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

Abstract

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 factors (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 nucleotide change in exon 10 of the FGD1 gene (G2559 s A) substituting a Gln for Arg in position 610. The mutation was found to segregate with the AAS phenotype 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 residue which has been involved in InsP binding in PH domains of other proteins. The same residue is often mutated in the Bruton's tyrosine kinase (Btk) gene in patients with an X-linked agammaglobulinemia. The Arg610Gln mutation represents the first case of a mutation in the PH domain of the FGD1 gene and additional evidence that mutations in PH domains can be associated to human diseases. ß

Phenotypic and molecular characterisation of the Aarskog–Scott syndrome: a survey of the clinical variability in light of FGD1 mutation analysis in 46 patients

“…The clinical data of the first reported cases of AAS with FGD1 mutations did not support those observations, as mental retardation did not appear to be part of the phenotype of mutated patients. 6,7 The recent discovery, however, that the FGD1 mutation P312L is associated to nonsyndromic X-linked mental retardation in a family, 8 and the presence of various developmental disabilities and/or behavioural disorders in five of the 12 mutated patients in this study confirms that developmental disabilities may be part of the AAS phenotype. Severe mental retardation, as reported by Lebel et al, 8 was not noted in the present group of mutated patients; 12 of our AAS patients had severe mental retardation, and all 12 were found to be negative for FGD1 mutations.…”

“…As previously reported, 6 carrier females often show minor dysmorphic features such as hypertelorism and widow's peak. In the absence of obvious clinical manifestations, we suggest that a minutious physical examination of female family members should be performed as a support for possible X-linked inheritance.…”

“…As in the previously reported studies, 6,7 in only a minority of patients with the clinical diagnosis of AAS was an FGD1 mutation found. We detected eight FGD1 mutations, all novel, in nine out of 46 probands, accounting for 19.56% of the patients (Tables 1 and 2).…”

“…As the clinical criteria were not substantially different from those applied in other studies, 6,7 this relatively higher percentage may be explained by the large number of typical patients and by the presence of familial cases with evidence of X-linked inheritance. In three of the four families in which there were more than one affected male, we detected an FGD1 mutation (the families of the probands 26, 58, 90), while in the fourth family, despite a possible X-linked inheritance of the phenotype, no mutations were found.…”

Faciogenital Dysplasia Protein (FGD1) Regulates Export of Cargo Proteins from the Golgi Complex via Cdc42 Activation

“…Most of these structural motifs are known to be involved in signaling and/or subcellular localization. Indeed, most of the FGD1 mutations identified to date are in the DH/PH region (Orrico et al, 2000), the portion of FGD1 that is responsible for the specific activation of the Rho GTPase Cdc42 (the DH domain) and for membrane binding (the PH domain; Estrada et al, 2001).…”