A recurrent damaging missense variant at p.Ile500 of the SMAD4 gene was originally identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and a female proband with developmental delay (Deciphering Developmental Disorders Study, 2015). Geisheker et al., 2017 identified two novel ASD probands with a de novo damaging missense variant at p.Ile500, bringing the total number of de novo damaging missense variants at this position observed in NDD cases to 4 (P=2.07E-06, one-tailed binomial test, genome-wide correction); in contrast, no similar variants at p.Ile500 were observed in ExAC (allele count 0/45,376).
Molecular Function
This gene encodes a member of the Smad family of signal transduction proteins. Smad proteins are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to TGF-beta signaling. The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and recognizes an 8-bp palindromic sequence (GTCTAGAC) called the Smad-binding element (SBE). The Smad proteins are subject to complex regulation by post-translational modifications.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
The contribution of de novo coding mutations to autism spectrum disorder
