Identification of novel PROM1 mutations responsible for autosomal recessive maculopathy with rod-cone dystrophy
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To characterize two patients with macular and rod-cone dystrophy and identify the genetic basis for disease.
Ophthalmic examinations were performed for the family and the peripheral blood samples were collected for whole exome sequencing. The mutated sequences of PROM1 gene were cloned and expressed in cultured cell lines after transient transfection followed by analysis with confocal microscopy and bridge-PCR.
We reported that two patients, brothers in a family, were diagnosed with macular and rod-cone dystrophy. Phenotypically, both patients experience progressive visual impairment and nyctalopia. The fundus examination showed macular and choroid dystrophy with pigment deposits in the macular region. Functionally, photoreceptor response to electrophysiological stimulation was significantly compromised with more severe decline in rods. Genetic analysis by whole exome sequencing revealed two novel compound heterogeneous point mutations in PROM1 gene that co-segregate with patients in an autosomal recessive manner. Specifically, the c.C1902G(p.Y634X) nonsense mutation results in a truncated, labile, and mislocalized protein, while the c.C1682+3A>G intronic mutation disrupts messenger RNA splicing.
Our findings have identified two novel deleterious mutations in PROM1 gene that are associated with hereditary macular and rod-cone dystrophy in human.
KeywordsHereditary retinal disease Macular and rod-cone dystrophy PROM1
We are grateful to the family for their participation in the study.
This work was funded by the National Science and Technology Major Project for Drug Discovery of the Ministry of Science and Technology of China (2018ZX09301029-001), National Natural Science Foundation of China (81700828), National Key R&D Program of China (2017YFA0105300), Program for Eastern Young Scholar at Shanghai Institutions of Higher Learning (QD2016003), Shanghai Rising-Star Program (17QA1402800), Shanghai Pujiang Program (16PJ1408500), Frontier Project of Hospital Development Center (SHDC12016105), and Chenxing Project from Shanghai Jiao Tong University.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were approved by the medical ethics committee of Shanghai General Hospital (Shanghai First People’s Hospital) Affiliated to Shanghai Jiao Tong University (No. 2013KY096) and was conducted in accordance with the Declaration of Helsinki of the World Medical Association.
Informed consent was obtained from all individual participants included in the study.
- 1.Kannabiran C, Mariappan I (2018) Therapeutic avenues for hereditary forms of retinal blindness. J GenetGoogle Scholar
- 2.Dias MF, Joo K, Kemp JA et al (2017) Molecular genetics and emerging therapies for retinitis pigmentosa: basic research and clinical perspectives. Prog Retin Eye Res:1–25. https://doi.org/10.1016/j.preteyeres.2017.10.004
- 3.Abdelkader E, Enani L, Schatz P, Safieh L (2017) Severe retinal degeneration at an early age in Usher syndrome type 1B associated with homozygous splice site mutations in MYO7A gene. Saudi J OphthalmolGoogle Scholar
- 4.Kawamura Y, Suga A, Fujimaki T et al (2018) LRRTM4-C538Y novel gene mutation is associated with hereditary macular degeneration with novel dysfunction of ON-type bipolar cells. J Hum Genet. https://doi.org/10.1038/s10038-018-0465-4
- 6.Zernant J, Lee W, Nagasaki T et al (2018) Extremely hypomorphic and severe deep intronic variants in the ABCA4 locus result in varying Stargardt disease phenotypes. Cold Spring Harb Mol Case Stud. https://doi.org/10.1101/mcs.a002733
- 7.Miraglia S, Godfrey W, Yin AH et al (1997) A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning. Blood. https://doi.org/10.1126/science.1891716
- 8.Zhu L, Gibson P, Currle DS et al (2009) Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature. https://doi.org/10.1038/nature07589
- 9.Codega P, Silva-Vargas V, Paul A et al (2014) Prospective identification and purification of quiescent adult neural stem cells from their in vivo niche. Neuron. https://doi.org/10.1016/j.neuron.2014.02.039
- 10.Nie J, Mahato S, Mustill W et al (2012) Cross species analysis of Prominin reveals a conserved cellular role in invertebrate and vertebrate photoreceptor cells. Dev Biol. https://doi.org/10.1016/j.ydbio.2012.08.024
- 12.Sung CH, Tai AW (2000) Rhodopsin trafficking and its role in retinal dystrophies. Int Rev Cytol. https://doi.org/10.1016/S0074-7696(08)62706-0
- 14.Zhao L, Wang F, Wang H, Li Y, Alexander S, Wang K, Willoughby CE, Zaneveld JE, Jiang L, Soens ZT, Earle P, Simpson D, Silvestri G, Chen R (2015) Next generation sequencing-based molecular diagnosis of 82 retinitis pigmentosa probands from Northern Ireland. Hum Genet 134(2):217–230CrossRefGoogle Scholar
- 15.Eisenberger T, Neuhaus C, Khan AO, Decker C, Preising MN, Friedburg C, Bieg A, Gliem M, Issa PC, Holz FG, Baig SM, Hellenbroich Y, Galvez A, Platzer K, Wollnik B, Laddach N, Ghaffari SR, Rafati M, Botzenhart E, Tinschert S, Börger D, Bohring A, Schreml J, Körtge-Jung S, Schell-Apacik C, Bakur K, Al-Aama JY, Neuhann T, Herkenrath P, Nürnberg G, Nürnberg P, Davis JS, Gal A, Bergmann C, Lorenz B, Bolz HJ, Li T (2013) Increasing the Yield in Targeted Next-Generation Sequencing by Implicating CNV Analysis, Non-Coding Exons and the Overall Variant Load: The Example of Retinal Dystrophies. PLoS ONE 8(11):e78496CrossRefGoogle Scholar
- 17.Imani S, Cheng J, Shasaltaneh MD, Wei C, Yang L, Shangyi F, Zou H, Khan MA, Zhang X, Chen H, Zhang D, Duan C, Lv H, Li Y, Chen R, Junjiang F (2018) Genetic identification and molecular modeling characterization reveal a novel PROM1 mutation in Stargardt4-like macular dystrophy. Oncotarget 9(1):122–141CrossRefGoogle Scholar
- 19.Arrigoni FI, Matarin M, Thompson PJ, Michaelides M, McClements ME, Redmond E, Clarke L, Ellins E, Mohamed S, Pavord I, Hunt DM, Moore AT, Halcox J, Sisodiya SM (2011) Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy. Eur J Hum Genet 19(2):131–137CrossRefGoogle Scholar
- 22.Beryozkin A, Zelinger L, Bandah-Rozenfeld D, Shevach E, Harel A, Storm T, Sagi M, Eli D, Merin S, Banin E, Sharon D (2014) Identification of Mutations Causing Inherited Retinal Degenerations in the Israeli and Palestinian Populations Using Homozygosity Mapping. Invest Ophthalmol Vis Sci 55(2):1149CrossRefGoogle Scholar
- 23.Pras E, Abu A, Rotenstreich Y et al (2009) Cone-rod dystrophy and a frameshift mutation in the PROM1 gene. Mol Vis 15:1709–1716Google Scholar
- 24.Habibi I, Chebil A, Falfoul Y, Allaman-Pillet N, Kort F, Schorderet DF, El Matri L (2016) Identifying mutations in Tunisian families with retinal dystrophy. Sci Rep 6(1)Google Scholar
- 26.Wawrocka A, Skorczyk-Werner A, Wicher K et al (2018) Novel variants identified with next-generation sequencing in Polish patients with cone-rod dystrophy. Mol Vis 24:326–339Google Scholar
- 29.Mayer AK, Rohrschneider K, Strom TM, Glockle N, Kohl S, Wissinger B, Weisschuh N (2016) Homozygosity mapping and whole-genome sequencing reveals a deep intronic PROM1 mutation causing cone-rod dystrophy by pseudoexon activation. Eur J Hum Genet 24:459–462. https://doi.org/10.1038/ejhg.2015.144 CrossRefGoogle Scholar
- 30.Eidinger O, Leibu R, Newman H et al (2015) An intronic deletion in the PROM1 gene leads to autosomal recessive cone-rod dystrophy. Mol Vis 21:1295–1306Google Scholar
- 34.Desviat LR, Pérez B, Ugarte M (2012) Minigenes to confirm exon skipping mutations. Methods Mol Biol. https://doi.org/10.1007/978-1-61779-767-5_3
- 35.Attanasio C, David A, Neerman-Arbez M (2003) Outcome of donor splice site mutations accounting for congenital afibrinogenemia reflects order of intron removal in the fibrinogen alpha gene (FGA). Blood. https://doi.org/10.1182/blood-2002-03-0853
- 37.Boulanger-Scemama E, El Shamieh S, Démontant V, et al (2015) Next-generation sequencing applied to a large French cone and cone-rod dystrophy cohort: Mutation spectrum and new genotype-phenotype correlation. Orphanet J Rare Dis. https://doi.org/10.1186/s13023-015-0300-3
- 38.Zhang Q, Zulfiqar F, Xiao X, et al (2007) Severe retinitis pigmentosa mapped to 4p15 and associated with a novel mutation in the PROM1 gene. Hum Genet 122:293–299. https://doi.org/10.1007/s00439-007-0395-2