The FGD1 gene encodes a guanine nucleotide exchange factor (GEF) belonging to the DBL family of proteins. The FGD1 protein localizes preferentially to the trans-Golgi network of mammalian cells and activates Rho GTPase CDC42 by mediating the exchange of CDC42-bound GDP for GTP. FGD1 regulates secretory membrane trafficking and extracellular matrix remodeling, playing an important role in skeletal development and morphogenesis.
The protein is considered essential for normal embryogenesis in mammals. Mutations in the gene have been associated with Aarskog-Scott Syndrome (AAS), a condition characterized by facial, genital and skeletal anomalies.
The gene is located on the short arm of the X chromosome and spans a length of 50.7 kb of DNA. Its coding sequence is spread across 18 exons and it encodes a 106.5 kDa protein product made up of 961 amino acids. The FGD1 gene is found to be overexpressed in the fetal brain, adult brain, lung heart and placenta. The encoded protein consists of two catalytic domains in its central region, namely the DBL homology (DH) domain and the pleckstrin homology (PH) domain. It also contains a FYVE domain and an additional PH domain at its C-terminus and an N-terminal proline-rich domain with two putative Src homology 3 (SH3)-binding sites. Around 20 variants in the gene have been associated with AAS, including missense mutations, insertions, deletions, inversions and duplications. Of these, missense point mutations occurring in the catalytic central domains are the most common.
Hamzeh et al. (2017) described a consanguineous Emirati family with two AAS affected members. The 7-year-old male proband and his 3-year-old brother both suffered from developmental delay, short stature, aggressive and hyperactive behavior, brachydactyly, bilateral fifth finger clinodactyly and facial dysmorphia. The patients were both found to carry the novel FGD1 variant c.53del (p.Pro18Argfs*106) in a hemizygous state while their mother was a heterozygous carrier. The mutation was not found in the GalaxC™ Allele Frequency Database or in dbSNP, 1,000-genomes, Leiden Open Variation Database, EVS or ExAC. It was predicted to result in a frameshift that produces an ‘out of frame’ translation of 105 erroneous amino acids, followed by a premature termination codon at position 106.
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