influence inhibitory tone in adult cortical circuits.

Targeted sequencing of three large French-Canadian cohorts comprising SCZ, autism spectrum disorder, and intellectual disability patients revealed a novel heterozygous missense variant c.596A>G (p.Tyr199Cys) in SLC12A2 in a single unrelated SCZ proband ([PMID:26955005]). No NKCC1 coding variants were observed in the ASD or ID cohorts.

A complementary genome-wide association study in a Thai population (115 SCZ cases, 173 controls) identified two intergenic SNPs near CTXN3–SLC12A2, rs245178 and rs698172, significantly associated with SCZ risk (P=0.006 and P=0.003, respectively) ([PMID:22643131]).

Functional analyses of the p.Tyr199Cys variant in Xenopus laevis oocytes demonstrated a gain-of-function effect, with increased Cl⁻-dependent and bumetanide-sensitive NKCC1 currents under hypotonic conditions compared to wild-type transporter. These data support a pathogenic mechanism whereby enhanced NKCC1 activity perturbs GABAergic inhibition.

Overall, genetic support for SLC12A2 involvement in SCZ is limited, based on a single coding variant in one proband and SNP associations. However, the concordant functional gain-of-function evidence indicates that dysregulated NKCC1 activity may contribute to SCZ pathogenesis. Replication in independent cohorts and familial segregation studies are needed to strengthen the gene–disease relationship.

Key take-home: A heterozygous gain-of-function SLC12A2 variant implicates NKCC1 dysregulation in schizophrenia, suggesting potential for targeted modulation of chloride cotransport in therapeutic strategies.

References

• Journal of psychiatric research • 2016 • Gain-of-function missense variant in SLC12A2, encoding the bumetanide-sensitive NKCC1 cotransporter, identified in human schizophrenia. PMID:26955005
• Behavioral and brain functions : BBF • 2012 • Association of CTXN3-SLC12A2 polymorphisms and schizophrenia in a Thai population. PMID:22643131

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