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Homozygotes carrying an autosomal dominant TIGR mutation do not manifest glaucoma

Nature Genetics volume 19, pages 319–321 (1998)Cite this article

Autosomal dominant disorders typically result in more severe clinical manifestations in mutant homozygotes than in heterozygotes1. Huntington disease is the only reported non-neoplastic human pathology in which no phenotypic variance has been detected between these two types of carriers, and where the mutant allele is truly dominant over its wild-type counterpart2. Primary open-angle glaucoma (POAG), a leading cause of blindness worldwide, is characterized by progressive degeneration of the optic nerve and is usually associated with intraocular hypertension3 (OHT). Several loci involved in glaucoma have been localized4,5. Recently, mutations in the trabecular meshwork-inducible glucocorticoid response (TIGR) gene, also known as myocilin6, mapping to the GLC1A locus at 1q23-q25, were identified in families affected by autosomal dominant POAG (refs 7, 8, 9, 10). We investigated a French-Canadian family, pedigree GV-001, in which POAG was transmitted as an autosomal dominant trait linked to the GLC1A locus11. The large size of this kindred and its relative isolation in eastern Québec allowed us to assess the effects of a TIGR mutation present in double dosage in four adult homozygotes. These individuals were asymptomatic for the disorder, with POAG affecting only the heterozygotes.

It was expected that these siblings would carry two wild-type copies of TIGR in a proportion of approximately 25%, and approximately 75% would harbour at least one mutant allele. It was also anticipated that a high proportion of these adults would be affected. Phenotypic evaluation showed only two sibs to be affected: son VI-3 and daughter VI-4 (Fig. 1a). The other eight sibs displayed normal eye structure and function. Examination of the grandchildren revealed that brothers VII-4 and VII-5 were also affected (Fig. 1a).

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Figure 1: Phenotype/genotype correlation studies of the K423E TIGR mutation in pedigree GV-001.
Figure 2: Characterization of a carrier homozygous for the K423E TIGR mutation.

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Acknowledgements

We are grateful to the family members for their participation. We thank M.-F. M. and B.B. for their assistance, G. Cantin for pedigree reconstruction and D. Arbour, J. Bergeron, S. Lahoud and J.-P. Leblanc for contributing clinical information. We acknowledge C. Lemay and F. Simard of the CHUL Eye Bank for their generous contribution. This work was supported by the Medical Research Council of Canada, The Glaucoma Research Foundation and the National Institutes of Health. S. M. was supported by an MRC studentship. P.F. and V.R. were, respectively, 'chercheur-boursier' and 'chercheur-boursier clinicien' of the Fonds de la Recherche en Santé du Québec.

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Authors and Affiliations

  1. Laboratory of Molecular Endocrinology, Centre Hospitalier de l'Université Laval (CHUL), Research Center, T3-67, 2705 Laurier Blvd., Québec City, G1V 4G2, Province of Québec, Canada

    Jean Morissette, Steve Moisan, Stéphane Dubois, Eric Winstall, Diana Vermeeren, Micheline Plante & Vincent Raymond

  2. Généthon, 1 rue de l'Internationale , Evry, 91000, France

    Christian Clépet

  3. Department of Ophthalmology, Cellular Pharmacology and Molecular Biology Laboratories, University of California at San Francisco Medical Center, San Francisco, 94143-0730, California, USA

    Thai Nguyen & Jon Polansky

  4. Department of Ophthalmology, Université Laval and St.-Sacrement Hospital, Québec City, G1S 4L8, Québec, Canada

    Gilles Côté & Jean-Louis Anctil

  5. Department of Ophthalmology, Université de Montréal and Maisonneuve-Rosemont Hospital, Montréal, H1T 2M4, Québec, Canada

    Marcel Amyot

  6. Neuroscience Research Unit, CHUL Research Center, Québec City, G1V 4G2, Province of Québec, Canada

    Pierre Falardeau

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Correspondence to Vincent Raymond.

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Morissette, J., Clépet, C., Moisan, S. et al. Homozygotes carrying an autosomal dominant TIGR mutation do not manifest glaucoma. Nat Genet 19, 319–321 (1998). https://doi.org/10.1038/1203

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