FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2022776635> ?p ?o ?g. }

• W2022776635 endingPage "633" @default.
• W2022776635 startingPage "625" @default.
• W2022776635 abstract "Rod-cone dystrophy (RCD), also known as retinitis pigmentosa, is a progressive inherited retinal disorder characterized by photoreceptor cell death and genetic heterogeneity. Mutations in many genes have been implicated in the pathophysiology of RCD, but several others remain to be identified. Herein, we applied whole-exome sequencing to a consanguineous family with one subject affected with RCD and identified a homozygous nonsense mutation, c.226C>T (p.Arg76∗), in KIZ, which encodes centrosomal protein kizuna. Subsequent Sanger sequencing of 340 unrelated individuals with sporadic and autosomal-recessive RCD identified two other subjects carrying pathogenic variants in KIZ: one with the same homozygous nonsense mutation (c.226C>T [p.Arg76∗]) and another with compound-heterozygous mutations c.119_122delAACT (p.Lys40Ilefs∗14) and c.52G>T (p.Glu18∗). Transcriptomic analysis in mice detected mRNA levels of the mouse ortholog (Plk1s1) in rod photoreceptors, as well as its decreased expression when photoreceptors degenerated in rd1 mice. The presence of the human KIZ transcript was confirmed by quantitative RT-PCR in the retina, the retinal pigment epithelium, fibroblasts, and whole-blood cells (highest expression was in the retina). RNA in situ hybridization demonstrated the presence of Plk1s1 mRNA in the outer nuclear layer of the mouse retina. Immunohistology revealed KIZ localization at the basal body of the cilia in human fibroblasts, thus shedding light on another ciliary protein implicated in autosomal-recessive RCD. Rod-cone dystrophy (RCD), also known as retinitis pigmentosa, is a progressive inherited retinal disorder characterized by photoreceptor cell death and genetic heterogeneity. Mutations in many genes have been implicated in the pathophysiology of RCD, but several others remain to be identified. Herein, we applied whole-exome sequencing to a consanguineous family with one subject affected with RCD and identified a homozygous nonsense mutation, c.226C>T (p.Arg76∗), in KIZ, which encodes centrosomal protein kizuna. Subsequent Sanger sequencing of 340 unrelated individuals with sporadic and autosomal-recessive RCD identified two other subjects carrying pathogenic variants in KIZ: one with the same homozygous nonsense mutation (c.226C>T [p.Arg76∗]) and another with compound-heterozygous mutations c.119_122delAACT (p.Lys40Ilefs∗14) and c.52G>T (p.Glu18∗). Transcriptomic analysis in mice detected mRNA levels of the mouse ortholog (Plk1s1) in rod photoreceptors, as well as its decreased expression when photoreceptors degenerated in rd1 mice. The presence of the human KIZ transcript was confirmed by quantitative RT-PCR in the retina, the retinal pigment epithelium, fibroblasts, and whole-blood cells (highest expression was in the retina). RNA in situ hybridization demonstrated the presence of Plk1s1 mRNA in the outer nuclear layer of the mouse retina. Immunohistology revealed KIZ localization at the basal body of the cilia in human fibroblasts, thus shedding light on another ciliary protein implicated in autosomal-recessive RCD. Rod-cone dystrophy (RCD), also known as retinitis pigmentosa (MIM 268000), is a heterogeneous group of inherited retinal disorders affecting rod photoreceptors in the majority of cases and causing secondary cone degeneration.1Hartong D.T. Berson E.L. Dryja T.P. Retinitis pigmentosa.Lancet. 2006; 368: 1795-1809Abstract Full Text Full Text PDF PubMed Scopus (2277) Google Scholar Population-based studies have indicated that there are one million affected individuals worldwide.1Hartong D.T. Berson E.L. Dryja T.P. Retinitis pigmentosa.Lancet. 2006; 368: 1795-1809Abstract Full Text Full Text PDF PubMed Scopus (2277) Google Scholar Subjects diagnosed with RCD initially complain of night blindness due to rod dysfunction, as well as subsequent progressive constriction of their visual field, abnormal color vision, and eventually loss of central vision due to cone photoreceptor involvement.1Hartong D.T. Berson E.L. Dryja T.P. Retinitis pigmentosa.Lancet. 2006; 368: 1795-1809Abstract Full Text Full Text PDF PubMed Scopus (2277) Google Scholar RCD is inherited as a Mendelian trait in most cases; 30%–40% is autosomal dominant, 50%–60% is autosomal recessive, and 5%–15% is X-linked.1Hartong D.T. Berson E.L. Dryja T.P. Retinitis pigmentosa.Lancet. 2006; 368: 1795-1809Abstract Full Text Full Text PDF PubMed Scopus (2277) Google Scholar Candidate-gene approaches—for example, those comparing human phenotypes to similar phenotypes observed in animal models—are widely used for identifying gene defects leading to inherited retinal diseases.2Audo I. Kohl S. Leroy B.P. Munier F.L. Guillonneau X. Mohand-Saïd S. Bujakowska K. Nandrot E.F. Lorenz B. Preising M. et al.TRPM1 is mutated in patients with autosomal-recessive complete congenital stationary night blindness.Am. J. Hum. Genet. 2009; 85: 720-729Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 3Zeitz C. van Genderen M. Neidhardt J. Luhmann U.F. Hoeben F. Forster U. Wycisk K. Mátyás G. Hoyng C.B. Riemslag F. et al.Mutations in GRM6 cause autosomal recessive congenital stationary night blindness with a distinctive scotopic 15-Hz flicker electroretinogram.Invest. Ophthalmol. Vis. Sci. 2005; 46: 4328-4335Crossref PubMed Scopus (120) Google Scholar, 4Wycisk K.A. Zeitz C. Feil S. Wittmer M. Forster U. Neidhardt J. Wissinger B. Zrenner E. Wilke R. Kohl S. Berger W. Mutation in the auxiliary calcium-channel subunit CACNA2D4 causes autosomal recessive cone dystrophy.Am. J. Hum. Genet. 2006; 79: 973-977Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 5Zeitz C. Kloeckener-Gruissem B. Forster U. Kohl S. Magyar I. Wissinger B. Mátyás G. Borruat F.X. Schorderet D.F. Zrenner E. et al.Mutations in CABP4, the gene encoding the Ca2+-binding protein 4, cause autosomal recessive night blindness.Am. J. Hum. Genet. 2006; 79: 657-667Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar However, with the emergence of massively parallel sequencing techniques, considerable efforts are now being made to report known and novel genes implicated in the pathophysiology of inherited retinal disease.6Audo I. Bujakowska K. Orhan E. El Shamieh S. Sennlaub F. Guillonneau X. Antonio A. Michiels C. Lancelot M.E. Letexier M. et al.The familial dementia gene revisited: a missense mutation revealed by whole-exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family.Hum. Mol. Genet. 2014; 23: 491-501Crossref PubMed Scopus (21) Google Scholar, 7Audo I. Bujakowska K. Orhan E. Poloschek C.M. Defoort-Dhellemmes S. Drumare I. Kohl S. Luu T.D. Lecompte O. Zrenner E. et al.Whole-exome sequencing identifies mutations in GPR179 leading to autosomal-recessive complete congenital stationary night blindness.Am. J. Hum. Genet. 2012; 90: 321-330Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 8Siemiatkowska A.M. van den Born L.I. van Hagen P.M. Stoffels M. Neveling K. Henkes A. Kipping-Geertsema M. Hoefsloot L.H. Hoyng C.B. Simon A. et al.Mutations in the mevalonate kinase (MVK) gene cause nonsyndromic retinitis pigmentosa.Ophthalmology. 2013; 120: 2697-2705Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 9Zeitz C. Jacobson S.G. Hamel C.P. Bujakowska K. Neuillé M. Orhan E. Zanlonghi X. Lancelot M.E. Michiels C. Schwartz S.B. et al.Congenital Stationary Night Blindness ConsortiumWhole-exome sequencing identifies LRIT3 mutations as a cause of autosomal-recessive complete congenital stationary night blindness.Am. J. Hum. Genet. 2013; 92: 67-75Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar In the present study, we applied whole-exome sequencing (WES) to five members (including one affected by RCD) of a consanguineous family (family A [128], Figure 1) to identify the underlying gene defect. We detected a homozygous nonsense mutation, c.226C>T (p.Arg76∗), in the third exon of KIZ, coding for centrosomal protein kizuna (KIZ). The study protocol was conducted in accordance with the Declaration of Helsinki, national guidelines, and the regional ethics committee. Prior to testing and after explanation of the study and its potential outcome, informed consent was obtained from RCD subjects and their family members. Each subject underwent an ophthalmic examination with clinical assessment as previously described.10Audo I. Manes G. Mohand-Saïd S. Friedrich A. Lancelot M.E. Antonio A. Moskova-Doumanova V. Poch O. Zanlonghi X. Hamel C.P. et al.Spectrum of rhodopsin mutations in French autosomal dominant rod-cone dystrophy patients.Invest. Ophthalmol. Vis. Sci. 2010; 51: 3687-3700Crossref PubMed Scopus (42) Google Scholar At a time when next-generation sequencing (NGS) approaches were not commonly used, index subject CIC00173 II.2 (family A, Figure 1) was excluded upon screening by microarray analysis and direct Sanger sequencing for known mutations in EYS and C2orf71 (a major and a minor gene, respectively, implicated in RCD).11Audo I. Sahel J.A. Mohand-Saïd S. Lancelot M.E. Antonio A. Moskova-Doumanova V. Nandrot E.F. Doumanov J. Barragan I. Antinolo G. et al.EYS is a major gene for rod-cone dystrophies in France.Hum. Mutat. 2010; 31: E1406-E1435Crossref PubMed Scopus (73) Google Scholar, 12Audo I. Lancelot M.E. Mohand-Saïd S. Antonio A. Germain A. Sahel J.A. Bhattacharya S.S. Zeitz C. Novel C2orf71 mutations account for ∼1% of cases in a large French arRP cohort.Hum. Mutat. 2011; 32: E2091-E2103Crossref PubMed Scopus (25) Google Scholar Because exon ORF15 in RPGR (MIM 312610) is not targeted by existing NGS panels,13Audo I. Bujakowska K.M. Léveillard T. Mohand-Saïd S. Lancelot M.E. Germain A. Antonio A. Michiels C. Saraiva J.P. Letexier M. et al.Development and application of a next-generation-sequencing (NGS) approach to detect known and novel gene defects underlying retinal diseases.Orphanet J. Rare Dis. 2012; 7: 8Crossref PubMed Scopus (134) Google Scholar we also analyzed it by Sanger sequencing but found no pathogenic variant. Subsequently, we performed targeted NGS on the index subject’s DNA by using a panel of 120 genes previously found to carry mutations in retinal diseases (this panel was modified and improved since our previous study).13Audo I. Bujakowska K.M. Léveillard T. Mohand-Saïd S. Lancelot M.E. Germain A. Antonio A. Michiels C. Saraiva J.P. Letexier M. et al.Development and application of a next-generation-sequencing (NGS) approach to detect known and novel gene defects underlying retinal diseases.Orphanet J. Rare Dis. 2012; 7: 8Crossref PubMed Scopus (134) Google Scholar This survey did not reveal any pathogenic variant, and we therefore proceeded to WES. Exons of DNA samples were captured and investigated as reported before with in-solution enrichment methodology (SureSelect Human All Exon Kits version 3, Agilent) and NGS (Illumina HiSeq, Illumina). Image analysis and base calling were performed with real-time analysis software (Illumina).6Audo I. Bujakowska K. Orhan E. El Shamieh S. Sennlaub F. Guillonneau X. Antonio A. Michiels C. Lancelot M.E. Letexier M. et al.The familial dementia gene revisited: a missense mutation revealed by whole-exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family.Hum. Mol. Genet. 2014; 23: 491-501Crossref PubMed Scopus (21) Google Scholar, 9Zeitz C. Jacobson S.G. Hamel C.P. Bujakowska K. Neuillé M. Orhan E. Zanlonghi X. Lancelot M.E. Michiels C. Schwartz S.B. et al.Congenital Stationary Night Blindness ConsortiumWhole-exome sequencing identifies LRIT3 mutations as a cause of autosomal-recessive complete congenital stationary night blindness.Am. J. Hum. Genet. 2013; 92: 67-75Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 13Audo I. Bujakowska K.M. Léveillard T. Mohand-Saïd S. Lancelot M.E. Germain A. Antonio A. Michiels C. Saraiva J.P. Letexier M. et al.Development and application of a next-generation-sequencing (NGS) approach to detect known and novel gene defects underlying retinal diseases.Orphanet J. Rare Dis. 2012; 7: 8Crossref PubMed Scopus (134) Google Scholar Bioinformatic analysis of sequencing data was based on a pipeline (Consensus Assessment of Sequence and Variation 1.8, Illumina) that performs alignment, variant calling (single-nucleotide variants [SNVs] and indels), and coverage analysis. Annotation of genetic variation was done by an in-house pipeline (IntegraGen). To rapidly identify the pathogenic variant, we applied WES to all five members of the consanguineous family A (Figure 1). For all subjects, the overall sequencing coverage of the captured regions was 94% and 85% for a 10× and 25× depth of coverage, respectively, resulting in a mean sequencing depth of 80× per base. Filtering approaches were subsequently applied for identification of candidate mutation(s). Referenced variants that occurred homozygously or heterozygously with a minor allele frequency (MAF) ≥ 0.005 in dbSNP137, HapMap,14Altshuler D.M. Gibbs R.A. Peltonen L. Altshuler D.M. Gibbs R.A. Peltonen L. Dermitzakis E. Schaffner S.F. Yu F. Peltonen L. et al.International HapMap 3 ConsortiumIntegrating common and rare genetic variation in diverse human populations.Nature. 2010; 467: 52-58Crossref PubMed Scopus (1999) Google Scholar 1000 Genomes,15Abecasis G.R. Altshuler D. Auton A. Brooks L.D. Durbin R.M. Gibbs R.A. Hurles M.E. McVean G.A. 1000 Genomes Project ConsortiumA map of human genome variation from population-scale sequencing.Nature. 2010; 467: 1061-1073Crossref PubMed Scopus (5938) Google Scholar and the NHLBI Exome Sequencing Project Exome Variant Server (EVS)16Tennessen J.A. Bigham A.W. O’Connor T.D. Fu W. Kenny E.E. Gravel S. McGee S. Do R. Liu X. Jun G. et al.Broad GOSeattle GONHLBI Exome Sequencing ProjectEvolution and functional impact of rare coding variation from deep sequencing of human exomes.Science. 2012; 337: 64-69Crossref PubMed Scopus (1213) Google Scholar were removed.6Audo I. Bujakowska K. Orhan E. El Shamieh S. Sennlaub F. Guillonneau X. Antonio A. Michiels C. Lancelot M.E. Letexier M. et al.The familial dementia gene revisited: a missense mutation revealed by whole-exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family.Hum. Mol. Genet. 2014; 23: 491-501Crossref PubMed Scopus (21) Google Scholar, 7Audo I. Bujakowska K. Orhan E. Poloschek C.M. Defoort-Dhellemmes S. Drumare I. Kohl S. Luu T.D. Lecompte O. Zrenner E. et al.Whole-exome sequencing identifies mutations in GPR179 leading to autosomal-recessive complete congenital stationary night blindness.Am. J. Hum. Genet. 2012; 90: 321-330Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 9Zeitz C. Jacobson S.G. Hamel C.P. Bujakowska K. Neuillé M. Orhan E. Zanlonghi X. Lancelot M.E. Michiels C. Schwartz S.B. et al.Congenital Stationary Night Blindness ConsortiumWhole-exome sequencing identifies LRIT3 mutations as a cause of autosomal-recessive complete congenital stationary night blindness.Am. J. Hum. Genet. 2013; 92: 67-75Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar This step reduced the number of variants from 4,572 to 0 indels and from 55,051 SNVs to two compound-heterozygous missense variants in OBSCN (MIM 608616), one homozygous missense variant in four different genes (CTNNA3 [MIM 607667], PRRX2 [MIM 604675], UNCX, and PTCD3 [MIM 614918]), and one nonsense exchange in KIZ. Sanger sequencing confirmed all variants except the UNCX mutation, which turned out to be a false positive. In order to identify a potential disease-causing effect of missense substitutions, we investigated their species conservation and their predicted impact on the protein structure.17Adzhubei I.A. Schmidt S. Peshkin L. Ramensky V.E. Gerasimova A. Bork P. Kondrashov A.S. Sunyaev S.R. A method and server for predicting damaging missense mutations.Nat. Methods. 2010; 7: 248-249Crossref PubMed Scopus (9295) Google Scholar, 18Kumar P. Henikoff S. Ng P.C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm.Nat. Protoc. 2009; 4: 1073-1081Crossref PubMed Scopus (5007) Google Scholar All missense variants, except the ones in OBSCN, were excluded after consideration of the previously mentioned characteristics. The compound-heterozygous mutations in OBSCN were absent in genetic public databases, conserved across species, and predicted to be probably damaging and deleterious by PolyPhen-2 and SIFT. However, given that consanguinity among parents was reported for family A (Figure 1), homozygous variants represent the most likely candidate, although this does not totally exclude underlying causative compound-heterozygous mutations (K.M. Bujakowska et al., 2011, ARVO, abstract). The homozygous nonsense mutation (c.226C>T [p.Arg76∗]; RefSeq accession number NM_018474.4) located in exon 3 of KIZ cosegregated with the phenotype (family A in Figure 1 and Table 1). It represents a rare variant (rs202210819) that was detected heterozygously in 5 out of 5,920 individuals in the NHLBI EVS (MAF = 0.0004 in European Americans exclusively because it was not found among African Americans). After our discrete filtering approach, which identified candidate mutations in KIZ and OBSCN, we performed stratification on the basis of functional impact and gave a greater weight to the likelihood that the homozygous stop codon in KIZ was the most deleterious.Table 1KIZ Mutations Causing RCDIndex individualFamilyExonNucleotide ExchangeaRefSeq NM_018474.4.Allele StateProtein EffectCIC00173 (II.2)A (128)3c.226C>Thomozygousp.Arg76∗CIC01611 (II.1)B (951)3c.226C>Thomozygousp.Arg76∗CIC01225 (II.1)C (737)1c.52G>Theterozygousp.Glu18∗2c.119_122delAACTheterozygousp.Lys40Ilefs∗14a RefSeq NM_018474.4. Open table in a new tab To further evaluate which of the two genes might be the most likely to carry the pathogenic variants underlying autosomal-recessive RCD, we assessed genetic expression of both genes. Ubiquitous expression of KIZ, including in the eye, was found in UniGene. The KIZ mouse ortholog (Plk1s1, also known as Gm114) showed higher expression in rod photoreceptors of the retinal-cell-type comparative transcriptome atlas20Siegert S. Cabuy E. Scherf B.G. Kohler H. Panda S. Le Y.Z. Fehling H.J. Gaidatzis D. Stadler M.B. Roska B. Transcriptional code and disease map for adult retinal cell types.Nat. Neurosci. 2012; 15 (S1–S2): 487-495Crossref PubMed Scopus (195) Google Scholar than in cone photoreceptors and horizontal, bipolar, amacrine, ganglion, and microglia cells (Figure 2A).20Siegert S. Cabuy E. Scherf B.G. Kohler H. Panda S. Le Y.Z. Fehling H.J. Gaidatzis D. Stadler M.B. Roska B. Transcriptional code and disease map for adult retinal cell types.Nat. Neurosci. 2012; 15 (S1–S2): 487-495Crossref PubMed Scopus (195) Google Scholar The in-house rd1 mouse transcriptomic database revealed a significant decrease in the Plk1s1 mRNA level from day 12 to day 21 (p < 0.05) when photoreceptors degenerated, which was in keeping with rod photoreceptor expression (Figure 2B). In addition, Strunnikova et al.21Strunnikova N.V. Maminishkis A. Barb J.J. Wang F. Zhi C. Sergeev Y. Chen W. Edwards A.O. Stambolian D. Abecasis G. et al.Transcriptome analysis and molecular signature of human retinal pigment epithelium.Hum. Mol. Genet. 2010; 19: 2468-2486Crossref PubMed Scopus (188) Google Scholar reported KIZ expression in the human retinal pigment epithelium (RPE).21Strunnikova N.V. Maminishkis A. Barb J.J. Wang F. Zhi C. Sergeev Y. Chen W. Edwards A.O. Stambolian D. Abecasis G. et al.Transcriptome analysis and molecular signature of human retinal pigment epithelium.Hum. Mol. Genet. 2010; 19: 2468-2486Crossref PubMed Scopus (188) Google Scholar Similarly to KIZ, OBSCN was found to be ubiquitously expressed in UniGene. In contrast, mRNA expression was not reported in the mouse retinal-cell-type comparative transcriptome atlas.20Siegert S. Cabuy E. Scherf B.G. Kohler H. Panda S. Le Y.Z. Fehling H.J. Gaidatzis D. Stadler M.B. Roska B. Transcriptional code and disease map for adult retinal cell types.Nat. Neurosci. 2012; 15 (S1–S2): 487-495Crossref PubMed Scopus (195) Google Scholar Furthermore, the in-house rd1 mouse transcriptomic database reported no changes in Obscn mRNA levels during photoreceptor degeneration (data available upon request). To support transcriptomic database results and further document the implication of KIZ in retinal physiology, we performed quantitative real-time PCR, which revealed that the KIZ transcript was most abundant in the retina, followed by the RPE, whole-blood cells, and fibroblasts (p ≤ 0.01, Figure 2C). Subsequent Sanger sequencing of the PCR products confirmed correct KIZ-fragment amplification. Because transcriptomic data were only reported in the mouse retina at postnatal day 7 and there was no available information on expression location,22Magdaleno S. Jensen P. Brumwell C.L. Seal A. Lehman K. Asbury A. Cheung T. Cornelius T. Batten D.M. Eden C. et al.BGEM: an in situ hybridization database of gene expression in the embryonic and adult mouse nervous system.PLoS Biol. 2006; 4: e86Crossref PubMed Scopus (186) Google Scholar we performed RNA in situ hybridization in the adult mouse retina as previously described23Di Meglio T. Nguyen-Ba-Charvet K.T. Tessier-Lavigne M. Sotelo C. Chédotal A. Molecular mechanisms controlling midline crossing by precerebellar neurons.J. Neurosci. 2008; 28: 6285-6294Crossref PubMed Scopus (53) Google Scholar, 24Orhan E. Prézeau L. El Shamieh S. Bujakowska K.M. Michiels C. Zagar Y. Vol C. Bhattacharya S.S. Sahel J.A. Sennlaub F. et al.Further insights into GPR179: expression, localization, and associated pathogenic mechanisms leading to complete congenital stationary night blindness.Invest. Ophthalmol. Vis. Sci. 2013; 54: 8041-8050Crossref PubMed Scopus (17) Google Scholar by using a riboprobe encompassing exons 8–14 of Plk1s1 mRNA (RefSeq NM_001033298.3). Plk1s1 was found to be expressed in the outer nuclear layer, corresponding to photoreceptor nuclei, in the mouse retina (Figure 2D and 2E). All together, these results support our hypothesis that the nonsense variant in KIZ is the most convincing underlying defect for RCD in subject II.2 of family A (Figure 1). Further screening of coding and flanking exonic regions of KIZ in 340 unrelated individuals with autosomal-recessive and sporadic RCD by direct Sanger sequencing (PCR protocol and primer sequences are available upon request) identified two other subjects with mutations in this gene. Interestingly, another subject (CIC01611 II.1 in family B [951]) had the same nonsense variant (homozygous c.226C>T [p.Arg76∗]) found in subject CIC00173 II.2 (Figure 1). Subject CIC00173 was of North African Sephardic Jewish ancestry, and CIC01611 was of Spanish ancestry, and neither was aware of any family connection. To investigate whether the stop variant represents a founder alteration, we performed haplotype analysis for each of the index subjects (CIC00173 II.2 from family A) and CIC01611 II.1 from family B) by selecting 11 microsatellite DNA markers flanking the KIZ locus.25Goldstein D.B. Ruiz Linares A. Cavalli-Sforza L.L. Feldman M.W. An evaluation of genetic distances for use with microsatellite loci.Genetics. 1995; 139: 463-471PubMed Google Scholar These markers were distributed over a physical distance of ≈7.38 Mb, corresponding to ≈10.5 cM (genetic distance according to Marshfield genetic maps). Both subjects were found to share a common haplotype of five polymorphic microsatellites (DS20S54, DS20S63, DS20S190, DS20S868, and DS20S180) flanking KIZ and spanning ≈1.75 cM (1.18 Mb) (Figure 1). This result suggests that c.226C>T (p.Arg76∗) is most likely a founder mutation causing autosomal-recessive RCD in the southern European population. CIC01225 II.3 in family C (737), an additional individual with sporadic RCD, carried compound-heterozygous mutations: nonsense mutation c.52G>T (p.Glu18∗) in exon 1 and deletion c.119_122delAACT (p.Lys40Ilefs∗14) in exon 3 (Table 1). Cosegregation analysis revealed that the father was heterozygous for the nonsense mutation and the mother was heterozygous for the frameshift deletion (Figure 1). The identified defects most likely result in nonsense-mediated mRNA decay or truncated KIZ with a loss of function as a putative disease mechanism. Additional KIZ polymorphisms identified from screening the RCD cohort and their respective frequencies are provided in Table S1. Overall, KIZ mutations in the studied cohort would account for about 1% of autosomal-recessive RCD. This might be a slight overestimation given that a majority of the 340 affected individuals included in this work had already been investigated and excluded for carrying defects in known genes implicated in retinal diseases. The three affected individuals with KIZ variants in this study were all diagnosed with RCD in their late teens on the basis of night blindness followed by changes in midperipheral visual fields and undetectable responses in a full-field electroretinogram by approximately 35 years of age. Index II.2 of family A (CIC00173, Figure 1) was a 50-year-old male subject of North African Jewish Sephardic descent and had unaffected first-cousin parents. The index subject was overweight and complained of moderate hearing difficulties. Best-corrected visual acuity (BCVA) was 20/800 in the right eye and 20/640 in the left eye. A kinetic visual-field test revealed decreased central retinal sensitivity in addition to bilateral peripheral-field constriction. Fundus changes were typical of RCD with additional macular thinning (Figures 3A–3C). Index II.1 of family B (CIC01611, Figure 1) was a 34-year-old subject of Spanish descent. His medical and familial history was noncontributory. BCVA was 20/20 in both eyes. A binocular kinetic visual field using the III4e stimulus showed an annular scotoma in the midperiphery and preservation of the peripheral isopter. Fundus changes were typical of RCD with macular preservation (Figures 3D–3F). Index II.3 of family C (CIC01225, Figure 1) was a 51-year-old male subject of a mixed Italian and French descent. His history was significant for a congenital ichthyosis that was well tolerated. There was no familial history of systemic or ocular disease. BCVA was 20/40 in the right eye and 20/32 in the left. A binocular kinetic visual field using the III4e stimulus was reduced to the central 10° with bitemporal islands of perception peripherally. Fundus changes were typical of RCD with relative macular preservation (Figures 3G–3I). KIZ is a 12 kb gene clustering on the short arm of chromosome 20 at 20p11.23 (Figure 1). It harbors 13 exons and encodes a 673 aa protein that belongs to the kizuna family (Figure 1). It plays a critical role during cell-cycle progression while it undergoes sequential phosphorylation.26Dephoure N. Zhou C. Villén J. Beausoleil S.A. Bakalarski C.E. Elledge S.J. Gygi S.P. A quantitative atlas of mitotic phosphorylation.Proc. Natl. Acad. Sci. USA. 2008; 105: 10762-10767Crossref PubMed Scopus (1252) Google Scholar, 27Oshimori N. Ohsugi M. Yamamoto T. The Plk1 target Kizuna stabilizes mitotic centrosomes to ensure spindle bipolarity.Nat. Cell Biol. 2006; 8: 1095-1101Crossref PubMed Scopus (122) Google Scholar Oshimori et al.27Oshimori N. Ohsugi M. Yamamoto T. The Plk1 target Kizuna stabilizes mitotic centrosomes to ensure spindle bipolarity.Nat. Cell Biol. 2006; 8: 1095-1101Crossref PubMed Scopus (122) Google Scholar demonstrated that KIZ is a centrosomal substrate for PLK1, given that the latter mediates its phosphorylation at amino acid residue Thr379. During mitosis, KIZ localizes to mature centrioles and interacts with PLK1 in order to protect the centrosome from collapsing during spindle formation in a Thr379-phosphorylation-dependent manner.27Oshimori N. Ohsugi M. Yamamoto T. The Plk1 target Kizuna stabilizes mitotic centrosomes to ensure spindle bipolarity.Nat. Cell Biol. 2006; 8: 1095-1101Crossref PubMed Scopus (122) Google Scholar Stabilized centrosomes resist microtubule-mediated pulling and pushing forces and thus ensure the spindle bipolarity required for accurate separation of chromosomes during mitosis.28Bettencourt-Dias M. Glover D.M. Centrosome biogenesis and function: centrosomics brings new understanding.Nat. Rev. Mol. Cell Biol. 2007; 8: 451-463Crossref PubMed Scopus (412) Google Scholar, 29Conroy P.C. Saladino C. Dantas T.J. Lalor P. Dockery P. Morrison C.G. C-NAP1 and rootletin restrain DNA damage-induced centriole splitting and facilitate ciliogenesis.Cell Cycle. 2012; 11: 3769-3778Crossref PubMed Scopus (35) Google Scholar At the plasma membrane, the mother centriole can serve as the basal body where ciliogenesis begins, thus giving rise to either motile or immotile cilia, which exist on most cells in the human body.30Dawe H.R. Farr H. Gull K. Centriole/basal body morphogenesis and migration during ciliogenesis in animal cells.J. Cell Sci. 2007; 120: 7-15Crossref PubMed Scopus (212) Google Scholar Ciliogenesis can be either linked to the cell cycle or associated with cell differentiation.30Dawe H.R. Farr H. Gull K. Centriole/basal body morphogenesis and migration during ciliogenesis in animal cells.J. Cell Sci. 2007; 120: 7-15Crossref PubMed Scopus (212) Google Scholar To investigate a potential association between KIZ and cilia in humans, we induced cilia formation in a serum-free human fibroblast cell culture as described elsewhere.31Schmid F. Glaus E. Barthelmes D. Fliegauf M. Gaspar H. Nürnberg G. Nürnberg P. Omran H. Berger W. Neidhardt J. U1 snRNA-mediated gene therapeutic correction of splice defects caused by an exceptionally mild BBS mutation.Hum. Mutat. 2011; 32: 815-824Crossref PubMed Scopus (49) Google Scholar Co" @default.
• W2022776635 created "2016-06-24" @default.
• W2022776635 creator A5002890443 @default.
• W2022776635 creator A5003413277 @default.
• W2022776635 creator A5007612103 @default.
• W2022776635 creator A5021422523 @default.
• W2022776635 creator A5022872436 @default.
• W2022776635 creator A5030345626 @default.
• W2022776635 creator A5032089630 @default.
• W2022776635 creator A5035486536 @default.
• W2022776635 creator A5064593570 @default.
• W2022776635 creator A5065963816 @default.
• W2022776635 creator A5068238465 @default.
• W2022776635 creator A5077263630 @default.
• W2022776635 creator A5077263714 @default.
• W2022776635 creator A5078358993 @default.
• W2022776635 creator A5083982156 @default.
• W2022776635 creator A5084805443 @default.
• W2022776635 creator A5085774459 @default.
• W2022776635 creator A5088923173 @default.
• W2022776635 date "2014-04-01" @default.
• W2022776635 modified "2023-10-16" @default.
• W2022776635 title "Whole-Exome Sequencing Identifies KIZ as a Ciliary Gene Associated with Autosomal-Recessive Rod-Cone Dystrophy" @default.
• W2022776635 cites W1565206912 @default.
• W2022776635 cites W1907733689 @default.
• W2022776635 cites W1976370114 @default.
• W2022776635 cites W1980740976 @default.
• W2022776635 cites W1982926671 @default.
• W2022776635 cites W1984996211 @default.
• W2022776635 cites W1987754412 @default.
• W2022776635 cites W1993215762 @default.
• W2022776635 cites W1996485763 @default.
• W2022776635 cites W2000662971 @default.
• W2022776635 cites W2001510870 @default.
• W2022776635 cites W2005071155 @default.
• W2022776635 cites W2005073257 @default.
• W2022776635 cites W2020650477 @default.
• W2022776635 cites W2021296813 @default.
• W2022776635 cites W2021712425 @default.
• W2022776635 cites W2038352675 @default.
• W2022776635 cites W2040686049 @default.
• W2022776635 cites W2041384212 @default.
• W2022776635 cites W2043230710 @default.
• W2022776635 cites W2044068827 @default.
• W2022776635 cites W2045779425 @default.
• W2022776635 cites W2048997930 @default.
• W2022776635 cites W2059145105 @default.
• W2022776635 cites W2064207737 @default.
• W2022776635 cites W2068729649 @default.
• W2022776635 cites W2068972095 @default.
• W2022776635 cites W2085580220 @default.
• W2022776635 cites W2089769294 @default.
• W2022776635 cites W2091025893 @default.
• W2022776635 cites W2100240480 @default.
• W2022776635 cites W2101861839 @default.
• W2022776635 cites W2103693357 @default.
• W2022776635 cites W2107916366 @default.
• W2022776635 cites W2108370245 @default.
• W2022776635 cites W2112391462 @default.
• W2022776635 cites W2122481797 @default.
• W2022776635 cites W2124708335 @default.
• W2022776635 cites W2128094487 @default.
• W2022776635 cites W2138570147 @default.
• W2022776635 cites W2140568375 @default.
• W2022776635 cites W2144015228 @default.
• W2022776635 cites W2154261437 @default.
• W2022776635 cites W2154421528 @default.
• W2022776635 cites W2162590238 @default.
• W2022776635 cites W2167706986 @default.
• W2022776635 cites W2171777347 @default.
• W2022776635 cites W4211099883 @default.
• W2022776635 doi "https://doi.org/10.1016/j.ajhg.2014.03.005" @default.
• W2022776635 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3980423" @default.
• W2022776635 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/24680887" @default.
• W2022776635 hasPublicationYear "2014" @default.
• W2022776635 type Work @default.
• W2022776635 sameAs 2022776635 @default.
• W2022776635 citedByCount "48" @default.
• W2022776635 countsByYear W20227766352014 @default.
• W2022776635 countsByYear W20227766352015 @default.
• W2022776635 countsByYear W20227766352016 @default.
• W2022776635 countsByYear W20227766352017 @default.
• W2022776635 countsByYear W20227766352018 @default.
• W2022776635 countsByYear W20227766352019 @default.
• W2022776635 countsByYear W20227766352020 @default.
• W2022776635 countsByYear W20227766352021 @default.
• W2022776635 countsByYear W20227766352022 @default.
• W2022776635 countsByYear W20227766352023 @default.
• W2022776635 crossrefType "journal-article" @default.
• W2022776635 hasAuthorship W2022776635A5002890443 @default.
• W2022776635 hasAuthorship W2022776635A5003413277 @default.
• W2022776635 hasAuthorship W2022776635A5007612103 @default.
• W2022776635 hasAuthorship W2022776635A5021422523 @default.
• W2022776635 hasAuthorship W2022776635A5022872436 @default.
• W2022776635 hasAuthorship W2022776635A5030345626 @default.
• W2022776635 hasAuthorship W2022776635A5032089630 @default.
• W2022776635 hasAuthorship W2022776635A5035486536 @default.
• W2022776635 hasAuthorship W2022776635A5064593570 @default.

• next