Abstract
Objectives
Our aim was to determine the molecular cause of autosomal dominant familial retinal arteriolar tortuosity (FRAT) in a family with three affected subjects.
Material and methods
Ophthalmologic evaluation included determination of best-corrected visual acuity (BCVA), slit-lamp and dilated fundus inspection, applanation tonometry, fundus photography, and fluorescein retinal angiography (FA). Molecular methods included whole exome sequencing analysis and Sanger sequencing validation of putative causal mutation in DNA from affected individuals.
Results
Typical signs of familial retinal arteriolar tortuosity were observed in all three patients. Exome sequencing identified a heterozygous c.1528G > A (p. Gly510Arg) mutation in COL4A1. Sanger sequencing confirmed that all three patients harbored the same pathogenetic mutation in COL4A1. The p. Gly510Arg variant in COL4A1 was absent in DNA from an available unaffected daughter, from a set of control alleles, and from publicly available databases.
Conclusions
The molecular basis of familial retinal arteriolar tortuosity was identified for the first time, thus expanding the human phenotypes linked to COL4A1 mutations. Interestingly, the COL4A1 p.Gly510Arg mutation has been previously identified in a family with HANAC (Hereditary Angiopathy with Nephropathy, Aneurysm and Cramps), a multisystemic disease featuring retinal arteriolar tortuosity. No cerebral, neurologic, renal, cardiac or vascular anomalies were recognized in the pedigree described here. These data indicate that identical mutations in COL4A1 can originate both eye-restricted and systemic phenotypes.
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References
Beyer EM (1958) Familiare tortuositas der kleinen netzhautarterien mit makulablutung. Klin Monatsbl Augenheilkd 132:532–539
Goldberg MF, Pollack IP, Green WR (1972) Familial retinal arteriolar tortuosity with retinal hemorrhage. Am J Ophthalmol 73:183–191
Bartlett WJ, Price J (1983) Familial retinal arteriolar tortuosity with retinal hemorrhage. Am J Ophthalmol 95:556–558
Kayazawa F, Machida T (1983) Retinal arteriolar tortuosity with macular hemorrhage. Ann Ophthalmol 15:42–43
Clearkin IG, Rose H, Patterson A, Mody CH (1986) Development of retinal arteriolar tortuosity in previously unaffected family members. Trans Ophthalmol Soc U K 105:568–574
Sutter FK, Helbig H (2003) Familial retinal arteriolar tortuosity: a review. Surv Ophthalmol 48:245–255
Wells CG, Kalina RE (1985) Progressive inherited retinal arteriolar tortuosity with spontaneous retinal hemorrhages. Ophthalmology 92:1015–1024
Sears J, Gilman J, Sternberg P Jr (1998) Inherited retinal arteriolar tortuosity with retinal hemorrhages. Arch Ophthalmol 116:1185–1188
Desmettre T, Moreau JM, Plaisier E (2006) Autosomal dominant syndrome of retinal arterial tortuosity. J Fr Ophtalmol 29:e8
Seo JH, Kim I, Yu HG (2009) A case of carotid aneurysm in familial retinal arterial tortuosity. Korean J Ophthalmol 23:57–58
Ishizaki M, Westerhausen-Larson A, Kino J, Hayashi T, Kao WW (1993) Distribution of collagen IV in human ocular tissues. Invest Ophthalmol Vis Sci 34:2680–2689
Sarthy V (1993) Collagen IV mRNA expression during development of the mouse retina: an in situ hybridization study. Invest Ophthalmol Vis Sci 34:145–152
Qin P, Piechocki M, Lu S, Kurpakus MA (1997) Localization of basement membrane-associated protein isoforms during development of the ocular surface of mouse eye. Dev Dyn 209:367–376
Hann CR, Springett MJ, Wang X, Johnson DH (2001) Ultrastructural localization of collagen IV, fibronectin, and laminin in the trabecular meshwork of normal and glaucomatous eyes. Ophthalmic Res 33:314–324
Gould DB, Phalan FC, Breedveld GJ, van Mil SE, Smith RS, Schimenti JC, Aguglia U, van der Knaap MS, Heutink P, John SW (2005) Mutations in COL4A1 cause perinatal cerebral hemorrhage and porencephaly. Science 308:1167–1171
Breedveld G, de Coo IF, Lequin MH, Arts WF, Heutink P, Gould DB, John SW, Oostra B, Mancini GM (2006) Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. J Med Genet 43:490–495
Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, Bousser MG, Heutink P, Miner JH, Tournier-Lasserve E, John SW (2006) Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med 354:1489–1496
Lanfranconi S, Markus HS (2010) COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Stroke 41:e513–e518
Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M, Goizet C (2010) Ophthalmological features associated with COL4A1 mutations. Arch Ophthalmol 128:483–489
Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, Marro B, Desmettre T, Cohen SY, Roullet E, Dracon M, Fardeau M, Van Agtmael T, Kerjaschki D, Antignac C, Ronco P (2007) COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. N Engl J Med 357:2687–2695
Plaisier E, Alamowitch S, Gribouval O, Mougenot B, Gaudric A, Antignac C, Roullet E, Ronco P (2005) Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: A novel syndrome. Kidney Int 67:2354–2360
Labelle-Dumais C, Dilworth DJ, Harrington EP, de Leau M, Lyons D, Kabaeva Z, Manzini MC, Dobyns WB, Walsh CA, Michele DE, Gould DB (2011) COL4A1 mutations cause ocular dysgenesis, neuronal localization defects, and myopathy in mice and Walker-Warburg syndrome in humans. PLoS Genet 7:e1002062
Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P (2010) Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Am J Med Genet A 152A:2550–2555
Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, Ronco P (2009) Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Neurology 73:1873–1882
Persikov AV, Ramshaw JA, Brodsky B (2005) Prediction of collagen stability from amino acid sequence. J Biol Chem 280:19343–19349
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Financial support was provided by Mexican Research Council CONACYT Grant 169352.
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Juan C. Zenteno and Jaume Crespí Contributed equally to this work and should be considered equivalent first authors.
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Zenteno, J.C., Crespí, J., Buentello-Volante, B. et al. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. Graefes Arch Clin Exp Ophthalmol 252, 1789–1794 (2014). https://doi.org/10.1007/s00417-014-2800-6
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DOI: https://doi.org/10.1007/s00417-014-2800-6