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D. Rivera, J. C. Zenteno; A New GJA1 (Connexin 43) Mutation Causing Oculodentodigital Dysplasia Associated to Novel Features. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1325.
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© ARVO (1962-2015); The Authors (2016-present)
Oculodentodigital Dysplasia (ODDD) is an autosomal dominant syndrome characterized by facial (hypoplastic alae nasi, prominent collumela, and thin anteverted nares), ocular (microcornea, microftalmia, glaucoma, cataract, iris anomalies), dental (microdontia, enamel hypoplasia, anodontia) and limb (syndactily of fingers and toes) abnormalities. ODDD is caused by mutations on the gene GJA1 (Gap Junction protein Alpha 1) that encodes for the protein Cx43 (Connexin 43). To date approximately 30 GJA1 mutations have been described in subjects with ODDD from different ethnic backgrounds but no clear genotype-phenotype correlation has been identified. Here we describe an eight year old Mexican boy with a novel GJA1 mutation.
The child presented congenital umbilical hernia, syndactyly of the 4th and 5th fingers in both hands as well as clinodactyly. At the age of 8 he was referred to our institute for decreased vision. At physical examination he presented hypoplastic alae nasi, anteverted nares, and narrow nasal bridge. On ophthalmoscopic examination he presented a best corrected visual acuity of 20/30 OD, 20/60 OS bilateral microcornea (10mm), optociliary veins and intraocular pressure of 14 mmHg OU. The 2 exons of GJA1 were amplified by PCR and directly sequenced in forward and reverse directions in DNA from the propositus and his parents. Forty six GJA1 alleles from 23 healthy Mexican mestizo subjects were included as controls.
A novel heterozygous transversion of G>T in the nucleotide 5 (5 G>T), which encoded for a missense mutation from glycine (GGT) to valine (GTT) in the second aminoacid (G2V) of Cx 43, was identified in DNA from the ODDD patient. Both parents were negative for the mutation. Familial biological relationship was confirmed by analyzing 9 unlinked single nucleotide polymorphisms (SNPs). The mutation was confirmed in the propositus using restriction analysis of the amplified PCR product since the 5G>T change abolishes a Tsp45I enzyme restriction site (5’-GTSAC-3’) located in the second GJA1 codon. Forty six control alleles tested negative for the mutation using restriction analysis.
The G2V mutation described here is the most amino terminal mutation described to date. Two novel ODDD associated features (umbilical hernia and optociliary veins) were recognized in this subject. These findings increase the already pleiotropic clinical spectrum of ODDD. We compare the phenotype of this patient with the phenotype of other ODDD patients with mutations in the same Cx 43 domain.
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