HGNC Approved Gene Symbol: FGD1
SNOMEDCT: 14921002; ICD10CM: Q87.19;
Cytogenetic location: Xp11.22 Genomic coordinates (GRCh38): X:54,445,454-54,496,234 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.22 | Aarskog-Scott syndrome | 305400 | X-linked recessive | 3 |
| Intellectual developmental disorder, X-linked syndromic 16 | 305400 | X-linked recessive | 3 |
Using positional methods to clone the gene that is mutant in Aarskog-Scott syndrome (AAS; 305400), Pasteris et al. (1994) isolated YAC clones spanning the t(X;8) breakpoint associated with the disorder. The predicted length of the FGD1 protein is 961 amino acids. It has strong homology to RAS-like RHO/RAC guanine nucleotide exchange factors (GEFs), and contains a cysteine-rich zinc finger-like region and 2 potential SH3-binding sites.
Pasteris et al. (1995) isolated the mouse Fgd1 homolog. The mouse cDNA clones contained a 2,880-bp open reading frame predicted to encode a protein of 960 amino acids, 1 amino acid shorter than the human FGD1 open reading frame. Comparison of the mouse and human sequences within the coding region indicated 94.7% identity (96.3% similarity) at the amino acid level. The results and observations strongly suggested to Pasteris et al. (1995) that the mouse will serve as a useful model for studying and characterizing the Fgd1 development signal transduction system.
Pasteris et al. (1994) determined that the FGD1 gene contains more than 19 exons spanning 100 kb.
Pasteris et al. (1994) identified the FGD1 gene within the X-linked Aarskog-Scott syndrome region on Xp11.21.
Using interspecific backcross analysis, Pasteris et al. (1995) mapped the Fgd1 gene to the X chromosome of the mouse.
Zheng et al. (1996) reported that a fragment of the FGD1 protein encompassing the PH and Dbl (DH) homology domains binds specifically to the Rho GTPase CDC42 (116952) and can stimulate the GDP-GTP exchange of the isoprenylated form of CDC42. Cells expressing this FGD1 fragment activated 2 elements downstream of CDC42, namely, Jun kinase (165160) and p70 S6 kinase. The authors concluded that FGD1, through its PH and DH homology domains, acts as a CDC42-specific GDP-GTP exchange factor.
Estrada et al. (2001) used subcellular fractionation to show that endogenous Fgd1 protein is localized in the cytosolic and Golgi and plasma membrane fractions of mouse calvarial cells. Immunocytochemical studies in mammalian cell lines confirmed the localization of Fgd1 and showed that the proline-rich N-terminal region is necessary and sufficient for Fgd1 subcellular localization to the plasma membrane and Golgi complex. Microinjection studies revealed that the N-terminal Fgd1 domain inhibits filopodia formation, suggesting that this region downregulates GEF function. The authors hypothesized that the Fgd1 Cdc42GEF protein may be involved in the regulation of Cdc42 activity at the subcortical actin cytoskeleton and Golgi complex.
Gao et al. (2001) isolated and characterized fgd1, the C. elegans homolog of the human FGD1 gene. Comparative sequence analyses show that fgd1 and FGD1 share a similar structural organization and a high degree of sequence identity throughout shared signaling domains. Buechner et al. (1999) had shown that several genes (designated Exc) are involved in excretory cell morphogenesis in nematodes. Interference with fgd1 expression resulted in excretory cell abnormalities and cystic dilation of the excretory cell canals. Molecular lesions associated with 2 exc5 alleles affected the fgd1 gene, and fgd1 transgenic expression rescued the Exc5 phenotype. The authors concluded that the fgd1 transcript corresponded to the exc5 gene. Transgenic expression studies showed that fgd1 has a limited pattern of expression that is confined to the excretory cell during development, a finding suggesting that the C. elegans FGD1 protein might function in a cell-autonomous manner. Serial observations indicated that fgd1 mutations lead to developmental excretory cell abnormalities that cause cystic dilation and interfere with canal process extension. The authors hypothesized that fgd1 plays a critical role in excretory cell morphogenesis and cellular organization.
Hou et al. (2003) demonstrated that Fgd1 interacts directly with cortactin (EMS1; 164765) and mammalian actin-binding protein-1 (mAbp1), actin-binding proteins that regulate actin polymerization through the Arp2/3 complex (see 604221). Yeast 2-hybrid studies, biochemical studies, and immunoprecipitation studies demonstrated interaction of both cortactin and mAbp1 Src homology-3 (SH3) domains with a single Fgd1 SH3-binding domain (SH3-BD). Fgd1 SH3-BD mutations disrupted binding. Fgd1 colocalized with cortactin and mAbp1 in lamellipodia and membrane ruffles. In immunocytochemical studies using truncated cortactin proteins, the cortactin SH3 domain targeted Fgd1 to the subcortical actin cytoskeleton, and abnormal Fgd1 localization resulted in actin cytoskeletal abnormalities and significant changes in cell shape and viability. The authors concluded that interaction among these 3 proteins plays an important role in regulating cell shape.
Invadopodia are proteolytically active membrane protrusions that extend from the ventral surface of invasive tumor cells grown on an extracellular matrix. Ayala et al. (2009) found that FGD1 was a transient component of invadopodia in human cancer cell lines and was required for invadopodia biogenesis and local degradation of the extracellular matrix through activation of CDC42. FGD1 was highly expressed in most prostate cancer cells examined, but not in normal prostate tissue, and FGD1 staining was highest in more aggressive lesions. FGD1 expression was also high in infiltrating ductal breast carcinomas, but not in normal breast epithelial cells.
Aarskog-Scott Syndrome (Faciogenital Dysplasia)
By SSCP analysis, Pasteris et al. (1994) identified a mutation cosegregating with the FGD1 gene in affected members of a family with Aarskog-Scott syndrome; see 300546.0001.
Orrico et al. (2000) analyzed 13 unrelated patients with a clinical diagnosis of Aarskog-Scott syndrome. One patient carried an arg610-to-gln mutation (300546.0002) located in 1 of the 2 pleckstrin homology (PH) domains of the FGD1 gene. It corresponded to a highly conserved residue that had been involved in phosphoinositide binding in PH domains of other proteins. Critical missense mutations within the PH domain of the Bruton tyrosine kinase gene (BTK; 300300) result in X-linked agammaglobulinemia (300755).
Using SSCP analysis of the FGD1 gene, Schwartz et al. (2000) identified a missense mutation (300546.0003) in a familial case of Aarskog-Scott syndrome and a deletion mutation (300546.0004) in a sporadic case. The authors were unable to detect alterations in the FGD1 gene in propositi from 25 other familial cases, including the families originally described by Aarskog (1970) and Scott (1971), or in 15 sporadic cases. They suggested that mutational mechanisms not detected using standard analysis of coding sequence genomic DNA may cause the disorder.
Orrico et al. (2004) performed SSCP analysis of the FGD1 gene in 46 male patients with a clinical diagnosis of AAS. They identified 8 mutations, all novel, including 4 deletions, 1 insertion, and 3 missense mutations. One mutation, 528insC (300546.0006), was found in 2 independent families. The mutations were scattered over the entire coding sequence, and there were no apparent genotype/phenotype correlations. No global differences in clinical findings were found between probands with or without mutations, but those with mutations presented with a fuller clinical spectrum of the phenotype. Orrico et al. (2004) concluded that mutations in the FGD1 gene account for a minority of X-linked AAS cases.
Orrico et al. (2007) reported 2 brothers with features consistent with Aarskog-Scott syndrome in whom they identified a truncating mutation in the FGD1 gene (300546.0010). The older brother had unusually severe craniofacial abnormalities involving right hemifacial microsomia with right microtia.
Orrico et al. (2010) identified mutations in the FGD1 gene in 11 (18.33%) of 60 European patients with a clinically suspected diagnosis of Aarskog-Scott syndrome. Nine mutations were novel, including 3 missense mutations, 4 truncating mutations, an in-frame deletion, and a splice site mutation. One mutation (R656X; 300546.0012) was recurrent, present in 3 unrelated families. There were no apparent genotype/phenotype correlations.
Aarskog-Scott Syndrome and Attention Deficit-Hyperactivity Disorder
Orrico et al. (2005) reported a 16-year-old boy who was evaluated for attention deficit-hyperactivity disorder (ADHD; 143465) and low intelligence quotient, in whom they noted dysmorphic features reminiscent of AAS. Genetic analysis demonstrated an R408Q mutation in the FGD1 gene (300546.0007). Orrico et al. (2005) noted that this case confirms the highly variable expressivity of AAS and suggests that FGD1 may play a role in ADHD susceptibility.
X-linked Syndromic Intellectual Developmental Disorder 16
Lebel et al. (2002) described 3 brothers with severe X-linked syndromic intellectual developmental disorder (MRXS16; see 305400) and a pro312-to-leu (P312L; 300546.0005) missense mutation in the FGD1 gene. The authors stated that there was little in the clinical features to suggest Aarskog-Scott syndrome. One of the brothers had cupped ears and one had partial shawl scrotum. All 3 had short stature and small feet.
In a family with Aarskog-Scott syndrome (AAS; 305400) with 2 affected brothers and a carrier mother, Pasteris et al. (1994) used SSCP to demonstrate an insertion mutation in the FGD1 gene; an additional guanine residue after nucleotide 2122 resulted in a frameshift predicted to cause premature translation termination at codon 469.
In an Italian family with faciogenital dysplasia (AAS; 305400), Orrico et al. (2000) identified a 2559G-A transition in exon 10 of the FGD1 gene, resulting in an arg610-to-gln (R610Q) change in the protein product. The mutation was found to segregate with the Aarskog phenotype in affected males and carrier females. It was of particular interest because of involvement of the pleckstrin homology domain.
In 2 Italian male cousins with Aarskog-Scott syndrome (AAS; 305400), Schwartz et al. (2000) identified a 2296G-A alteration in the FGD1 gene, causing an arg522-to-his (R522H) change in the third structural conserved region of the GEF domain of the protein. The arginine at codon 522 is highly conserved, and the bulkier histidine probably alters the conformation of the GEF domain. The mutation eliminated an AciI restriction site in the normal sequence, which segregated with the syndrome in the family.
In a sporadic case of Aarskog-Scott syndrome (AAS; 305400) from Germany, Schwartz et al. (2000) identified a deletion of 4 exons of the FGD1 gene. The exact extent of the deletion was not determined, but at a minimum the altered protein lacked a portion of the GEF domain, a portion of a PH1 domain, and a leucine zipper domain.
Lebel et al. (2002) described 3 brothers with X-linked syndromic intellectual developmental disorder-16 (MRXS16; see 305400) who had a 934C-T transition in exon 4 of the FGD1 gene, resulting in a pro312-to-leu (P312L) missense mutation. The mutation was predicted to eliminate a beta-turn, creating an extra-long stretch of coiled sequence that may affect the orientations of the SH3-binding domain and the first structural conserved region. The mother was found to have the same mutation. None of the affected brothers had distinct craniofacial, skeletal, or genital findings suggestive of Aarskog syndrome. One brother (individual III-1) had a large head with bitemporal narrowing, prominence of the right antitragus, an open mouth, a high-arched palate, limited elbow extension, short feet, and short stature. Another brother (individual III-4) had mild cupping and anteversion of the right ear, prominence of the antitragus, a high-arched palate, stiffness of the finger joints, limited elbow extension, small inverted feet, and reduced testicular volume. The youngest brother (individual III-5) had a large head, a high-arched palate, partial shawl scrotum, repaired right cryptorchidism, small feet, short stature, and a constant tremor of the upper limbs.
In a Belgian and an Italian family with Aarskog-Scott syndrome (AAS; 305400), Orrico et al. (2004) identified a 528insC mutation in the FGD1 gene, causing a frameshift after codon 176 and resulting in termination at codon 216. The mutation was associated with mild mental impairment in the Belgian family but was not associated with any neurodevelopmental disability in the Italian family.
In a 16-year-old boy with attention deficit-hyperactivity disorder, low intelligence quotient and dysmorphic features reminiscent of Aarskog-Scott syndrome (see 305400), Orrico et al. (2005) identified a 1223G-A transition in exon 6 of the FGD1 gene, predicted to cause an arg408-to-gln (R408Q) substitution. Orrico et al. (2005) remarked that the high clinical variability of Aarskog-Scott syndrome patients suggests that analysis of the FGD1 gene should not be restricted to typical cases only, and that additional studies will clarify the influence FGD1 variations on behavioral phenotypes.
Shalev et al. (2006) described the clinical variability of Aarskog syndrome (AAS; 305400) in an Arab family living in Israel with 7 affected individuals. Sequencing studies revealed a 2189delA mutation in exon 15 of the FGD1 gene. The clinical variability involved particularly their cognitive skills, raising the question of whether other genetic factors might be involved in the phenotypic evolution of the disorder. The affected individuals were in 5 separate sibships connected through carrier females.
In a boy with Aarskog-Scott syndrome, attention deficit-hyperactivity disorder, and borderline intelligence (see 305400), Kaname et al. (2006) identified a 1327G-T transversion in exon 6 of the FGD1 gene, resulting in an arg433-to-leu (R433L) substitution in the RhoGEF domain of the protein. Kaname et al. (2006) noted that Orrico et al. (2005) had reported a patient with Aarskog-Scott syndrome and ADHD who had a mutation in the same domain of FGD1 (R408Q; 300546.0007).
In 2 brothers with features consistent with Aarskog-Scott syndrome (AAS; 305400), Orrico et al. (2007) identified a 1-bp insertion (945insC) in exon 4 of the FGD1 gene, predicted to cause truncation of the protein at codon 319. The brothers' phenotype included short stature, hypertelorism, shawl scrotum, brachydactyly with mild soft tissue webbing between the fingers, and normal intelligence. The older brother had unusually severe craniofacial abnormalities involving right hemifacial microsomia with right microtia. Their sister and mother, who also carried the mutation and had random X-inactivation patterns, exhibited short stature and joint laxity. All affected members of the family had a curved linear dimple beneath the lower lip, a feature noted in some of the earliest described patients (see Sugarman et al., 1973).
In a boy with Aarskog-Scott syndrome (AAS; 305400), Bottani et al. (2007) identified a 1396A-G transition in the FGD1 gene, resulting in a met466-to-val (M466V) substitution in the H4 region of the RhoGEF domain. The unaffected parents were of Kosovar Albanian origin, and the mother was found to carry the mutation. The patient had classic features of AAS with normal neurologic status and good school performance. At age 9 years, he developed generalized seizures and was found to have unilateral focal frontoparietal polymicrogyria (see 610031), which had not previously been described in this syndrome.
In 3 unrelated patients with Aarskog-Scott syndrome (AAS; 305400), Orrico et al. (2010) identified a 1966C-T transition in exon 12 of the FGD1 gene, resulting in an arg656-to-ter (R656X) substitution.
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