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Contribution of SNRNP200 Sequence Variations to Retinitis Pigmentosa

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Contribution of SNRNP200 Sequence Variations to Retinitis Pigmentosa Eye (2013) 27, 1204–1213 & 2013 Macmillan Publishers Limited All rights reserved 0950-222X/13 www.nature.com/eye 1 1 1 1 LABORATORY STUDY Contribution X Zhang , TYY Lai , SWY Chiang , POS Tam , DTL Liu1,2, CKM Chan1,3, CP Pang1,2, of SNRNP200 C Zhao4 and LJ Chen1,2 sequence variations to retinitis pigmentosa Abstract mutations in two respective patients affirmed that SNRNP200 contributes to a proportion Purpose Mutations in the SNRNP200 gene of overall RP. have been reported to cause autosomal Eye (2013) 27, 1204–1213; doi:10.1038/eye.2013.137; dominant retinitis pigmentosa (adRP). In this published online 26 July 2013 study, we evaluate the mutation profile of SNRNP200 in a cohort of southern Chinese 1Department of Keywords: retinitis pigmentosa; SNRNP200; RP patients. Ophthalmology and Visual mutation Sciences, The Chinese Methods Twenty adRP patients from University of Hong Kong, 11 families and 165 index patients with Hong Kong, China non-syndromic RP with mixed inheritance patterns were screened for mutations in the Introduction 2Department of mutation hotspots of SNRNP200. These Ophthalmology and Visual Retinitis pigmentosa (RP; MIM268000; included exons 12–16, 22–32, and 38–45, Sciences, Prince of Wales Mendelian Inheritance in Man; National Center Hospital, The Chinese which covered the two helicase ATP-binding for Biotechnology Information, Bethesda, MD, University of Hong Kong, domains in DEAD-box and two sec-63 USA) refers to a clinically and genetically Hong Kong, China domains. The targeted regions were diverse group of diffuse retinal dystrophies. amplified by polymerase chain reaction and 3Hong Kong Eye Hospital, The prevalence of RP is about 1/4000 to 1/6000 analyzed by direct DNA sequencing, Hong Kong, China in certain populations1–3 with no significant followed by in silico analyses. ethnic difference and affects more than 1 million 4 Results Totally 26 variants were identified, Department of individuals worldwide.4 Presenting symptoms Ophthalmology, Nanjing 18 of which were novel. Three non- of RP are various, but the typical ones include Medical University First synonymous variants (p.C502R, p.R1779H Affiliated Hospital, Nanjing, the following: (1) nyctalopia (night blindness) China and p.I698V) were found exclusively in as a hallmark, most commonly the earliest patients. Two of them, p.C502R and symptom in RP; (2) constricted visual fields, Correspondence: p.R1779H, were each identified in one usually peripheral, and even central visual loss LJ Chen, Department of simplex RP patient, whereas p.I698V occurred in advanced cases; and (3) photopsia (seeing Ophthalmology and Visual in one patient with unknown inheritance 5 Sciences, The Chinese flashes of light). These symptoms usually occur 6 University of Hong Kong, pattern. All three residues are highly during the third decade, although they can Hong Kong Eye Hospital, conserved in SNRNP200 orthologs. occur earlier depending on the inheritance 147K Argyle Street, Nevertheless, only p.C502R and p.R1779H pattern.7 The fundus hallmarks include Kowloon, Hong Kong 852, were predicted to affect protein function by arteriolar attenuation, mid-peripheral China. in silico analyses, suggesting these two Tel: þ 852 39435810; perivascular bone-spicule pigmentation, Fax: þ 852 27159490. variants are likely to be disease-causing tessellated fundus appearance, and waxy disc E-mail: lijia_chen@ mutations. Notably, all mutations previously pallor.8 RP can occur as a simplex disorder cuhk.edu.hk identified in other study populations were without known family history (35–50%) or not detected in this study. inherit in autosomal dominant (ad) (10–30%), Received: 7 December 2012 Conclusions Our results reveal a distinct autosomal recessive (ar) (10–45%), and X-linked Accepted in revised form: 4,9 21 May 2013 mutation profile of the SNRNP200 gene in (xl) (0–15%) patterns. Also it may present as Published online: 26 July a southern Chinese cohort of RP patients. part of systemic disorders, which are usually 2013 The identification of two novel candidate autosomal recessive.10 SNRNP200 and RP X Zhang et al 1205 Genetically RP is a highly heterogeneous condition. sec-63-like domains remain unknown, the associations More than 60 RP genes have been identified, while 23, of the translocon and Brr2p with RNA–protein 36, and 3 genes were responsible for adRP, arRP, and complexes (the ribosome and spliceosome, respectively) xlRP, respectively (RetNet, the Retinal Information indicate that sec-63 may act as a ribosome receptor. Network, University of Texas Houston Health Science The two initially reported SNRNP200 mutations are both Center, Houston, TX, accessed on 22 November 2012). located in the first sec-63 domain, suggesting this domain Despite this large number of genes, the vast majority was could be a mutation hotspot in individuals of Chinese mapped in populations other than Chinese. Up to date descent. Further, the contribution of SNRNP200 to RP has no single gene or mutation contributes to a large also been investigated in a group of Americans with proportion of RP in Chinese has been reported,11–19 mixed descent.32 The p.S1087L was also identified in this as does p.P23H of rhodopsin (RHO, MIM 180380) in study, along with another three disease-causing Caucasians. The RP33 locus, initially mapped to mutations (DCM), p.R681C, p.R681H, and p.Y689C. chromosomal region 2cen-q12.1, was identified in a large Besides, a new mutation p.Q885E was recently identified Chinese family with adRP.20 Subsequent studies had in another four generations of Chinese family.33 All four identified two mutations, p.S1087L21 and p.R1090L,22 mutations (p.R681C, p.R681H, p.Y689C, and p.Q885E) in the small nuclear ribonucleoprotein 200 kDa (U5) are located in the first DEAD-box of SNRNP200. (SNRNP200, MIM 601664) gene to be segregated with In this study, we screened the regions containing all the RP in two respective large Chinese adRP families. DEAD-box and sec-63 domains in SNRNP200 that may SNRNP200 is a member of the RNA intron-splicing factor cover the mutation hotspots in a southern Chinese cohort protein family and is widely expressed in human tissues. of 185 RP patients and 178 control subjects in order It encodes a U5 small nuclear ribonucleoprotein 200 kDa to further evaluate the contributions of SNRNP200 helicase, which is a 2136-amino acid splice-complex in Chinese RP. enzyme containing two pairs of DEAD-box, each followed by a Secretory(sec)-63 domain. DEAD-box Materials and methods proteins are ubiquitous enzymes that use ATP to Study subjects rearrange RNA and RNA–protein structures. They consist of a helicase core containing 12 conserved motifs Twenty adRP patients from 11 families and 165 unrelated involved in ATP binding, RNA binding, and ATP non-syndromic RP patients were recruited from the hydrolysis.23 They all possess an ATPase activity that Hong Kong Eye Hospital and the Prince of Wales is stimulated by RNA, giving rise to a broad range of Hospital, Hong Kong. All were Han Chinese. The biochemical effects in vitro. Thus, they can often unwind diagnosis was based upon typical RP presentations short RNA duplexes. This property, together with their according to ocular examinations that included slit-lamp structural similarity to the well-characterized DNA biomicroscopy, full-field electroretinography, visual helicases, has led to their common designation as ‘RNA fields, and fundus photography. Besides, best-corrected helicases.’ However, they also can displace RNA-bound visual acuity (BCVA) and intraocular pressure as proteins, accelerate RNA strand annealing or RNA assessed by applanation tonometry were recorded. folding, and act as RNA clamps to form stable Patients with syndromic RP, such as Bardet-Biedl ribonucleoprotein (RNP) complexes.23 In yeast, the sec-63 syndrome and Usher syndrome, or end-stage syphilitic domain is required to reconstitute post-translational neuroretinitis, and cancer-associated retinopathy were translocation in protoliposomes.24 Yeast BiP/Kar2p binds excluded. A group of 178 unrelated healthy control to a DnaJ domain of sec-63 and mediates the import of subjects, aged above 60 years, were also recruited. They polypeptides into the endoplasmic reticulum (ER) were given complete ophthalmic examinations and lumen25 and the export of misfolded proteins into the confirmed free of RP or other major eye diseases except cytoplasm.26 The DnaJ domain of sec-63 is known to face for mild senile cataract. This study was approved by the ER lumen.27 The large cytoplasmic portion of sec-63 the Ethics Committee on Human Research, the Chinese has no known homolog in other proteins. Sequence University of Hong Kong. Informed consents were analysis demonstrated significant similarity between this obtained from all study subjects. All procedures region and two regions of the helicases family typified by were conducted in accordance with the tenets yeast Brr2p and human U5-200 kD.28,29 These RNA of the Declaration of Helsinki. helicases contain two sec63-like domains, each lying C-terminal to an ATPase domain. The Brr2p N-terminal Mutational screening of the SNRNP200 gene ATPase domain is essential for in vitro RNA unwinding in U4/U6 small ribonucleoprotein particles In order to evaluate the contribution of the potentially (snRNPs).30,31 Although the functions of the helicase mutation hotspots in SNRNP200, we screened 24 exons Eye SNRNP200 and RP X Zhang et al 1206 of the gene, including exons 12–16, 22–32, and 38–45, in (GI: 40217847) was used with default parameter setting. all the study subjects. Exons 12–15 and exons 30–32 cover The specific amino-acid location in the protein was the two helicase ATP-binding domains, whereas exon compared among various organisms from pre-computed 16 covers the first connection of the helicase ATP-binding NCBI BLAST searches. The output score represented a domain and the helicase CTER, which could be the normalized probability for how the amino-acid hotspot in Americans.32 Exons 22–29 and exons 38–45 substitution was tolerated.
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