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Akiko Suga, Yuichi Kawamura, Kazutoshi Yoshitake, Kazushige Tsunoda, Akira Murakami, Takeshi Iwata; Novel mutation in LRRTM4 is associated with dominantly inherited macular dystrophy with reduced ON-bipolar cell response. Invest. Ophthalmol. Vis. Sci. 2018;59(9):6076.
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© ARVO (1962-2015); The Authors (2016-present)
Inherited macular dystrophy contains heterozygous group of diseases with number of causal genes. The effect of each gene mutation to macular function is still largely in question. We identified a novel candidate causal gene mutation from a three generation Japanese family affected by macular dystrophy, and performed in vitro and in vivo analyses to understand the pathological process at molecular level.
Four affected and one unaffected member of a Japanese family with dominantly inherited macular dystrophy were clinically investigated. Genomes of four affected and four unaffected family members were extracted and analyzed by whole exome sequencing (WES) using HiSeq 4000 (Illumina). Reads were mapped to the reference human genome (hs37d5). Candidate causal gene mutations were selected according to the snpEff score and the allele frequence in the 1,000 Genomes database, ExAC database, HGVD, and our in-house database. Causal gene expression in the retina was examined by RT-PCR and immunohistochemistry. Knock in mouse model was generated by CRISPR/Cas9 system. Synaptic marker expressions were tested by immunohistochemistry.
Patients were first assessed at the ages of 5 years to 56 years. Their visual acuity was 0.03 to 0.1. Fundus images and OCT images revealed macular degeneration in patients. Whole-field ERG showed remaining photoreceptor response probably from the peripheral retina, though, ON-type rod bipolar response was remarkably reduced. WES analyses identified a novel mutation in LRRTM4 (p.C538Y; NP_001128217.1 ), as a candidate mutation for macular dystrophy. LRRTM4 mRNA and protein expressions increased during the period corresponding to the retinal synaptogenesis. LRRTM4 protein was detected in the dendritic tips of ON-type rod bipolar cells in the matured retina.
Rare allele frequency and gene expression patterns suggested that a mutation in the post-synaptic gene, LRRTM4, was associated with macular dystrophy with reduced ON-type rod bipolar cell response.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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