Clinical utility gene card for: Aarskog–Scott Syndrome (faciogenital dysplasia) – update 2015

Orrico, Alfredo; Galli, Lucia; Clayton‐Smith, Jill

doi:10.1038/ejhg.2014.178

Cited by 16 publications

(11 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To the best of our knowledge, the FGD1 gene is the only known causative gene for ASS ( 1 ). A total of 61 variants have been identified in the FGD1 gene, including 32 missense variants, 6 nonsense variants, 16 frameshift variants, 4 splice site variants, 1 in-frame deletion and 2 gross deletions ( 19 ). In the present study, a novel hemizygous variant of the FGD1 gene was successfully identified in a Chinese patient with ASS.…”

Section: Discussionmentioning

confidence: 99%

Novel variant in the FGD1 gene causing Aarskog-Scott syndrome

Niu

Wang

et al. 2017

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Aarskog-Scott syndrome (ASS) is a rare, X-linked recessive inherited disorder. Affected individuals may develop short stature and exhibit distinctive skeletal and genital development. Mutations in the FYVE, rhogef and pleckstrin homology domain-containing protein 1 (FGD1) gene, located within the Xp11.21 region, are responsible for the occurrence of ASS. Since it is rare and complex, it can take a long time to obtain a definitive clinical diagnosis unless clinicians are familiar with the disease. In the present study, whole-exome sequencing (WES) was performed to screen for causal variants in a Chinese pediatric patient who exhibited a number of clinical symptoms of ASS, including short stature, facial abnormalities, stubby metacarpals and swollen testis. DNA sequencing revealed a novel c.1270 A>G mutation in exon 6 of the FGD1 gene, which led to an amino acid conversion of asparagine to aspartic acid on codon 424 and in silico analysis indicated that this novel missense mutation was pathogenic. The present study identified a novel variant of the FGD1 gene and to the best of our knowledge, is the first report of ASS in a Chinese individual. The results indicated that WES is an effective tool for the diagnosis of rare and complex syndromes such as ASS.

show abstract

Section: Discussionmentioning

confidence: 99%

Novel variant in the FGD1 gene causing Aarskog-Scott syndrome

Niu

Wang

et al. 2017

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

show abstract

“…Faciogenital dysplasia (FGDY) is a rare X-linked disorder that manifests in defects of bone development such as disproportional acromelic short stature, abnormal face shape, as well as cardiac, ocular, urogenital abnormalities and mental retardation (Aarskog, 1970; Orrico et al, 2015). FGDY is caused by loss-of-function mutations in the FGD1 gene that encodes a 961 amino acid FGD1 protein that acts as a specific GEF for the small Rho GTPase CDC42 (Pasteris et al, 1994; Zheng et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…FGDY is caused by loss-of-function mutations in the FGD1 gene that encodes a 961 amino acid FGD1 protein that acts as a specific GEF for the small Rho GTPase CDC42 (Pasteris et al, 1994; Zheng et al, 1996). The predicted frequency of clinical manifestation of FGDY is about 1:25,000 (Orrico et al, 2015). The FGD1 protein is expressed in regions of active osteogenesis in developing long bones (Gorski et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Identification of CDC42 Effectors Operating in FGD1-Dependent Trafficking at the Golgi

Egorov

Polishchuk

2019

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Loss of function mutations in the FGD1 gene cause a rare X-linked disease, faciogenital dysplasia (FGDY, also known as Aarskog-Skott syndrome), which is associated with bone and urogenital abnormalities. The FGD1 gene encodes à CDC42-specific guanine nucleotide exchange factor. The mutations are frequently located in the DH module of FGD1 preventing its transformation to the active form. We previously reported that Golgi-associated FGD1 regulates post-Golgi transport of some conventional and bone-specific proteins in a CDC42-dependent manner. However, the downstream targets of FGD1/CDC42 signaling that operate to support transport from the Golgi remain elusive. Here, we demonstrate that Golgi-localized CDC42 effectors might be involved in FGD1-mediated post-Golgi transport, probably through coordination of Golgi membrane and cytoskeleton dynamics. Overexpression of effector-specific CDC42 mutants (exhibiting preferential affinities for PAK1, IQGAP1, N-WASP, or PAR6) only partially rescue membrane trafficking in FGD1-deficient cells, indicating that the orchestrated activities of several downstream targets of CDC42 are required to support FGD1-mediated export from the Golgi. Our findings provide new insights into understanding the molecular mechanisms behind FGD1/CDC42-dependent transport events and uncover new targets whose potential might be explored for correction of membrane trafficking in FGDY.

show abstract

“…To date, 63 mutations in FGD1 have been reported in AAS ( Orrico et al 2014 ; Pérez-Coria et al 2015 ). The FGD1 gene contains 18 exons that code for a specific guanine nucleotide exchange factor (GEF) for the Rho protein CDC42 that is critical for embryogenesis ( Gorski et al 2000 ).…”

Section: Introductionmentioning

confidence: 99%

“…The 961-amino-acid FGD1 protein has five discrete domains, including a proline-rich domain, an SH3-binding domain, a Rho GEF homology domain, two PH domains, and a cysteine-rich Zn 2+ -finger domain. Missense, frameshift, nonsense, splice site, branch point, and large and small in-frame deletion mutations have been reported to cause AAS ( Orrico et al 2014 ). Interestingly, these mutations are randomly distributed throughout the protein's functional domains, indicating a loss-of-function mechanism of pathogenesis in AAS through the disruption of GEF catalytic activity and/or protein localization of FGD1 ( Orrico et al 2000 , 2004 , 2010 ; Schwartz et al 2000 ; Bedoyan et al 2009 ).…”

Section: Introductionmentioning

confidence: 99%

A novel FGD1 mutation in a family with Aarskog–Scott syndrome and predominant features of congenital joint contractures

Griffin

Farley

Antonellis

et al. 2016

Cold Spring Harb Mol Case Stud

View full text Add to dashboard Cite

Mutations in FGD1 cause Aarskog–Scott syndrome (AAS), an X-linked condition characterized by abnormal facial, skeletal, and genital development due to abnormal embryonic morphogenesis and skeletal formation. Here we report a novel FGD1 mutation in a family with atypical features of AAS, specifically bilateral upper and lower limb congenital joint contractures and cardiac abnormalities. The male proband and his affected maternal uncle are hemizygous for the novel FGD1 mutation p.Arg921X. This variant is the most carboxy-terminal FGD1 mutation identified in a family with AAS and is predicted to truncate the FGD1 protein at the second to last amino acid of the carboxy-terminal pleckstrin homology (PH) domain. Our study emphasizes the importance of the 3′ peptide sequence in the structure and/or function of the FGD1 protein and further demonstrates the need to screen patients with X-linked congenital joint contractures for FGD1 mutations.

show abstract

Clinical utility gene card for: Aarskog–Scott Syndrome (faciogenital dysplasia) – update 2015

Cited by 16 publications

References 20 publications

Novel variant in the FGD1 gene causing Aarskog-Scott syndrome

Novel variant in the FGD1 gene causing Aarskog-Scott syndrome

Identification of CDC42 Effectors Operating in FGD1-Dependent Trafficking at the Golgi

A novel FGD1 mutation in a family with Aarskog–Scott syndrome and predominant features of congenital joint contractures

Contact Info

Product

Resources

About