Zilin Zhong, Min Yan, Wan Sun, Zehua Wu, Liyun Han, Zheng Zhou, Fang Zheng, Jianjun Chen | Scientific Reports | 6 | 37840 | 25 November 2016 | https://doi.org/10.1038/srep37840
Abstract
Retinitis pigmentosa (RP) is a heterogeneous set of hereditary eye diseases, characterized by selective death of photoreceptor cells in the retina, resulting in progressive visual impairment. Approximately 20–40% of RP cases are autosomal dominant RP (adRP). In this study, a Chinese ADRP family previously localized to the region between D1S2819 and D1S2635 was sequenced via whole-exome sequencing and a variant c.1345C > G (p.R449G) was identified in PRPF3. The Sanger sequencing was performed in probands of additional 95 Chinese ADRP families to investigate the contribution of PRPF3 to adRP in Chinese population and another variant c.1532A > C (p.H511P) was detected in one family. These two variants, co-segregate with RP in two families respectively and both variants are predicted to be pathological. This is the first report about the spectrum of PRPF3 mutations in Chinese population, leading to the identification of two novel PRPF3 mutations. Only three clustered mutations in PRPF3 have been identified so far in several populations and all are in exon 11. Our study expands the spectrum of PRPF3 mutations in RP. We also demonstrate that PRPF3 mutations are responsible for 2.08% of adRP families in this cohort indicating that PRPF3 mutations might be relatively rare in Chinese ADRP patients.
Introduction
Retinitis pigmentosa (RP) refers to a heterogeneous set of hereditary retinal degenerative disorders which are responsible for the blindness of more than 1.5 million people worldwide and affect about 1 in 1000 people in China. RP is characterized by a selective death of photoreceptors that are light-sensing cells in the retina, resulting in progressive visual impairment1,2,3.There are three modes of Mendelian inheritance in RP—autosomal-dominant RP (adRP), autosomal-recessive RP (arRP), and X-linked RP (XLRP)1. Approximately 20–40% of RP cases are ADRP and mutations in over 20 genes are known to cause ADRP. Amongst ADRP causative genes are an unusual class— pre-mRNA splicing genes4— eight of which are ubiquitous core snRNP proteins (PRPF3, PRPF8, PRPF31, PRPF4, SNRNP200, and PRPF6) and splicing factors (RP9 and DHX38). Mutations in those genes ubiquitously expressed and essential for splicing, have so far been reported to cause a disease that displays retina-specific phenotype5.
PRPF3 (RP18, OMIM 601414) gene spans approximately 32 kb at chromosome 1q216, contains 16 exons and encodes a protein of 683 amino acids in length with a calculated molecular weight of 77 kDa7, which is a human homologue of the yeast U4/U6-associated splicing factor Prp3. Only three clustered PRPF3 mutations, c.1482C > T (p.T494M), c.1478C > T (p.P493S) and c.1466C > A (p.A489D), have been identified thus far in RP in several populations. The mutation T494M is the most frequently detected substitution in PRPF3 while P493S occurs rather sporadically5. All the mutations are in the exon11 (c.1427–1526) of PRPF3 and previous surveys failed to identify mutations outside of this exon. Therefore, only the region c.1427–1526 was screened for testing PRPF3 mutations in some reported studies8,9. In this work, we identified two novel PRPF3 mutations, c.1345C > G (p.R449G) and c.1532A > C (p.H511P), in two Chinese families with adRP. Furthermore, our study demonstrates that PRPF3 mutations are responsible for 2.08% of adRP families in our cohort indicating that PRPF3 mutation might be relatively rare in Chinese patients with adRP.
Clinical Evaluations of adRP Families
The pedigree of Family 020001 indicates a dominant inheritance pattern of three generations (Fig. 1). Medical history of all the affected individuals shows that early onset of night blindness is at age 4 to 10 years old, with subsequent loss of far peripheral vision after 20 years. Clinical details of that family were previously described10. Additional 95 Chinese families had a primary diagnosis of RP based on clinical descriptions provided by the referring clinicians at the time of enrollment. The inheritance pattern of those RP families is AD (Fig. 1).
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