Molecular study of the MFRP gene in patients with posterior microphthalmia (MCOP) supports its role in autosomal recessive MCOP pathogenesis

Abstract

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, have been reported in autosomal recessive MCOP (arMCOP), often found in consanguineous families. Here, we aimed to identify the underlying genetic cause of arMCOP in seven unrelated patients from different ethnic origins.

Methods : All patients underwent detailed ophthalmological evaluations and Sanger sequencing of the coding region of MFRP (NM_031433.2). Two patients originating from a consanguineous marriage underwent homozygosity mapping using SNP arrays.

Results : In the patients who underwent homozygosity mapping MFRP was found in a homozygous region of 10.2 and 6.2 Mb respectively. Overall, eight distinct MFRP mutations were found in the patients studied. Five patients were homozygous for an MFRP mutation: two missense variants with predicted pathogenic effect (c.1231T>C p.Y411H, novel; c.1549C>T p.R517W, known) and three frameshift mutations (c.1090_1094del p.T364*, novel; c.498del p.N167T*25 and c.498dup p.N167fs*, known). Moreover, a sixth patient was compound heterozygous for a nonsense mutation (c.955C>T p.Q319*, novel) and novel deletion of 6,2 kb (c.1-6088_54+40delinsA), predicted to abolish the transcription initiation site. The seventh patient was heterozygous for a known frameshift mutation (c.491_492insT p.N167Qfs*34), 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. Sight threatening complications such as angle closure glaucoma were seen in one patient.

Conclusions : Eight distinct MFRP mutations were identified in all patients studied. Four of these mutations were novel, including a genomic rearrangement, reported here for the first time. No clear genotype-phenotype correlations could be observed. A recent report by Dinculescu et al (2012) suggested that MFRP-associated retinal dystrophy might be a target for gene therapy. The identification of new families with MFRP mutations might offer opportunities for potential gene-based therapies.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.