title: Insertion of 16 amino acids in the BAR domain of the oligophrenin 1 protein causes mental retardation and cerebellar hypoplasia in an Italian family.
abstract: We observed a three-generation family with two maternal cousins and an uncle affected by mental retardation (MR) with cerebellar hypoplasia. X-linked inheritance and the presence of cerebellar malformation suggested a mutation in the OPHN1 gene. In fact, mutational screening revealed a 2-bp deletion that abolishes a donor splicing site, resulting in the inclusion of the initial 48 nucleotides of intron 7 in the mRNA. This mutation determines the production of a mutant oligophrenin 1 protein with 16 extra amino acids inserted in-frame in the N-terminal BAR (Bin1/amphiphysin/Rvs167) domain. This is the first case of a mutation in OPHN1 that does not result in the production of a truncated protein or in its complete loss. OPHN1 (ARHGAP41) encodes a GTPase-activating (GAP) protein belonging to the GRAF subfamily characterized by an N-terminal BAR domain, followed by a pleckstrin-homology (PH) domain and the GAP domain. GRAF proteins play a role in endocytosis and are supposed to dimerize via their BAR domain, that induces membrane curvature. The extra 16 amino acids cause the insertion of 4.4 turns in the third alpha-helix of the BAR domain and apparently impair the protein function. In fact, the clinical phenotype of these patients is identical to that of patients with loss-of-function mutations.
authors.affiliation: Istituto di Genetica Medica, Università Cattolica, Roma, Italy.
authors.forename: Filomena
authors.initials: F
authors.lastname: Pirozzi
authors.forename: Francesca Romana
authors.initials: FR
authors.lastname: Di Raimo
authors.forename: Ginevra
authors.initials: G
authors.lastname: Zanni
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Pierre
authors.initials: P
authors.lastname: Billuart
authors.forename: Tommaso
authors.initials: T
authors.lastname: Tartaglione
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Tabolacci
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancaccio
authors.forename: Giovanni
authors.initials: G
authors.lastname: Neri
authors.forename: Pietro
authors.initials: P
authors.lastname: Chiurazzi
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000235:genetics*; D001483:Base Sequence; D002531:Cerebellum / Q000002:abnormalities* / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D050172:Genes, X-Linked; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
chemical_list: D000596:Amino Acids; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C111952:OPHN1 protein, human