Glutamate Receptor Interacting Protein 1 (GRIP1; MIM#604597) is a scaffolding protein that interacts with FRAS1/FREM protein complexes and required for their localization. The first report of GRIP1 in association with Fraser syndrome 3 was in Vogel, et.al 2012 (PMID:22510445), which reported in 2 independent fetuses with homozygous loss of function GRIP1 variants and phenotypes consistent with Fraser syndrome. Biallelic or homozygous loss of function (nonsense, frameshift, canonical splice, and deletion) variants in GRIP1 have since been reported in multiple additional affected individuals in the literature with Fraser Syndrome 3 (PMIDs:24357607, 33709629). The mechanism for GRIP1 in association with Fraser Syndrome 3 is loss of function and it is inherited in an autosomal recessive pattern. GRIP1 knockout mouse models have variable background dependent phenotypes including embryonic lethality with severe bullous disorder, haemorrhagic bullae, limb malformations including syndactyly and polydactyly, uni- or bilateral cryptophthalmos, and absent kidneys (PMIDs:11983858, 14730302). GRIP1 localization studies in mouse and in vitro models demonstrate the presence of GRIP1 at the basal cell layer in developing epidermis and co-localization with Fras1 and Frem2 in epithelial cells (PMID:11983858, 14730302). Given the genetic and functional evidence, GRIP1 is classified as Definitive for Fraser Syndrome 3. Of note, missense variants in GRIP1 have also been implicated in Congential Anomalies of the Kidney and Urinary Tract (CAKUT) (PMID:24700879, 26489027, 26539891, 33226606), however curation of GRIP1 for CAKUT and associated phenotypes is out of the scope of the Prenatal Gene Curation Expert Panel.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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