title: Three novel GJA1 missense substitutions resulting in oculo-dento-digital dysplasia (ODDD) - further extension of the mutational spectrum.
abstract: Oculodentodigital dysplasia (ODDD) is a clinically variable genetic disorder caused by mutations of the GJA1 gene, predominantly inherited in an autosomal dominant fashion. In rare cases ODDD can also exhibit autosomal recessive mode of inheritance. The phenotype of ODDD comprises craniofacial (short and narrow palpebral fissure, thin, narrow nose with hypoplastic alae nasi), dental (oligodontia, hypoplastic enamel), and digital abnormalities (syndactyly of finger 4/5, hypoplastic phalanges). Ocular manifestation is typical and involves microphthalmia, microcornea, glaucoma, congenital malformations of iris or vitreous, ectopic pupils or strabismus. To date, only 67 GJA1 mutations have been described to underlie ODDD and most of them (i.e. 97%) represent missense substitutions. In this report, we describe three (two familial and one sporadic) non-consanguineous cases presenting with ODDD features in whom we identified novel missense heterozygous mutations of the GJA1 gene: c.317T>G (p. L106R), c.G139C (p.D47H), and c.C257A (p.S86Y). The first two mutations were inherited from an affected parent, whereas the latter one occurred de novo. The mutations affect highly conserved amino acid residues located in the different portions of the GJA1 protein. Our report broadens the spectrum of probably pathogenic mutations associated with ODDD phenotype and demonstrates that the amino acid substitutions at highly conserved positions 47, 86, 106 may affect protein functioning and lead to the development of this syndrome. Together with molecular data, we provide a brief clinical description of the affected individuals.
authors: Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland; NZOZ Center for Medical Genetics GENESIS, Poznan, Poland. Electronic address: jamsheer@wp.pl.
authors: Aleksander
authors: A
authors: Jamsheer
authors: Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.
authors: Anna
authors: A
authors: Sowińska-Seidler
authors: Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.
authors: Magdalena
authors: M
authors: Socha
authors: Department of Genetics, Wroclaw Medical University, Wroclaw, Poland.
authors: Agnieszka
authors: A
authors: Stembalska
authors: Genetic Services of Western Australia, King Edward Memorial Hospital for Women, Subiaco, Australia.
authors: Cathy
authors: C
authors: Kiraly-Borri
authors: Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland; NZOZ Center for Medical Genetics GENESIS, Poznan, Poland.
authors: Anna
authors: A
authors: Latos-Bieleńska
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D002675:Child, Preschool; D018031:Connexin 43 / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000235:genetics*; D005124:Eye Abnormalities / Q000235:genetics*; D019066:Facies; D005260:Female; D005385:Fingers / Q000002:abnormalities; D005532:Foot Deformities, Congenital / Q000235:genetics*; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D017422:Sequence Analysis, DNA; D013576:Syndactyly / Q000235:genetics*; D014071:Tooth Abnormalities / Q000235:genetics*
chemical_list: D018031:Connexin 43; C500216:GJA1 protein, human
keywords: Connexin 43; GJA1; Missense mutation; ODDD; ODDS; Oculo-dento-digital dysplasia; Oculo-dento-osseous syndrome