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Detection of Splicing Abnormalities and Genotype-Phenotype

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Detection of Splicing Abnormalities and Genotype-Phenotype CLINICAL RESEARCH www.jasn.org Detection of Splicing Abnormalities and Genotype- Phenotype Correlation in X-linked Alport Syndrome Tomoko Horinouchi,1 Kandai Nozu,1 Tomohiko Yamamura,1 Shogo Minamikawa,1 Takashi Omori,2 Keita Nakanishi,1 Junya Fujimura,1 Akira Ashida,3 Mineaki Kitamura,4 Mitsuhiro Kawano,5 Wataru Shimabukuro,6 Chizuko Kitabayashi,7 Aya Imafuku,8 Keiichi Tamagaki ,9 Koichi Kamei,10 Kenjirou Okamoto,11 Shuichiro Fujinaga,12 Masafumi Oka,13 Toru Igarashi,14 Akinori Miyazono,15 Emi Sawanobori ,16 Rika Fujimaru,17 Koichi Nakanishi,18 Yuko Shima,19 Masafumi Matsuo,20 Ming Juan Ye,1 Yoshimi Nozu,1 Naoya Morisada,1 Hiroshi Kaito,1 and Kazumoto Iijima1 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background X-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by muta- tions in the COL4A5 gene. Genotype-phenotype correlation in male XLAS is relatively well established; relative to truncating mutations, nontruncating mutations exhibit milder phenotypes. However, transcript comparison between XLAS cases with splicing abnormalities that result in a premature stop codon and those with nontruncating splicing abnormalities has not been reported, mainly because transcript analysis is not routinely conducted in patients with XLAS. Methods We examined transcript expression for all patients with suspected splicing abnormalities who were treated at one hospital between January of 2006 and July of 2017. Additionally, we recruited 46 males from 29 families with splicing abnormalities to examine genotype-phenotype correlation in patients with truncating (n=21, from 14 families) and nontruncating (n=25, from 15 families) mutations at the transcript level. Results We detected 41 XLAS families with abnormal splicing patterns and described novel XLAS atypical splicing patterns (n=14) other than exon skipping caused by point mutations in the splice consensus se- quence. The median age for developing ESRD was 20 years (95% confidence interval, 14 to 23 years) among patients with truncating mutations and 29 years (95% confidence interval, 25 to 40 years) among patients with nontruncating mutations (P=0.001). Conclusions We report unpredictable atypical splicing in the COL4A5 gene in male patients with XLAS and reveal that renal prognosis differs significantly for patients with truncating versus nontruncating splicing abnormalities. Our results suggest that splicing modulation should be explored as a therapy for XLAS with truncating mutations. J Am Soc Nephrol 29: 2244–2254, 2018. doi: https://doi.org/10.1681/ASN.2018030228 Alport syndrome is an inherited type IV collagen disease Received March 1, 2018. Accepted May 23, 2018. that causes kidney disorder and usually develops into Published online ahead of print. Publication date available at ESRD, accompanied by sensorineural hearing loss and www.jasn.org. ocular abnormalities. X-linked Alport syndrome Correspondence: Dr. Kandai Nozu, Department of Pediatrics, (XLAS) accounts for approximately 85% of cases of Kobe University Graduate School of Medicine, 7-5-1 Kusunoki- Alport syndrome; notably pathogenic variants can be cho, Chuo, Kobe, Hyogo 6500017, Japan. Email: [email protected] detected in the COL4A5 (NM: 000495.4) gene, which u.ac.jp encodes the a5 chain of type IV collagen [a5(IV)].1 Copyright © 2018 by the American Society of Nephrology 2244 ISSN : 1046-6673/2908-2244 JAmSocNephrol29: 2244–2254, 2018 www.jasn.org CLINICAL RESEARCH The genotype-phenotype correlation in male XLAS is relatively Significance Statement well established; missense mutations (i.e., nontruncating muta- tions) exhibit milder phenotypes compared with truncating mu- X-linked Alport syndrome (XLAS) is a progressive hereditary ne- tations.2–4 Jais et al.2 reported that, by the age of 30, the probability phropathy caused by mutations in the COL4A5 gene. Previous of developing ESRD was 90% in cases that included large re- studies have shown genotype-phenotype correlations, but this study is the first to demonstrate that splicing mutations that create a arrangements and small frameshift mutations, but 50% in cases premature stop codon and a truncated transcript are associated with missense mutations. Bekheirnia et al.3 also reported that the with worse prognosis. The investigators also find that, for splicing average age at ESRD onset was 22 years for those with large or small mutations, transcriptional analysis is necessary to accurately esti- deletions, 25 years for those with truncating mutations, and 37 mate renal prognosis and in silico predictive tools are not often fi years for those with missense mutations. Regarding splice site mu- useful. The ndings suggest consideration of therapeutic ap- proaches to changing truncating mutation into nontruncating 2 tations, Jais et al. analyzed 29 families with mutations in consensus transcription for XLAS. splice sites, revealing that 70% of those developed ESRD by 30 years of age. In addition, Bekheirnia et al.3 studied 24 families with con- sensus splice sites and reported that the average age of onset of Among these, 71 (25%) exhibited truncating variants, 159 ESRD was 28 years old. These data suggest that cases with splice site (57%) exhibited nontruncating variants, and 49 (18%) exhibi- variants tend to show moderate severity (i.e., between the severities ted splicing variants. Among the 49 families with splicing var- observed with missense and nonsense mutations). However, in iants, eight families were excluded for the following reasons: these studies, transcript analysiswasnotconducted.Therefore,a possession of COL4A5 variants with somatic mosaic in a male comparison between truncating and nontruncating mutations (i.e., patient, one case; the 47,XXY karyotype, two cases; merging between cases where the number of deleted nucleotide numbers is with COL4A4 variant, one case; merging with missense or is not a multiple of 3) at the transcript level, to determine splicing COL4A5 variant, one case; merging with membranoprolifera- abnormalities in the COL4A5 gene, has not yet been performed. In tive GN, one case; and impossible to analyze mRNA, two cases. some other inherited diseases, in-frame splice site variants exhibit We included the remaining 41 families and described 14 pa- milder phenotypes relative to those caused by truncating mutations tients with atypical splicing patterns; other than exon skipping (e.g., Becker muscular dystrophy and Duchenne muscular dystro- caused by point mutations in the splice consensus sequence, phy [DMD]).5 In XLAS, it is critical to know the difference between these patterns had never been reported. In addition, to examine truncating transcripts, which result in a premature stop codon, and the genotype-phenotype correlation of male patients with nontruncating transcripts, in order to estimate renal prognosis, XLAS, we excluded 11 families with only female patients and perform genetic counseling, and develop further treatment strate- one family with exon 49 skipping because exons 49–51 are gies (e.g., exon skipping therapy, which is already approved by the known as a noncollagenous domain and the skipping of exon US Food and Drug Administration [FDA] for DMD). 49 may result in a severe phenotype. Ultimately, we included 29 However, it is very difficult to make a reliable prediction of families with 46 male patients; we divided these patients into splicing patternswithouttranscriptionalanalysis.Thusfar,wehave two groups with truncating or nontruncating variants at the detected 41 families with splicing abnormalities, including typical transcript level, then compared their clinical severity of disease. (n=16) and atypical (n=25) splicing patterns. Among them, we In our analysis, we included family members who had not un- have previously reported on 11 families with atypical splicing dergone their own DNA analysis but exhibited obvious urine patterns6; since then, we have analyzed an additional 14 families. abnormalities or renal dysfunction. Most patients were fol- In this study, we report on patients with atypical splicing lowed in a variety of local hospitals throughout Japan. Blood patterns (n=14) and examine the genotype-phenotype corre- samples and data were sent to our laboratory after acceptance lation in male patients with XLAS with variants in the COL4A5 of the request for mutational analysis. When we have detected gene that cause aberrant splicing, including those typical and variants that may possibly affect RNA splice processing, we atypical splicing patterns that have been proven by transcript have routinely analyzed the transcripts to confirm the muta- analysis (46 male patients from 29 families). tion-induced splicing abnormalities. In this study, we selected only patients with proven splicing variants. METHODS Mutational Analyses Mutational analysis of COL4A5 was performed by several meth- Ethical Consideration ods: (1) targeted next-generation sequencing using a custom All procedures were reviewed and approved by the Institutional disease panel, including COL4A3, COL4A4,andCOL4A5 genes; Review Board of Kobe University School of Medicine. In- (2) conventional direct sequencing using the Sanger method for formed consent was obtained from patients or their parents. all exons and exon-intron boundaries; (3) multiplex ligation- dependent probe amplification to detect copy-number varia- Participants and Inclusion Criteria tions; and (4) RT-PCR of mRNA and direct sequencing to detect A total of 279 families were genetically defined as having XLAS
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