Genetic, Clinical, and Pathologic Backgrounds of Patients with Autosomal Dominant Alport Syndrome

Kamiyoshi, Naohiro; Nozu, Kandai; Fu, Xue Jun; Morisada, Naoya; Nozu, Yoshimi; Ye, Ming Juan; Imafuku, Aya; Miura, Kenichiro; Yamamura, Takehira; Minamikawa, Shogo; Shono, Atsuko; Ninchoji, Takeshi; Morioka, Ichiro; Nakanishi, Koichi; Yoshikawa, Norishige; Kono, Hiroshi; Iijima, Kazumoto

doi:10.2215/cjn.01000116

Cited by 96 publications

(111 citation statements)

References 26 publications

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“…Published data showed that most of the heterozygous mutations found in COL4A4 are glycine at different positions [Kamiyoshi et al, 2016;Wu et al, 2016]. Compared to other reports, except for the clinical phenotype caused by heterozygous COL4A4 , the glycine substitution reported here is similar to that found in the literature [Jefferson et al, 1997;Kamiyoshi et al, 2016;Wu et al, 2016]. We also reported 2 nonsense heterozygous mutations in 2 probands, manifesting in mild phenotypes.…”

Section: Discussionsupporting

confidence: 84%

“…Analyzing correlations between genotype and phenotype, we found that the clinical phenotypes of the 3 probands manifested in mild phenotypes of microhematuria, proteinuria without higher serum creatinine levels, and progressive renal injury. Published data showed that most of the heterozygous mutations found in COL4A4 are glycine at different positions [Kamiyoshi et al, 2016;Wu et al, 2016]. Compared to other reports, except for the clinical phenotype caused by heterozygous COL4A4 , the glycine substitution reported here is similar to that found in the literature [Jefferson et al, 1997;Kamiyoshi et al, 2016;Wu et al, 2016].…”

Section: Discussionsupporting

confidence: 82%

“…Therefore, the initial clinical diagnosis was IgA nephropathy, which was then modified to ADAS after genetic testing. Kamiyoshi et al [2016] reported 2 ADAS patients with IgA deposits that may have been misdiagnosed with IgA nephropathy [Kamiyoshi et al, 2016]. Here, we have shown that patients with partial IgA nephropathy may carry collagen mutations and that differential diagnosis should be performed using genetic testing techniques if necessary.…”

Section: Discussionmentioning

confidence: 83%

“…COL4A4 heterozygous mutations can lead to ADAS and TBMN [Rana et al, 2005;Kamiyoshi et al, 2016]. In patients with ADAS, typical pathological changes of GBM include lamellation, splitting, thinning, or thickening [Kruegel et al, 2013;Liu et al, 2017].…”

Section: Discussionmentioning

confidence: 99%

“…Pathologically, features of these 2 diseases are similar in that they may show thin basement membrane change. Additionally, both ADAS and TBMN may present hematuria and exhibit normal GBM immunofluorescence staining of the collagen α3 and α5 chains [Kamiyoshi et al, 2016;Xu et al, 2016]. Comparison of the clinical phenotypes of the ADAS patient, FA-I1, with his daughter, who inherited the same COL4A4 p.Ser513Glufs * 2 heterozygous mutation locus, showed that the father presented with hematuria, proteinuria and an audiological lesion, while his daughter only had isolated hematuria without extra renal manifestations.…”

Section: Discussionmentioning

confidence: 99%

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Three Novel Heterozygous COL4A4 Mutations Result in Three Different Collagen Type IV Kidney Disease Phenotypes

Gao²,

Cui³

et al. 2018

Cytogenet Genome Res

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Thin basement membrane nephropathy (TBMN), autosomal dominant Alport syndrome (ADAS), and focal segmental glomerulosclerosis (FSGS) are kidney diseases that differ in clinical diagnosis, treatment, and prognosis. Nevertheless, they may result from the same causative genes. Here, we report 3 COL4A4 heterozygous mutations (p.Gly208Arg, p.Ser513Glufs*2, and p.Met1617Cysfs*39) that lead to 3 different collagen type IV kidney disease phenotypes, manifesting as TBMN, ADAS, and FSGS. Using bioinformatics analyses and pedigree verification, we show that these novel variants are pathogenetic and cosegregate with TBMN, ADAS, and FSGS. Furthermore, we found that the collagen type IV-associated kidney disease phenotypes are heterogeneous, with overlapping pathology and genetic mutations. We propose that COL4A4-associated TBMN, ADAS, and FSGS should be considered as collagen type IV kidney disease subtypes that represent different phases of disease progression.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Three Novel Heterozygous COL4A4 Mutations Result in Three Different Collagen Type IV Kidney Disease Phenotypes

Gao²,

Cui³

et al. 2018

Cytogenet Genome Res

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Effect of heterozygous pathogenic COL4A3 or COL4A4 variants on patients with X‐linked Alport syndrome

Zhang

Ding

Zhang

et al. 2019

Molec Gen & Gen Med

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Background Alport syndrome is an inherited renal disease caused by mutations in COL4A3 , COL4A4, or COL4A5 genes. Coexisting mutations in either two of the three genes in Alport patients have been reported recently. However, the effect of heterozygous mutations in COL4A3 or COL4A4 genes in X‐linked Alport syndrome (XLAS) patients is unclear. Methods Using targeted next‐generation sequencing, six unrelated Chinese children were identified to have a combination of a pathogenic variant in COL4A5 and a heterozygous mutation in COL4A3 or COL4A4 . They were three males and three females. Another three XLAS males each with only one pathogenic variant in COL4A5 were included. The clinical data were analyzed and compared between the males in two groups (group 1, males with a pathogenic variant in COL4A5 and a heterozygous pathogenic variant in COL4A3 or COL4A4 ; group 2, males with only one pathogenic variant in COL4A5 ). Results Patients with XLAS who also had heterozygous pathogenic COL4A3 or COL4A4 variants accounted for 1% of Alport syndrome. In this study, three children showed coexisting pathogenic variants in COL4A5 and COL4A3 . Two children showed pathogenic variants in COL4A5 and COL4A4 . One child had pathogenic variants in the three COL4A3‐5 genes, in which the pathogenic variant in COL4A5 was de novo and the pathogenic variants in COL4A4 and COL4A3 were inherited independently (in trans). The site and type of mutations in COL4A5 were similar between the two groups. It was revealed that males in group 1 presented more severe proteinuria than males in group 2 ( p < 0.05 ). Conclusion The present study provides further evidence for complicated genotype in Alport syndrome. For the first time, we reported a case with three pathogenic variants in COL4A5 , COL4A3 , and COL4A4 genes. Moreover, we found that heterozygous pathogenic COL4A3 or COL4A4 variants are likely to make XLAS disease more serious.

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Novel mutations of COL4A3, COL4A4, and COL4A5 genes in Chinese patients with Alport Syndrome using next generation sequence technique

Zhao

Chen

Wei

et al. 2019

Molec Gen & Gen Med

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Background Alport syndrome (AS) is an inherited progressive renal disease caused by mutations in COL4A3, COL4A4, and COL4A5 genes. The large sizes of these genes and the absence of mutation hot spots have complicated mutational analysis by routine PCR‐based approaches. In recent years, the development of next‐generation sequencing (NGS) has made possible the time‐ and cost‐effective and accurate analysis of the three genes in a single step. Methods Here, we analyze COL4A3, COL4A4, and COL4A5 simultaneously in 29 AS patients using NGS. Candidate mutations were validated by classic Sanger sequencing and Real‐time PCR. Results Twenty two new mutations and 10 known mutations were detected. Of those novel mutations, 18, 3, and 1 mutations were detected in COL4A5, COL4A4, and COL4A3, respectively. Twenty six patients showed X‐linked inheritance, one showed autosomal recessive inheritance and two showed digenic inheritance (DI). Conclusion A comparison of the clinical manifestations caused by different types of mutations in COL4A5 suggested that large fragment mutations are relatively more severe than the other missense mutations and AS by some mutations may show inter‐ and intra‐familial phenotypic variability. It is important to consider these transmission patterns in the clinical evaluation according to the results of genetic testing, especially for DI. Twenty two new mutations can expand the genotypic spectrum of AS.

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Genetic, Clinical, and Pathologic Backgrounds of Patients with Autosomal Dominant Alport Syndrome

Cited by 96 publications

References 26 publications

Three Novel Heterozygous<b><i> COL4A4</i></b> Mutations Result in Three Different Collagen Type IV Kidney Disease Phenotypes

Three Novel Heterozygous<b><i> COL4A4</i></b> Mutations Result in Three Different Collagen Type IV Kidney Disease Phenotypes

Effect of heterozygous pathogenic COL4A3 or COL4A4 variants on patients with X‐linked Alport syndrome

Novel mutations of COL4A3, COL4A4, and COL4A5 genes in Chinese patients with Alport Syndrome using next generation sequence technique

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