GDI1 – Non-syndromic X-linked Intellectual Disability

GDI1 encodes αGDI, a regulator of Rab GTPase cycling, and hemizygous variants cause X-linked intellectual disability. In a Chinese NS-XLID family, exome sequencing identified a novel missense variant c.710G>T (p.Gly237Val) segregating with intellectual disability in three affected males (PMID:28863211). The substitution maps to the Rab-binding domain and molecular dynamics predicts a conformational change impairing Rab interaction. The inheritance is X-linked recessive, supported by segregation in two additional affected relatives within the pedigree. Functional studies demonstrate that Gdi1-null mice recapitulate working memory and associative learning deficits, which are rescued by glycolysis inhibition (PMID:33309713). These findings provide limited genetic but strong experimental evidence linking GDI1 to Non-syndromic X-linked intellectual disability. Key Take-home: Consider GDI1 sequencing in diagnostic workflows for X-linked intellectual disability due to its established impact on Rab GTPase cycling and cognitive function.

References

• Genetics and Molecular Biology • 2017 • Exome sequencing identifies a novel mutation of the GDI1 gene in a Chinese non-syndromic X-linked intellectual disability family PMID:28863211
• Metabolism: Clinical and Experimental • 2021 • Inhibiting glycolysis rescues memory impairment in an intellectual disability Gdi1-null mouse PMID:33309713

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