Mutations in the Genes for Interphotoreceptor Matrix Proteoglycans, IMPG1 and IMPG2, in Patients with Vitelliform Macular Lesions
1
Klinik und Poliklinik für Augenheilkunde, Universitätsklinikum Regensburg, 93053 Regensburg, Germany
2
Institut für Humangenetik, Universität Regensburg, 93053 Regensburg, Germany
3
Lehrstuhl für Genetische Epidemiologie, Universität Regensburg, 93053 Regensburg, Germany
4
Department of Ophthalmology, University of Bonn, 53113 Bonn, Germany
5
Oxford Eye Hospital, OUH NHS Foundation Trust and the Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford, Oxford OX1 3BD, UK
6
Klinik für Augenheilkunde, Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany
7
Klinik für Augenheilkunde, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert Ludwigs Universität Freiburg, 79085 Freiburg, Germany
8
Klinik für Augenheilkunde, Universitätsklinikum Köln, 50937 Köln, Germany
9
Forschungsinstitut für Augenheilkunde, Universitätsklinikum Tübingen, 72076 Tübingen, Germany
*
Author to whom correspondence should be addressed.
Genes 2017, 8(7), 170; https://doi.org/10.3390/genes8070170
Received: 19 May 2017 / Revised: 20 June 2017 / Accepted: 20 June 2017 / Published: 23 June 2017
(This article belongs to the Special Issue Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations and Inheritance Models)
A significant portion of patients diagnosed with vitelliform macular dystrophy (VMD) do not carry causative mutations in the classic VMD genes BEST1 or PRPH2. We therefore performed a mutational screen in a cohort of 106 BEST1/PRPH2-negative VMD patients in two genes encoding secreted interphotoreceptor matrix proteoglycans-1 and -2 (IMPG1 and IMPG2). We identified two novel mutations in IMPG1 in two simplex VMD cases with disease onset in their early childhood, a heterozygous p.(Leu238Pro) missense mutation and a homozygous c.807 + 5G > A splice site mutation. The latter induced partial skipping of exon 7 of IMPG1 in an in vitro splicing assay. Furthermore, we found heterozygous mutations including three stop [p.(Glu226*), p.(Ser522*), p.(Gln856*)] and five missense mutations [p.(Ala243Pro), p.(Gly1008Asp), p.(Phe1016Ser), p.(Tyr1042Cys), p.(Cys1077Phe)] in the IMPG2 gene, one of them, p.(Cys1077Phe), previously associated with VMD. Asymptomatic carriers of the p.(Ala243Pro) and p.(Cys1077Phe) mutations show subtle foveal irregularities that could characterize a subclinical stage of disease. Taken together, our results provide further evidence for an involvement of dominant and recessive mutations in IMPG1 and IMPG2 in VMD pathology. There is a remarkable similarity in the clinical appearance of mutation carriers, presenting with bilateral, central, dome-shaped foveal accumulation of yellowish material with preserved integrity of the retinal pigment epithelium (RPE). Clinical symptoms tend to be more severe for IMPG1 mutations.
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Keywords:
vitelliform macular dystrophy; IMPG1; IMPG2; interphotoreceptor matrix; optical coherence tomography
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
MDPI and ACS Style
Brandl, C.; Schulz, H.L.; Charbel Issa, P.; Birtel, J.; Bergholz, R.; Lange, C.; Dahlke, C.; Zobor, D.; Weber, B.H.F.; Stöhr, H. Mutations in the Genes for Interphotoreceptor Matrix Proteoglycans, IMPG1 and IMPG2, in Patients with Vitelliform Macular Lesions. Genes 2017, 8, 170.
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