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Editors Selection IGR 12-2
Basic research: Genetics: Myocilin gene dosage
Comment by Julie Richards on:
18060 Myocilin variants in Indian patients with open-angle glaucoma, Bhattacharjee A; Acharya M; Mukhopadhyay A et al., Archives of Ophthalmology, 2007; 125: 823-829
See also comment(s) by Ravi Thomas & Subhabrata Chakrabarti •Often one copy of a causative mutation in the myocilin (MYOC) primary open-angle glaucoma gene (POAG) appears to be enough to cause disease, but what happens when a second copy of a MYOC mutation is present? Bhattacharjee et al. (457) propose a MYOC disease model with earlier onset in homozygotes than in heterozygotes, based on two copies of MYOC Gly399Asp in a POAG case whoseunaffected parents each carry only one copy. MYOC gene dosage has been discussed before in studies of a Gln48His homozygote with congenital glaucoma,1 a Gly326Arg homozygote showing greater severity than the heterozygotes,2 and multiple individuals homozygous for the causative mutation Lys423Glu who are unaffected.3 Bhattacharjee and colleagues concede that Gly399Asp might not be causative and suggest investigating a digenic mechanism since POAG occurs earlier in the presence of Gly399Val if a CYP1B1 mutation is also present.4 They highlight Parkinson's disease in one POAG case with Ala427Thr, which may be co-incidental since Parkinson's disease is absent from seven other Ala427Thr individuals;5 although they provide no new data on the relationship between glaucoma and Parkinson s disease, their discussion of the published findings on γ-synuclein and MYOC is interesting in the context of a retrospective chart review reporting increased prevalence of glaucoma (23.7%) among individuals with Parkinson's disease.6 This work by Bhattacharjee and colleagues must be interpreted with caution because the association findings for individual sequence variants are not statistically significant and their gene dosage model is based on only a single case with two unaffected parents; however, this paper does add important new information on MYOC gene dosage, sequence variant prevalence, and clinical features to the growing body of information that has to be combined to be able to interpret findings for sequence variants too rare to classify based on individual studies.
References
- Chakrabarti S, Kaur K, Komatireddy S, Acharya M, Devi KR, Mukhopadhyay A, Mandal AK, Hasnain SE, Chandrasekhar G, Thomas R, Ray K. Gln48His is the prevalent myocilin mutation in primary open angle and primary congenital glaucoma phenotypes in India. Mol Vis 2005; 11: 111-3.
- Sarfarazi M, Chaterji R, Kocak-Midillioglu I, Kocak-Altintas A. Identification of a severely affected homozygote TIGR/MYOC mutation in a large family with Juvenile-Onset Primary Open Angle Glaucoma. IOVS 2007; 41: Abstract # 4362 Page S822.
- Morissette J, Clepet C, Moisan S, Dubois S, Winstall E, Vermeeren D, Nguyen TD, Polansky JR, Cote G, Anctil JL, Amyot M, Plante M, Falardeau P, Raymond V. Homozygotes carrying an autosomal dominant TIGR mutation do not manifest glaucoma. Nat Genet 1998; 19: 319-21.
- Vincent AL, Billingsley G, Buys Y, Levin AV, Priston M, Trope G, Williams-Lyn D, Heon E. Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene. Am J Hum Genet 2002; 70: 448-60.
- Faucher M, Anctil J-L, Rodrigue M-A, Duchesne A, Bergeron D, Blondeau P, Côté G, Dubois S, Bergeron J, Arseneault R, The Québec Glaucoma Network, Morissette J, Raymond V. Founder TIGR/myocilin mutations for glaucoma in the Québec population. Hum Mol Genet 2002; 11: 2077-90.
- Bayer AU, Keller ON, Ferrari F, Maag KP. Am J Ophthalmol: Association of glaucoma with neurodegenerative diseases with apoptotic cell death: Alzheimer's disease and Parkinson's disease. Am J Ophthalmol 2002; 133: 135-7.
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