Abstract
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.
Highlights
The interphotoreceptor matrix proteoglycans-1 and -2, known as sialoprotein associated with cones and rods (SPACR) and SPACRCAN, respectively, are large glycosylated protein components of the insoluble interphotoreceptor matrix (IPM) [1]
The study included a total of 106 patients with suspected vitelliform macular dystrophy (VMD) or adult-onset VMD (AVMD) who underwent routine genetic testing at the Institute of Human Genetics Regensburg and which were tested negative for mutations in the coding exons/flanking intronic sequences of BEST1 and PRPH2
In this study we have identified a series of novel mutations in the IMPG1/IMPG2 genes and provide supportive evidence for their causativity in the development of vitelliform macular dystrophy
Summary
The interphotoreceptor matrix proteoglycans-1 and -2, known as sialoprotein associated with cones and rods (SPACR) and SPACRCAN (a proteoglyCan related to SPACR), respectively, are large glycosylated protein components of the insoluble interphotoreceptor matrix (IPM) [1]. First evidence for an involvement of the interphotoreceptor matrix proteoglycans in the etiology of retinal degenerative disease was given when the heterozygous c.1736T > C/p.(Leu579Pro) mutation in the IMPG1 gene was shown to cause autosomal dominant benign concentric annular macular dystrophy (BCAMD) in a Dutch family [4]. This phenotype is characterized by an initial parafoveal hypopigmentation and good visual acuity which progresses to a retinitis pigmentosa-like manifestation. The RP phenotype is frequently accompanied by early macular abnormalities, ranging from minor pigment alterations to profound chorioretinal atrophy [6]
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