GRIP1 – Fraser Syndrome

Fraser syndrome (FS) is a rare autosomal recessive multiple congenital malformation syndrome characterized by cryptophthalmos, syndactyly, renal and genitourinary anomalies, and craniofacial dysmorphism. FS is genetically heterogeneous, with biallelic mutations in FRAS1, FREM2, and GRIP1 underpinning classic presentations. GRIP1 encodes a scaffolding protein that interacts with the FRAS1–FREM extracellular matrix complex during embryonic epithelial–mesenchymal adhesion.

Biallelic GRIP1 variants have been identified in four unrelated FS probands, including three consanguineous families with segregating mutations and one adolescent case, confirming autosomal recessive inheritance and familial co-segregation (4 total probands) (PMID:22510445)(PMID:33709629).

The variant spectrum comprises loss-of-function alleles, including donor splice site, frameshift, and nonsense changes. A representative truncating variant, c.2155C>T (p.Arg719Ter), has been reported in one family and is predicted to abrogate GRIP1 function (PMID:22510445).

Functional evidence is provided by murine Grip1 models, which recapitulate FS-like defects when disrupted, supporting a loss-of-function mechanism (PMID:22510445). Structural biology further demonstrates that the GRIP1 PDZ1–2 tandem forms a supramodule to bind the C-terminus of Fras1, elucidating the molecular basis of the GRIP1–FRAS1 interaction in FS pathogenesis (PMID:18155042).

No studies to date have disputed the causal role of GRIP1 in FS, and no alternative phenotypes have been assigned to the same biallelic variants in GRIP1.

Together, genetic segregation and concordant experimental models provide moderate clinical validity for GRIP1 in Fraser syndrome. Additional case series and functional rescue experiments could elevate this association. Key take-home: Biallelic loss-of-function variants in GRIP1 cause autosomal recessive Fraser syndrome, informing molecular diagnosis and genetic counseling.

References

• Journal of medical genetics • 2012 • Mutations in GRIP1 cause Fraser syndrome. PMID:22510445
• American journal of medical genetics. Part A • 2021 • The first adolescent case of Fraser syndrome 3, with a novel nonsense variant in GRIP1. PMID:33709629
• Journal of molecular biology • 2008 • Supramodular nature of GRIP1 revealed by the structure of its PDZ12 tandem in complex with the carboxyl tail of Fras1. PMID:18155042

Evidence Based Scoring (AI generated)