A 73,128 bp de novo deletion encompassing the OPN1LW/OPN1MW gene cluster in sporadic Blue Cone Monochromacy: a case report
Tóm tắt
Blue Cone Monochromacy (BCM) is a rare congenital cone dysfunction disorder with X-linked recessive mode of inheritance. BCM is caused by mutations at the OPN1LW/MW cone opsin gene cluster including deletions of the locus control region (LCR) and/or parts of the gene cluster. We aimed at investigating the clinical presentation, genetic cause and inheritance underlying a sporadic case of BCM. We report a 24-year-old male presenting with congenital photophobia, nystagmus and colour vision abnormalities. There was no history of retinal dystrophy in the family. Clinical diagnosis of BCM was supported by genetic investigations of the patient and his family members. Molecular genetic analysis of the OPN1LW/OPN1MW gene cluster revealed a novel deletion of about 73 kb in the patient encompassing the LCR. The deletion was absent in the X-chromosomes of both the mother and transmitting grandfather. The present report provides the clinical findings and the genetic basis underlying a sporadic BCM case which is caused by a de novo deletion within the OPN1LW/MW gene cluster originating from the mother’s germline due to Alu-repeat mediated recombination. This is the first report of a de novo deletion resulting in BCM, highlighting the importance to consider BCM and perform genetic testing for this condition in male patients with cone dysfunction also in the absence of a positive family history.
Tài liệu tham khảo
Nathans J, Davenport CM, Maumenee IH, Lewis RA, Hejtmancik JF, Litt M, et al. Molecular genetics of human blue cone monochromacy. Science. 1989;245(4920):831–8.
Winderickx J, Battisti L, Motulsky AG, Deeb SS. Selective expression of human X chromosome-linked green opsin genes. Proc Natl Acad Sci U S A. 1992;89(20):9710.
Nathans J, Maumenee IH, Zrenner E, Sadowski B, Sharpe LT, Lewis RA, et al. Genetic heterogeneity among blue-cone monochromats. Am J Hum Genet. 1993;53(5):987–1000.
Ayyagari R, Kakuk LE, Bingham EL, Szczesny JJ, Kemp J, Toda Y, et al. Spectrum of color gene deletions and phenotype in patients with blue cone monochromacy. Hum Genet. 2000;107(1):75–82.
Ayyagari R, Kakuk LE, Coats CL, Bingham EL, Toda Y, Felius J, et al. Bilateral macular atrophy in blue cone monochromacy (BCM) with loss of the locus control region (LCR) and part of the red pigment gene. Mol Vis. 1999;5:13.
Kellner U, Wissinger B, Tippmann S, Kohl S, Kraus H, Foerster MH. Blue cone monochromatism: clinical findings in patients with mutations in the red/green opsin gene cluster. Graefes Arch Clin Exp Ophthalmol. 2004;242(9):729–35.
Gardner JC, Liew G, Quan Y-H, Ermetal B, Ueyama H, Davidson AE, et al. Three different cone Opsin gene Array mutational mechanisms with genotype–phenotype correlation and functional investigation of cone Opsin variants. Hum Mutat. 2014;35(11):1354.
McCulloch DL, Marmor MF, Brigell MG, Hamilton R, Holder GE, Tzekov R, et al. ISCEV standard for full-field clinical electroretinography (2015 update). Doc Ophthalmol. 2015;130(1):1–12.
Cideciyan AV, Hufnagel RB, Carroll J, Sumaroka A, Luo X, Schwartz SB, et al. Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapy. Hum Gene Ther. 2013;24(12):993–1006.
Gisbert S, Schaeffel F. M to L cone ratios determine eye sizes and baseline refractions in chickens. Exp Eye Res. 2018;172:104–11.
Batzer MA, Deininger PL. Alu repeats and human genomic diversity. Nat Rev Genet. 2002;3(5):nrg798.
Liu GE, Alkan C, Jiang L, Zhao S, Eichler EE. Comparative analysis of Alu repeats in primate genomes. Genome Res. 2009;19(5):876.
Buena-Atienza E, Rüther K, Baumann B, Bergholz R, Birch D, Baere ED, et al. De novo intrachromosomal gene conversion from OPN1MW to OPN1LW in the male germline results in blue cone Monochromacy. Sci Rep. 2016;6:28253.