A mutation in the pleckstrin homology (PH) domain of the FGD1 gene in an Italian family with faciogenital dysplasia (Aarskog-Scott syndrome)

Aarskog-Scott Syndrome (AAS) is an X-linked disorder characterised by short stature and multiple facial, Limb and genital abnormalities. A gene, FGD1, altered in a patient with AAS phenotype, has been identified and found to encode a protein with homology to Rho/Rac guanine nucleotide exchange facto rs (Rho/Rac GEF), However, since this original report on identification of a mutated FGD1 gene in an AAS patient, no additional mutations in the FGD1 gene have been described. We analysed 13 independent patients with clinical diagnosis of AAS. One patient presented a mutation that results in a nucle otide change in exon TO of the FGD1 gene (G2559 > A) substituting a Gin for Arg in position 610, The mutation was found to segregate with the AAS phen otype in affected males and carrier females in the family of this patient. Interestingly, Arg-610 is located within one of the two pleckstrin homology (PH) domains of the FGD1 gene and it corresponds to a highly conserved res idue which has been involved in InsP binding in PH domains of other protein s, The same residue is often mutated in the Bruton's tyrosine kinase (Btk) gene in patients with an X-linked agammaglobulinemia. The Arg610Gln mutatio n represents the first case of a mutation in the PII domain of the FGD1 gen e and additional evidence that mutations in PH domains can be associated to human diseases. (C) 2000 Federation of European Biochemical Societies. Pub lished by Elsevier Science B.V. All rights reserved.