Abstract
Purpose
To characterize the ophthalmic findings, intrafamilial variability, and molecular genetic basis of oculodentodigital dysplasia (ODDD; MIM no. 164200).
Methods
Ophthalmic examination included best-corrected visual acuity, slit-lamp biomicroscopy, direct and indirect ophthalmoscopy, Goldmann applanation tonometry and A-scan ultrasonography. Blood samples were taken for DNA extraction and mutation screening of GJA1 (connexin 43).
Results
All three affected individuals had characteristic features of ODDD. The ophthalmic features were epicanthus, microcornea, and the presence of glaucoma. The ocular phenotype resulted from a heterozygous T>C transition at nucleotide 338 in GJA1 (L113P) that was not detected in 120 chromosomes of unaffected individuals. The L113P mutation results in a nonconservative substitution in the cytoplasmic loop of Cx43 (GJA1) and is predicted to disrupt the high-order structure of Cx43.
Conclusions
This report describes the ocular phenotype in a molecularly characterized ODDD syndrome family. The ocular features in this family highlight the key role Cx43 plays in eye development and in the development of glaucoma. L113P represents a pathogenic mutation in GJA1 (Cx43) and results in ODDD with marked intrafamilial variation in glaucoma type and severity.
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References
Meyer-Schwickerath G, Gruterich E, Weyers H . Mikrophthalmussyndrome. Klin Mbl Augenheilk 1957; 131: 18–30.
Paznekas WA, Boyadjiev SA, Shapiro RE, Daniels O, Wollnik B, Keegan CE et al. Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am J Hum Genet 2003; 72 (2): 408–418.
Traboulsi EI, Parks MM . Glaucoma in oculo-dento-osseous dysplasia. Am J Ophthalmol 1990; 109: 310–313.
Gladwin A, Donnai D, Metcalfe K, Schrander-Stumpel C, Brueton L, Verloes A et al. Localization of a gene for oculodentodigital syndrome to human chromosome 6q22-q24. Hum Mol Genet 1997; 6: 123–127.
Richardson R, Donnai D, Meire F, Dixon MJ . Expression of Gja1 correlates with the phenotype observed in oculodentodigital syndrome/type III syndactyly. J Med Genet 2004; 41: 60–67.
Weiss AH, Kousseff BG, Ross EA, Longbottom J . Simple microphthalmos. Arch Ophthalmol 1989; 107: 1625–1630.
Warburg M . Classification of microphthalmos and coloboma. J Med Genet 1993; 30: 664–669.
Kaye SB, Rao P . Developmental abnormalities of the cornea and anterior segment. In: Easty DL, Sparrow JM (eds). Oxford Textbook of Ophthalmology, 1st ed. Oxford University Press: Oxford, UK, 1999.
Dollfus H, Verloes A . Dysmorphology and the orbital region: a practical clinical approach. Surf Ophthalmol 2004; 49 (6): 547–561.
Frasson M, Calixto N, Cronemberger S, de Aguiar RA, Leao LL, de Aguiar MJ . Oculodentodigital dysplasia: study of ophthalmological and clinical manifestations in three boys with probably autosomal recessive inheritance. Ophthalmic Genet 2004; 25 (3): 227–236.
Joss SK, Ghazawy S, Tomkins S, Ahmed M, Bradbury J, Sheridan E . Variable expression of neurological phenotype in autosomal recessive oculodentodigital dysplasia of two sibs and review of the literature. Eur J Pediatr 2008; 167 (3): 341–345.
Pizzuti A, Flex E, Mingarelli R, Salpietro C, Zelante L, Dallapiccola B . A homozygous GJA1 gene mutation causes a Hallermann-Streiff/ODDD spectrum phenotype. Hum Mutat 2004; 23 (3): 286.
Richard G, Rouan F, Willoughby CE, Brown N, Chung P, Ryyanen M et al. Missense mutations in the GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome. Am J Hum Genet 2002; 70 (5): 1341–1348.
Lamartine J, Munhoz Essenfelder G, Kibar Z, Lanneluc I, Callouet E, Laoudj D et al. Mutations in GJB6 cause hidrotic ectodermal dysplasia. Nat Genet 2000; 26: 142–144.
Bruzzone R, White TW, Paul DL . Connections with connexins—the molecular basis of direct intercellular signalling. Eur J Biochem 1996; 238: 1–27.
Simon AM, Goodenough DA . Diverse functions of vertebrate gap junctions. Trends Cell Biol 1998; 8: 477–483.
Bevans CG, Kordel M, Rhee SK, Harris AL . Isoform composition of connexin channels determines selectivity among second messengers and uncharged molecules. J Biol Chem 1998; 273: 2808–2816.
Pizzuti A, Flex E, Mingarelli R, Salpietro C, Zelante L, Dallapiccola B . A homozygous GJA1 gene mutation causes a Hallermann-Streiff/ODDD spectrum phenotype. Hum Mutat 2004; 23: 286.
van Steensel MA, Spruijt L, van der Burgt I, Bladergroen RS, Vermeer M, Steijlen PM et al. A 2-bp deletion in the GJA1 gene is associated with oculo-dento-digital dysplasia with palmoplantar keratoderma. Am J Med Genet A 2005; 132: 171–174.
Kjaer KW, Hansen L, Eiberg H, Leicht P, Opitz JM, Tommerup N . Novel connexin 43 (GJA1) mutation causes oculo-dento-digital dysplasia with curly hair. Am J Med Genet 2004; 127A: 152–157.
Vitiello C, D'Adamo P, Gentile F, Vingolo EM, Gasparini P, Banfi S . A novel GJA1 mutation causes oculodentodigital dysplasia without syndactyly. Am J Med Genet A 2005; 133A: 58–60.
Shibayama J, Paznekas W, Seki A, Taffet S, Jabs EW, Delmar M et al. Functional characterization of connexin43 mutations found in patients with oculodentodigital dysplasia. Circ Res 2005; 96: 83–91.
Roscoe W, Veitch GIL, Gong X-Q, Pellegrino E, Bai D, McLachlan E et al. Oculodentodigital dysplasia-causing connexin43 mutants are non-functional and exhibit dominant effects on wild-type connexin43. J Biol Chem 2005; 280 (12): 11458–11466.
Willoughby CE, Arab S, Gandi R, Zeinal S, Arab S, Billingsley G et al. A novel R23T mutation in GJA8 encoding connexin 50 in an Iranian family with autosomal dominant congenital cataract. J Med Genet 2003; 40: e124.
Mackay D, Ionides A, Kibar Z, Rouleau G, Berry V, Moore A et al. Connexin 46 mutations in autosomal dominant congenital cataract. Am J Hum Genet 1999; 64: 1357–1364.
Shiels A, Mackay D, Ionides A, Berry V, Moore A, Bhattacharya S . A missense mutation in the human connexin 50 gene (GJA8) underlies autosomal dominant ‘zonular pulverulent’ cataract, on chromosome 1q. Am J Hum Genet 1998; 62: 526–532.
Berry V, Mackay D, Khaliq S, Francis PJ, Hameed A, Anwar K et al. Connexin 50 mutation in a family with congenital ‘zonular nuclear’ pulverulent cataract of Pakistani origin. Hum Genet 1999; 105: 168–170.
Sugar HS . Oculodentodigital dysplasia syndrome with angle-closure glaucoma. Am J Ophthalmol 1978; 86 (1): 36–38.
Vaney DI, Weiler R . Gap junctions in the eye: evidence for heteromeric, heterotypic and mixed-homotypic interactions. Brain Res Rev 2000; 32: 115–120.
Melo MB, Vasconcellos JP, Cella WP, Kneipp B, Rocha MN, Richeti F et al. Axenfeld–Rieger syndrome: coexistence of mutations in the FOXC1 and GJA1 genes. Invest Ophthalmol Vis Sci 2005; 46, E-Abstract 46.
Gould DB, John SW . Anterior segment dysgenesis and the developmental glaucomas are complex traits. Hum Mol Genet 2002; 11 (10): 1185–1193.
Polyakov AV, Shagina IA, Khlebnikova OV, Evgrafov OV . Mutation in the connexin 50 gene (GJA8) in a Russian family with zonular pulverulent cataract. Clin Genet 2001; 60: 476–478.
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This study was supported by Financial Support—British Medical Association.
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Musa, F., Ratajczak, P., Sahu, J. et al. Ocular manifestations in oculodentodigital dysplasia resulting from a heterozygous missense mutation (L113P) in GJA1 (connexin 43). Eye 23, 549–555 (2009). https://doi.org/10.1038/eye.2008.77
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DOI: https://doi.org/10.1038/eye.2008.77
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