Skip to main content

Advertisement

SpringerLink
Log in

A novel mutation in the PRPF31 in a North Indian adRP family with incomplete penetrance

Documenta Ophthalmologica Aims and scope Submit manuscript

Abstract

Purpose

To identify the underlying genetic defect for non-syndromic autosomal dominant retinitis pigmentosa (adRP) with incomplete penetrance in a North Indian family.

Methods

Family history and clinical data were collected. Linkage analysis using 72 fluorescently labeled microsatellite markers flanking all the 26 candidate genes known for adRP was performed. Mutation screening in candidate gene at the mapped region was performed by bi-directional DNA sequencing.

Results

Positive two-point lod scores > 1.0 (θ = 0.000) suggestive of linkage were obtained with markers D19S572, D19S927 and D19S926 at 19q13.42, in the vicinity of PRPF31 gene. Mutation screening in all the 14 exonic regions and intron–exon boundaries of PRPF31 revealed a novel change, i.e. c.896G>A (p.Cys299Tyr) in exon eight. The observed change segregated in heterozygous form in all the six affected members and in three carriers, consistent with incomplete penetrance. This substitution was not observed in tested 15 unaffected members and in 200 ethnically matched controls.

Conclusion

Present study describes mapping of a locus for non-syndromic adRP with incomplete penetrance at 19q13.42 in a North Indian family and identifies a novel missense mutation (p.Cys299Tyr) in PRPF31 localized at the mapped interval. The observed substitution lies in the NOP domain of PRPF31 that exhibit RNA and protein binding surfaces and thus may interfere in the formation of spliceosome complex. Due to p.Cys299Tyr substitution hydrogen bonds are generated, which may result in conformational changes and PRPF31 protein deformity. Present findings further substantiate the role of PRPF31 in adRP with incomplete penetrance and expand the mutation spectrum of PRPF31.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Zheng Y, Wang HL, Li LK, Xu L, Tellier L, Li XL, Huang XY, Li W, Niu TT, Yang HM, Zhang JG, Liu DN (2018) A novel mutation in PRPF31, causative of autosomal dominant retinitis pigmentosa, using BGISEQ-500 sequencer. Int J Ophthalmol 11:31–35. https://doi.org/10.18240/ijo.2018.01.06

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ferrari S, Di Iorio E, Barbaro V, Ponzin D, Sorrentino FS, Parmeggiani F (2011) Retinitis pigmentosa: genes and disease mechanisms. Curr Genomics 12:238–249. https://doi.org/10.2174/138920211795860107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wang DY, Chan WM, Tam PO, Chiang SW, Lam DS, Chong KK, Pang CP (2005) Genetic markers for retinitis pigmentosa. Hong Kong Med J 11:281–288

    CAS  PubMed  Google Scholar 

  4. Bunker CH, Berson EL, Bromley WC, Hayes RP, Roderick TH (1984) Prevalence of retinitis pigmentosa in Maine. Am J Ophthalmol 97:357–365. https://doi.org/10.1016/0002-9394(84)90636-6

    Article  CAS  PubMed  Google Scholar 

  5. Guillonneau X, Piriev NI, Danciger M, Kozak CA, Cideciyan AV, Jacobson SG, Farber DB (1999) A nonsense mutation in a novel gene is associated with retinitis pigmentosa in a family linked to the RP1 locus. Hum Mol Genet 8:1541–1546 PMID: 10401003

    Article  CAS  PubMed  Google Scholar 

  6. Mansergh FC, Millington-Ward S, Kennan A, Kiang AS, Humphries M, Farrar GJ, Humphries P, Kenna PF (1999) Retinitis pigmentosa and progressive sensorineural hearing loss caused by a C12258A mutation in the mitochondrial MITS2 gene. Am J Hum Genet 64:971–985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rivolta C, Sharon D, DeAngelis MM, Dryja TP (2002) Retinitis pigmentosa and allied diseases: numerous diseases, genes, and inheritance patterns. Hum Mol Genet 11:1219–1227. https://doi.org/10.1093/hmg/ddg073

    Article  CAS  PubMed  Google Scholar 

  8. Hartong DT, Berson EL, Dryja TP (2006) Retinitis pigmentosa. Lancet 368:1795–1809. https://doi.org/10.1016/S0140-6736(06)69740-7

    Article  CAS  PubMed  Google Scholar 

  9. Yuan L, Kawada M, Havlioglu N, Tang H, Wu JY (2005) Mutations in PRPF31 inhibit pre-mrna splicing of rhodopsin gene and cause apoptosis of retinal cells. J Neurosci 25:748–757. https://doi.org/10.1523/JNEUROSCI.2399-04.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rose AM, Shah AZ, Venturini G, Rivolta C, Rose GE, Bhattacharya SS (2013) Dominant PRPF31 mutations are hypostatic to a recessive CNOT3 polymorphism in retinitis pigmentosa: a novel phenomenon of “Linked Trans-Acting Epistasis”. Ann Hum Genet 78:62–71. https://doi.org/10.1111/ahg.12042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Maubaret CG, Vaclavik V, Mukhopadhyay R, Waseem NH, Churchill A, Holder GE, Moore AT, Bhattacharya SS, Webster AR (2011) Autosomal dominant retinitis pigmentosa with intrafamilial variability and incomplete penetrance in two families carrying mutations in PRPF8. Retina 52:9304–9309. https://doi.org/10.1167/iovs.11-8372

    Article  CAS  Google Scholar 

  12. Rivolta C, Benaglio P, Guillaumie T, Manes G, Harper S, Berson EL, Meunier I, Hamel CP (2014) Molecular characterization of SNRNP200 mutations causing autosomal dominant retinitis pigmentosa with incomplete penetrance and phenotypic variability. Invest Ophthalmol Vis Sci 55:3264

    Google Scholar 

  13. Dib C, Faure S, Fizames C, Samson D, Drouot N, Vignal A, Millasseau P, Marc S, Kazan J, Seboun E, Lathrop M, Gyapay G, Morissette J, Weissenbach J (1996) A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380:152–154. https://doi.org/10.1038/380152a0

    Article  CAS  PubMed  Google Scholar 

  14. Vanita V, Singh D, Robinson PN, Sperling K, Singh JR (2006) A novel mutation in the DNA-binding domain of MAF at 16q23.1 associated with autosomal dominant “cerulean cataract” in an Indian family. Am J Med Genet 140:558–566. https://doi.org/10.1002/ajmg.a.31126

    Article  CAS  PubMed  Google Scholar 

  15. Lathrop GM, Lalouel JM, Julier C, Ott J (1984) Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci USA 81:3443–3446 PMID: 6587361

    Article  CAS  PubMed  Google Scholar 

  16. Saini S, Robinson PN, Singh JR, Vanita V (2012) A novel 7 bp deletion in PRPF31 associated with autosomal dominant retinitis pigmentosa with incomplete penetrance in an Indian family. Exp Eye Res 104:82–88. https://doi.org/10.1016/j.exer.2012.09.010

    Article  CAS  PubMed  Google Scholar 

  17. Rio Frio T, Civic N, Ransijn A, Beckmann JS, Rivolta C (2008) Two trans-acting eQTLs modulate the penetrance of PRPF31 mutations. Hum Mol Genet 17:e3154–e3165. https://doi.org/10.1093/hmg/ddn212

    Article  CAS  Google Scholar 

  18. Vithana EN, Abu-Safieh L, Allen MJ, Carey A, Papaioannou M, Al-Maghtheh M, Ebenezer ND, Willis C, Moore AT, Bird AC, Hunt DM, Bhattacharya SS (2001) A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11). Mol Cell 8:375–381. https://doi.org/10.1016/S1097-2765(01)00305-7

    Article  CAS  PubMed  Google Scholar 

  19. Ghazaway S, Springell K, Gauba V, McKibbin MA, Inglehearn CF (2007) Dominant retinitis pigmentosa phenotype associated with a new mutation in the splicing factor PRPF31. Br J Ophthalmol 91:1411–1414. https://doi.org/10.1136/bjo.2006.105163

    Article  Google Scholar 

  20. Deery EC, Vithana EN, Newbold RJ, Gallon VA, Bhattacharya SS, Warren MJ, Hunt DM, Wilkie SE (2002) Disease mechanism for retinitis pigmentosa (RP11) caused by mutations in the splicing factor gene PRPF31. Hum Mol Genet 11:3209–3219 PMID: 12444105

    Article  CAS  PubMed  Google Scholar 

  21. Lu F, Huang L, Lei C, Sha G, Zheng H, Liu X, Yang J, Shi Y, Lin Y, Gong B, Zhu X, Ma S, Qiao L, Lin H, Cheng J, Yang Z (2013) A Novel PRPF31 mutation in a large Chinese family with autosomal dominant retinitis pigmentosa and macular degeneration. PLoS ONE 8:e78274. https://doi.org/10.1371/journal.pone.0078274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liu S, Li P, Dybkov O, Nottrott S, Hartmuth K, Luhrmann R, Carlomagno T, Wahl MC (2007) Binding of the human Prpf31 Nop domain to a composite RNA-protein platform in U4 snRNP. Science 316:115–120. https://doi.org/10.1126/science.1137924

    Article  CAS  PubMed  Google Scholar 

  23. Sullivan LS, Bowne SJ, Birch DG, Hughbanks-Wheaton D, Heckenlively JR, Lewis RA, Garcia CA, Ruiz RS, Blanton SH, Northrup H, Gire AI, Seaman R, Duzkale H, Spellicy CJ, Zhu J, Shankar SP, Daiger SP (2006) Prevalence of disease-causing mutations in families with autosomal dominant retinitis pigmentosa: a screen of known genes in 200 families. Invest Ophthalmol Vis Sci 47:3052–3064. https://doi.org/10.1167/iovs.05-1443

    Article  PubMed  PubMed Central  Google Scholar 

  24. Xu F, Sui R, Liang X, Li H, Jiang R, Dong F (2012) Novel PRPF31 mutations associated with Chinese autosomal dominant retinitis pigmentosa patients. Mol Vis 18:3021–3028 PMCID: PMC3534138

  25. Vithana E, Al-Maghtheh M, Bhattacharya SS, Inglehearn CF (1998) RP11 is the second most common locus for dominant retinitis pigmentosa. J Med Genet 35:174–175 PMID: 9556378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Waseem NH, Vaclavik V, Webster A, Jenkins SA, Bird AC, Bhattacharya SS (2007) Mutations in the gene coding for the pre-mRNA splicing factor, PRPF31, in patients with autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci 48:1330–1334. https://doi.org/10.1167/iovs.06-0963

    Article  PubMed  Google Scholar 

  27. Audo I, Bojakowska K, Mohand-Said S, Lancelot ME, Moskova-Doumanova V, Waseem NH, Antonio A, Sahel JA, Bhattacharya SS, Zeitz C (2010) Prevalence and novelty of PRPF31 mutations in French autosomal dominant rod-cone dystrophy patients and a review of published reports. BMC Med Genet 11:145. https://doi.org/10.1186/1471-2350-11-145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. McGee TL, Devoto M, Ott J, Berson EL, Dryja TP (1997) Evidence that the penetrance of mutations at the RP11 locus causing dominant retinitis pigmentosa is influenced by a gene linked to the homologous RP11 allele. Am J Hum Genet 61:1059–1066. https://doi.org/10.1086/301614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vithana EN, Abu-Safieh L, Pelosini L, Winchester E, Hornan D, Bird AC, Hunt DM, Bustin SA, Bhattacharya SS (2003) Expression of PRPF31 mRNA in patients with autosomal dominant retinitis pigmentosa: a molecular clue for incomplete penetrance? Invest Ophthalmol Vis Sci 44:e4204–e4209. https://doi.org/10.1167/iovs.03-0253

    Article  Google Scholar 

  30. Rivolta C, McGee TL, Rio Frio T, Jensen RV, Berson EL, Dryja TP (2006) Variation in retinitis pigmentosa-11 (PRPF31 or RP-11) gene expression between symptomatic and asymptomatic patients with dominant RP11 mutations. Hum Mutat 27:644–653. https://doi.org/10.1002/humu.20325

    Article  CAS  PubMed  Google Scholar 

  31. Venturini G, Rose AM, Shah AZ, Bhattacharya SS, Rivolta C (2012) CNOT3 is a modifier of PRPF31 mutations in retinitis pigmentosa with incomplete penetrance. PLoS Genet 8:e1003040. https://doi.org/10.1371/journal.pgen.1003040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chakravarti A, Kapoor A (2012) Genetics. Mendelian puzzles. Science 335:930–931. https://doi.org/10.1126/science.1219301

    Article  CAS  PubMed  Google Scholar 

  33. Rose AM, Shah AZ, Venturini G, Krishna A, Chakravarti A, Rivolta C, Bhattacharya SS (2016) Transcriptional regulation of PRPF31 gene expression by MSR1 repeat elements causes incomplete penetrance in retinitis pigmentosa. Sci Rep 6:19450. https://doi.org/10.1038/srep19450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rose AM, Krishan A, Chakarova CF, Moya L, Chambers SK, Hollands M, Llingworth JC, Williams SMG, McCabe HE, Shah AZ, Palmer CAN, Chakravarti A, Berg JN, Batra J, Bhattacharya SS (2018) MSR1 repeats modulate gene expression and affect risk of breast and prostate cancer. Ann Oncol 29:1292–1303. https://doi.org/10.1093/annonc/mdy082

    Article  CAS  PubMed  Google Scholar 

  35. Berson EL, Gouras P, Gunkel RD, Myrianthopoulos NC (1969) Dominant retinitis pigmentosa with reduced penetrance. Arch Ophthal 81:226–234 PMID: 5764686

    Article  CAS  PubMed  Google Scholar 

  36. Moore AT, Fitzke F, Jay M, Arden GB, Inglehearn CF, Keen TJ, Bhattacharya SS, Bird AC (1993) Autosomal dominant retinitis pigmentosa with apparent incomplete penetrance: a clinical, electrophysiological, psychophysical, and molecular genetic study. Br J Ophthalmol 77:473–479 PMID: 8025041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dong B, Chen J, Zhang X, Pan Z, Bai F, Li Y (2013) Two novel PRPF31 premessenger ribonucleic acid processing factor 31 homolog mutations including a complex insertion-deletion identified in Chinese families with retinitis pigmentosa. Mol Vis 19:2426–2435 PMCID: PMC3850970

  38. Hamel C (2006) Retinitis pigmentosa. Orphanet J Rare Dis 1:40. https://doi.org/10.1186/1750-1172-1-40

    Article  PubMed  PubMed Central  Google Scholar 

  39. Villanueva A, Willer JR, Bryois J, Dermitzakis ET, Katsanis N, Davis EE (2014) Whole exome sequencing of a dominant retinitis pigmentosa family identifies a novel deletion in PRPF31. Invest Ophthalmol Vis Sci 55:2121–2129. https://doi.org/10.1167/iovs.13-13827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Xiao X, Cao Y, Zhang Z, Xu Y, Zheng Y, Chen LJ, Pang P, Chen H (2017) Novel mutations in PRPF31 causing Retinitis pigmentosa identified using whole-exome sequencing. Invest Ophthalmol Vis Sci 58:6342–6350. https://doi.org/10.1167/iovs.17-22952

    Article  PubMed  Google Scholar 

  41. Rodriguez-Murillo L, Subaran R, Stewart WCL, Pramanik S, Marathe S, Barst RJ, Chung WK, Greenberg DA (2010) Novel loci interacting epistatically with bone morphogenetic protein receptor 2 cause familial pulmonary arterial hypertension. J Heart Lung Transpl 29:174–180. https://doi.org/10.1016/j.healun.2009.08.022

    Article  Google Scholar 

Download references

Acknowledgements

The authors are grateful to all the family members for their participation in this study and for their kind cooperation. We are thankful to the retina experts at the Dr. Daljit Singh Eye Hospital, Amritsar, Punjab and Dr. Shroff’s Charity Eye Hospital, New Delhi, India, for undertaking ophthalmic examinations of all the members of this family.

Funding

This work was supported in part by grant sanctioned from Department of Biotechnology, India BT/IN/German/13/VK/2010 IND 10/036 to VV under the framework of Indo-German bilateral cooperation for research. Authors are also thankful to DST-PURSE scheme from DST, Government of India for providing research grant to GNDU.

Author information

Author notes

  1. Sofia Bhatia and Shiwali Goyal have contributed equally to this work.

Authors and Affiliations

  1. Department of Human Genetics, Guru Nanak Dev University (GNDU), Amritsar, Punjab, 143005, India

    Sofia Bhatia, Shiwali Goyal & Vanita Vanita

  2. Dr. Daljit Singh Eye Hospital, Amritsar, Punjab, India

    Indu R. Singh & Daljit Singh

Authors
  1. Sofia Bhatia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shiwali Goyal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Indu R. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daljit Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vanita Vanita
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vanita Vanita.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Human and animal rights

The study conforms to the Declaration of Helsinki. No animals were used.

Informed consent

The present study adhered to the Tenets of the Declaration of Helsinki and was approved by the ethics committee of Guru Nanak Dev University, Amritsar. Written informed consent was obtained from all the participating individuals.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 16 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bhatia, S., Goyal, S., Singh, I.R. et al. A novel mutation in the PRPF31 in a North Indian adRP family with incomplete penetrance. Doc Ophthalmol 137, 103–119 (2018). https://doi.org/10.1007/s10633-018-9654-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10633-018-9654-x

Keywords

Search

Navigation