SLC13A5 – amelocerebrohypohidrotic syndrome

Autosomal recessive biallelic variants in SLC13A5 underlie amelocerebrohypohidrotic syndrome, a disorder characterized by early-onset epilepsy, global developmental delay, and amelogenesis imperfecta. In a multi-patient cohort, nine patients from six independent families harbored homozygous or compound heterozygous SLC13A5 mutations, and a separate consanguineous kindred contributed an additional proband (PMID:27261973; PMID:37706418).

Segregation of rare biallelic variants in all affected individuals, with unaffected heterozygous carriers, supports autosomal recessive inheritance. A total of 10 probands carrying missense and splice-site variants have been reported, including one recurrent splice-site change and multiple missense substitutions such as c.1462C>A (p.Leu488Met) (PMID:27261973).

Variant spectrum comprises predominantly missense substitutions (e.g., p.Leu488Met, p.Thr227Met, p.Gly219Arg, p.Tyr82Cys, p.Leu492Pro) and one canonical splice acceptor variant (c.1276-1G>A). No structural or deep-intronic alleles have been described to date, and no founder effects have been established.

Functional assays in heterologous cells demonstrate complete loss of NaCT citrate transport activity for all tested missense and splice variants, despite variable membrane localization (PMID:27261973; PMID:30054523). Slc13a5−/− mice recapitulate neuronal hyperexcitability, enhanced seizure propensity, and altered citrate homeostasis in brain and CSF, confirming a loss-of-function mechanism (PMID:32682952).

No reports to date dispute this association. Concordant genetic and experimental data define a clear loss-of-function mechanism without evidence for dominant-negative effects or alternative etiologies.

Integration of robust segregation in multiple families with consistent in vitro transport defects and an in vivo knockout phenotype supports a Strong gene–disease association. Key take-home: SLC13A5 genetic testing enables definitive diagnosis of amelocerebrohypohidrotic syndrome and informs potential avenues for targeted biochemical and metabolic interventions.

References

• Molecular Medicine (Cambridge, Mass.) • 2016 • Mutations in the Na(+)/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay PMID:27261973
• Journal of Postgraduate Medicine • 2024 • SOFT syndrome with kohlschutter-Tonz syndrome PMID:37706418
• Scientific Reports • 2018 • Analysis of naturally occurring mutations in the human uptake transporter NaCT important for bone and brain development and energy metabolism PMID:30054523
• Neurobiology of Disease • 2020 • Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus PMID:32682952

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