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Molecular study of the MFRP gene in patients with posterior microphthalmia (MCOP) supports its role in autosomal recessive MCOP pathogenesis
Author(s) -
Almoallem B.,
Arno G.,
De Zaeytijd J.,
Hull S.,
Suzani M.,
de Ravel T.J.L.,
Webster A.,
Leroy B.P.,
Moore T.,
De Baere E.
Publication year - 2016
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/j.1755-3768.2016.0470
Subject(s) - frameshift mutation , missense mutation , genetics , microphthalmia , nonsense mutation , compound heterozygosity , biology , disease gene identification , mutation , sanger sequencing , medicine , gene , exome sequencing
Purpose Posterior microphthalmia (MCOP) is a rare developmental disease restricted to the posterior segment of the eye. To date, mutations in the MFRP gene, encoding a frizzled‐related protein, reported in autosomal recessive MCOP (arMCOP).Here, we aimed to identify the genetic cause of arMCOP in seven patients from different ethnicity. Methods All patients underwent detailed ophthalmological evaluations and Sanger sequencing of the of MFRP (NM_031433.2). Two patients originating from a consanguineous marriage underwent homozygosity mapping using SNP arrays. Results MFRP was found in a homozygous region of 10.2 and 6.2 Mb in two patients respectively. Overall, eight distinct MFRP mutations were found in the patients studied. Five patients were homozygous for:two missense variants with predicted pathogenic effect (c.1231T > C, novel;c.1549C > T, known) and three frameshift mutations (c.1090_1094del, novel; c.498del and c.498dup, known). Moreover, a sixth patient was compound heterozygous for a nonsense mutation (c.955C > T, novel) and novel deletion of 6.2 kb (c.16088_54+40delinsA),predicted to abolish the transcription initiation site. The seventh patient was heterozygous for a known frameshift mutation (c.491_492insT),no second mutation was found so far. All patients had short axial length (13–16.5 mm),reduced visual acuity (0.15–0.8 logMAR) and hyperopia (+13D to +17.25D).Crowded optic discs were noticed in 7/7 and macular folds in 3/7 patients. Optical coherence tomography showed intraretinal cysts in 5/7 patients. Peripheral pigmentary changes were observed in 5/7 patients. Conclusions Eight distinct MFRP mutations four of which novel and the first report of a genomic rearrangement. No clear genotype‐phenotype correlations could be observed. This identification might offer opportunities for potential gene‐based therapies suggested by Dinculescu et al (2012).