title: Unilateral focal polymicrogyria in a patient with classical Aarskog-Scott syndrome due to a novel missense mutation in an evolutionary conserved RhoGEF domain of the faciogenital dysplasia gene FGD1.
abstract: Faciogenital dysplasia or Aarskog-Scott syndrome (AAS) is an X-linked disorder characterized by craniofacial, skeletal, and urogenital malformations and short stature. Mutations in the only known causative gene FGD1 are found in about one-fifth of the cases with the clinical diagnosis of AAS. FGD1 is a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase Cdc42 via its RhoGEF domain. The Cdc42 pathway is involved in skeletal formation and multiple aspects of neuronal development. We describe a boy with typical AAS and, in addition, unilateral focal polymicrogyria (PMG), a feature hitherto unreported in AAS. Sequencing of the FGD1 gene in the index case and his mother revealed the presence of a novel mutation (1396A>G; M466V), located in the evolutionary conserved alpha-helix 4 of the RhoGEF domain. M466V was not found in healthy family members, in >300 healthy controls and AAS patients, and has not been reported in the literature or mutation databases to date, indicating that this novel missense mutation causes AAS, and possibly PMG. Brain cortex malformations such as PMG could be initiated by mutations in the evolutionary conserved RhoGEF domain of FGD1, by perturbing the signaling via Rho GTPases such as Cdc42 known to cause brain malformation.
authors.affiliation: Division of Medical Genetics, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Armand
authors.initials: A
authors.lastname: Bottani
authors.forename: Alfredo
authors.initials: A
authors.lastname: Orrico
authors.forename: Lucia
authors.initials: L
authors.lastname: Galli
authors.forename: Olivier
authors.initials: O
authors.lastname: Karam
authors.forename: Charles-André
authors.initials: CA
authors.lastname: Haenggeli
authors.forename: Solène
authors.initials: S
authors.lastname: Ferey
authors.forename: Bernard
authors.initials: B
authors.lastname: Conrad
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D005145:Face / Q000002:abnormalities*; D040181:Genetic Diseases, X-Linked; D005835:Genitalia / Q000002:abnormalities*; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D064067:Rho Guanine Nucleotide Exchange Factors; D017386:Sequence Homology, Amino Acid; D013577:Syndrome
chemical_list: C490796:FGD1 protein, human; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors