GAS1 – Holoprosencephaly

GAS1 encodes a cell-surface co-receptor that enhances Sonic Hedgehog (SHH) signaling during ventral forebrain patterning. Rare heterozygous missense variants in GAS1 have been identified in nine unrelated holoprosencephaly (HPE) probands: two Brazilian patients with c.776G>A (p.Gly259Glu) and c.599C>G (p.Thr200Arg) (PMID:20583177) and five additional novel missense changes from a 394-patient HPE screen (PMID:21842183). Two of the Brazilian cases also harbored SHH mutations, suggesting possible digenic inheritance. No familial segregation has been reported. Based on nine probands, absence of segregation data, and supportive functional data, the gene–disease association is classified as Limited.

Functional assays demonstrate that GAS1 missense substitutions significantly reduce binding affinity for SHH, leading to decreased downstream pathway activation in vitro (PMID:21842183). GAS1-deficient mice and human iPSC-derived neuroepithelial models recapitulate forebrain malformations, implicating GAS1 haploinsufficiency in HPE pathogenesis via disrupted SHH and NOTCH integration (PMID:34698766). Moreover, SHH Asn¹¹⁵→Lys impairs GAS1 interaction, reinforcing the mechanistic link (PMID:19478089). No GAS1 variants were found in congenital hypopituitarism cohorts (PMID:25327282), supporting specificity for HPE.

Key Take-home: Heterozygous GAS1 missense variants constitute a Limited-validity, autosomal dominant risk factor for holoprosencephaly, underscoring GAS1 sequencing in undiagnosed HPE cases.

References

• American journal of medical genetics. Part A • 2010 • Holoprosencephaly and holoprosencephaly-like phenotype and GAS1 DNA sequence changes: Report of four Brazilian patients. PMID:20583177
• Human genetics • 2012 • Missense substitutions in the GAS1 protein present in holoprosencephaly patients reduce the affinity for its ligand, SHH. PMID:21842183
• Development (Cambridge, England) • 2021 • GAS1 is required for NOTCH-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium. PMID:34698766
• The Journal of biological chemistry • 2009 • A sonic hedgehog missense mutation associated with holoprosencephaly causes defective binding to GAS1. PMID:19478089

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