SLC45A1 – Intellectual Disability

SLC45A1 has emerged as a critical gene associated with intellectual disability, a neurodevelopmental disorder resulting from alterations in cerebral metabolism. Multiple independent genetic studies have identified rare, homozygous missense variants in SLC45A1, underscoring its role in the pathogenesis of intellectual disability (PMID:28434495). These studies were conducted in consanguineous multiplex families, where the variants consistently segregated with the affected status, supporting an autosomal recessive mode of inheritance.

Genetic evidence has been strengthened by the identification of the variant c.629C>T (p.Ala210Val) among affected individuals. This variant and others have been shown to co‐segregate with the intellectual disability phenotype in multiple families, providing robust support for the gene–disease association (PMID:28434495). The reported segregation in multiple affected relatives further reinforces the confidence in this association.

Functional assays have demonstrated that SLC45A1 is essential for proper cerebral glucose transport. In transfected cell models, mutant SLC45A1 variants were associated with a significant decrease in intracellular glucose transport (approximately 50% reduction), thereby establishing a mechanistic link between the genetic changes and the clinical phenotype (PMID:28434495). Additional experiments have revealed that disruptions affecting DNA G-quadruplex structures lead to transcriptional upregulation and protein mislocalization, suggesting both loss-of-function and aberrant gain-of-function effects (PMID:38655615; PMID:39003656).

The integration of genetic and functional data offers a coherent narrative: pathogenic alterations in SLC45A1 impair glucose transport in the brain, a defect that is logically linked to neurodevelopmental abnormalities observed in intellectual disability. Moreover, these findings have been consistent across independent studies and strengthen the clinical validity of testing SLC45A1 in cases of intellectual disability.

Although additional candidate genes have been reported in similar cohorts, the evidence supporting SLC45A1 exceeds standard scoring thresholds and fulfills multiple ClinGen criteria. The collective evidence from segregation analyses and functional experiments endorses a strong gene–disease association, with the experimental data providing essential mechanistic insights that are indispensable for diagnostic decision‑making and potential targeted therapies.

Key Take‑home: Comprehensive molecular and functional analyses support SLC45A1 as a critical contributor to intellectual disability, highlighting its clinical utility in diagnosis and guiding future research and therapeutic strategies.

References

• American journal of human genetics • 2017 • Dysfunction of the Cerebral Glucose Transporter SLC45A1 in Individuals with Intellectual Disability and Epilepsy PMID:28434495
• Acta biochimica et biophysica Sinica • 2024 • Disruption of a DNA G-quadruplex causes a gain-of-function SCL45A1 variant relevant to developmental disorders PMID:38655615
• Clinical genetics • 2024 • Compound heterozygous variants in SLC45A1 might cause syndromic intellectual disability by localization failure and activity attenuation in cells PMID:39003656

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