ARHGEF6 – X-linked Intellectual Disability

ARHGEF6 encodes a Rac1/Cdc42-specific guanine nucleotide exchange factor expressed ubiquitously and in early embryonic brain tissues, consistent with a role in neuronal morphogenesis (PMID:12063400). Yeast-two hybrid and co-immunoprecipitation studies demonstrate ARHGEF6 interaction with PARVB at lamellipodia and ruffles, and patient-derived ARHGEF6 deletions (Δaa56-83, Δaa396-776) abolish this binding, underscoring a mechanistic link to actin cytoskeleton regulation in neurons (PMID:12499396). Initial human reports proposed ARHGEF6 mutations as causative for X-linked mental retardation, but specific variant and segregation data remain limited.

A comprehensive reassessment of 106 XLID genes using exome data from 10 563 control X chromosomes found truncating variants in ARHGEF6 at a relatively high frequency, challenging its implication in monogenic X-linked intellectual disability (PMID:23871722). In the absence of additional unrelated probands or confirmatory segregation, the clinical validity of the ARHGEF6–X-linked intellectual disability association is considered Disputed. Nonetheless, functional studies provide Moderate evidence for a plausible pathogenic mechanism through dysregulation of RAC1/CDC42 signaling in neuronal cells. Further comprehensive case series and segregation analyses are required before ARHGEF6 variants can be reliably used in diagnostic panels.

Key Take-home: Despite mechanistic support, current genetic data dispute ARHGEF6 as a monogenic cause of X-linked intellectual disability; variant interpretation should proceed with caution.

References

• American Journal of Human Genetics • 2013 • XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing PMID:23871722
• Cytogenetics and Cell Genetics • 2001 • The mouse Arhgef6 gene: cDNA sequence, expression analysis, and chromosome assignment. PMID:12063400
• Human Molecular Genetics • 2003 • Interaction of alphaPIX (ARHGEF6) with beta-parvin (PARVB) suggests an involvement of alphaPIX in integrin-mediated signaling. PMID:12499396

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