Summary
Microglia are the resident immune cells of the central nervous system (CNS). They govern the immunogenicity of the retina, which is considered to be part of the CNS; however, it is not known how microglia develop in the eye. Here, we studied human-induced pluripotent stem cells (hiPSCs) that had been expanded into a self-formed ectodermal autonomous multi-zone (SEAM) of cells that partially mimics human eye development. Our results indicated that microglia-like cells, which have characteristics of yolk-sac-like linage cells, naturally develop in 2D eye-like SEAM organoids, which lack any vascular components. These cells are unique in that they are paired box protein 6 (PAX6)-positive, yet they possess some characteristics of mesoderm. Collectively, the data support the notion of the existence of an isolated, locally developing immune system in the eye, which is independent of the body’s vasculature and general immune system.
The genetic basis of Japanese autosomal recessive retinitis pigmentosa (ARRP) remains largely unknown. Herein, we applied a 2-step genome-wide association study (GWAS) in 640 Japanese patients. Meta-GWAS identified three independent peaks at P < 5.0 × 10−8, all within the major ARRP gene EYS. Two of the three were each in linkage disequilibrium with a different low frequency variant (allele frequency < 0.05); a known founder Mendelian mutation (c.4957dupA, p.S1653Kfs*2) and a non-synonymous variant (c.2528 G > A, p.G843E) of unknown significance. mRNA harboring c.2528 G > A failed to restore rhodopsin mislocalization induced by morpholino-mediated knockdown of eys in zebrafish, consistent with the variant being pathogenic. c.2528 G > A solved an additional 7.0% of Japanese ARRP cases. The third peak was in linkage disequilibrium with a common non-synonymous variant (c.7666 A > T, p.S2556C), possibly representing an unreported disease-susceptibility signal. GWAS successfully unraveled genetic causes of a rare monogenic disorder and identified a high frequency variant potentially linked to development of local genome therapeutics.
We identified a novel mutation of the tumor-associated calcium signal transducer 2 (TACSTD2) gene in a Japanese patient with gelatinous drop-like corneal dystrophy (GDLD). Genetic analysis revealed a novel homozygous mutation (c.798delG, which may result in frameshift mutation p.Lys267SerfsTer4) in the TACSTD2 gene. This mutated gene was devoid of its original function in helping the claudin (CLDN) 1 and 7 proteins transfer from the cytoplasm to the plasma membrane.
To uncover genetic basis of autosomal recessive retinitis pigmentosa (ARRP), we applied 2-step genome-wide association study (GWAS) in 640 Japanese patients prescreened with targeted re-sequencing. Meta-GWAS identified three independent peaks at P < 5.0x10 -8 , all within the major ARRP gene EYS. Two were each tagged by a low frequency variant (allele frequency < 0.05); a known founder Mendelian mutation (c.4957dupA, p.S1653Kfs*2) and a presumably hypomorphic non-synonymous variant (c.2528G>A, p.G843E). c.2528G>A newly solved 7.0% of Japanese ARRP cases, improving genetic diagnosis by 26.8% and simultaneously serving as a new attractive target for genome editing gene therapy. The third peak was tagged by an intronic common variant, representing a novel disease-susceptibility signal. GWAS successfully unraveled genetic causes of a rare "monogenic" disorder for the first time, which provided unexpected insights into significant KMN designed the overall study.
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