COL4A3 mutations cause focal segmental glomerulosclerosis

Xie, Jingya; Wu, Xu; Ren, Huaijin; Wang, W.; Wang, Z.; Pan, Xiaogang; Hao, Xiaoxin; Tong, Jinlu; Ma, Jin; Ye, Z.; Meng, Guang; Zhu, Yanchang; Kiryluk, Krzysztof; Kong, Xiao; Hu, Liwei; Chen, N.

doi:10.1093/jmcb/mjv023

Cited by 15 publications

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“…Previous studies have focused on the relationship between FSGS and AS and on that between IgA nephropathy and AS (Gast et al, ; Hines et al, ; Kamiyoshi et al, ; Lin et al, ; Malone et al, ; Xie et al, ), suggesting that AS has variable clinical phenotypes, AS patients who have proteinuria or AS patients who have proteinuria and whose renal biopsy results are consistent with changes in FSGS or in IgA nephropathy are sometimes misdiagnosed with a primary nephropathy such as FSGS. In recent years, several researches and cases reported that AS patients with COL4A5 mutations who have coinherited with COL4A3/COL4A4, MYO1E and LAMA5 mutations could exacerbated phenotypes (Lennon et al, ; Voskarides et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…The renal biopsy results suggested focal sclerosing nephritis, in which the onset includes hematuria and proteinuria. Multiple cohort studies (Gast et al, ; Kamiyoshi et al, ; Voskarides et al, ; Voskarides, Patsias, Pierides, & Deltas, ; Voskarides, Pierides, & Deltas, ; Xie et al, ) have revealed the correlation between FSGS and AS or TBMN, and the association of AS with collagen‐associated gene mutations ( COL4A3/COL4A4 ) is easily misdiagnosed as FSGS due to their clinical symptom similarities. These studies suggest that some of the unexplained familial hereditary nephritis may be AS, and with the development of gene sequencing technology, the diagnostic ratio of AS will increase.…”

Section: Discussionmentioning

confidence: 99%

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Genotype‐phenotype correlation and prognostic impact in Chinese patients with Alport Syndrome

Shang

Peng

Wang

et al. 2019

Molec Gen & Gen Med

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Background Alport Syndrome (AS) is a progressive hereditary glomerular disease. It is often accompanied by sensorineural hearing loss and ocular abnormalities and can sometimes develop into end stage renal disease (ESRD), which is caused by mutations in the genes encoding the collagen type IV family of proteins. Methods This study analyzed the association between the clinical data of seven AS families and genes and the disease progression of different mutation types, including COL4A3 (OMIM 120070)， COL4A4 (OMIM 120131), and COL4A5 (OMIM303630). Results A total of six new pathogenic mutation sites, one complex heterozygous mutation at COL4A3, and a combined mutation of COL4A5 and INF2 (OMIM 610982) were identified in this study. It was revealed that the clinical manifestations of X‐linked AS caused by mutations in the COL4A5 gene were more severe in males than in females. In addition, the difference in patient phenotype can be attributed to the location of gene mutations affecting the protein domain or functional domain. Our data suggested that the gene deletion and nonsense mutations had a high risk for progression to ESRD. Conclusion Our results revealed the spectrum of type IV collagen genes, which contribute to the enrichment of database resources and has important implications in the diagnosis, prognosis, and guiding treatment of AS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genotype‐phenotype correlation and prognostic impact in Chinese patients with Alport Syndrome

Shang

Peng

Wang

et al. 2019

Molec Gen & Gen Med

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“…In our study, compound heterozygous mutations p.G997E and p.G1167R in COL4A3 were identified in the ARAS patient IID2. Interestingly, Xie et al reported p.G997E heterozygous mutations in an FSGS patient, and the pathological manifestations showed typical focal segmental glomerulosclerosis [29]. However, the patient IID2, whose renal biopsy showed lamellation changes of the GBM and significantly decreased expression of the α5 chain in GBM, was diagnosed with ARAS.…”

Section: Discussionmentioning

confidence: 99%

Novel mutations in COL4A3, COL4A4, and COL4A5 in Chinese patients with Alport Syndrome

Liu

Wei

et al. 2017

PLoS ONE

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Alport syndrome (AS) is a clinically and genetically heterogeneous, progressive nephropathy caused by mutations in , , and , which encode type IV collagen. The large sizes of these genes and the absence of mutation hot spots have complicated mutational analysis by routine polymerase chain reaction (PCR)-based approaches. Here, in order to design a rapid and effective method for the genetic diagnosis of AS, we developed a strategy by utilizing targeted capture associated with next-generation sequencing (NGS) to analyze , , and simultaneously in 20 AS patients. All the coding exons and flanking sequences of , , and from the probands were captured followed by HiSeq 2500 sequencing. Candidate mutations were validated by classic Sanger sequencing and quantitative (q)PCR. Sixteen patients (16/20, 75%) showed X-linked inheritance, and four patients (4/20, 20%) showed autosomal recessive inheritance. None of the individuals had autosomal-dominant AS. Fifteen novel mutations, 6 known mutations, and 2 novel fragment deletions were detected by targeted capture and NGS. Of these novel mutations, 12, 3, and 2 mutations were detected in , , and , respectively. A comparison of the clinical manifestations caused by different types of mutations in suggested that nonsense mutations and glycine substitution by an acidic amino acid are more severe than the other missense mutations. Pathogenic mutations were detected in 20 patients. These novel mutations can expand the genotypic spectrum of AS. Our results demonstrated that targeted capture and NGS technology are effective in the genetic diagnosis of AS.

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“…Given that heterozygous COL4A3/COL4A4 mutations were observed in patients with familial FSGS , and FSGS can be secondary to TBMN and AS , FSGS may be only a pathological lesion process in the related kidney diseases or secondary to the GBM pathology. Therefore, COL4A3/COL4A4 ‐associated TBMN, FSGS and AS may be better classified as subtypes of collagen IV nephropathies, caused by collagen IV abnormalities, because of the clinical overlap and multiple mutations of the same gene in this group of disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Focal segmental glomerulosclerosis (FSGS) is a glomerular histological lesion associated with proteinuria and end‐stage renal disease (ESRD), and the incidence is about 2.3/100,000 in general population from the United States . FSGS is a morphological/histological pattern of injury rather than a specific glomerular disease, and it is characterized by focal [less than 50% of glomeruli was affected on light microscopy (LM)] and segmental [less than 50% of glomerular tuft was affected] glomerular sclerosis, and foot process effacement . Genetic or non‐genetic factors may lead to FSGS .…”

Section: Introductionmentioning

confidence: 99%

A novel heterozygous COL4A4 missense mutation in a Chinese family with focal segmental glomerulosclerosis

et al. 2016

J Cellular Molecular Medi

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Focal segmental glomerulosclerosis (FSGS) is the most common glomerular histological lesion associated with high‐grade proteinuria and end‐stage renal disease. Histologically, FSGS is characterized by focal segmental sclerosis with foot process effacement. The aim of this study was to identify the disease‐causing mutation in a four‐generation Chinese family with FSGS. A novel missense mutation, c.1856G>A (p.Gly619Asp), in the collagen type IV alpha‐4 gene (COL4A4) was identified in six patients and it co‐segregated with the disease in this family. The variant is predicted to be disease‐causing and results in collagen IV abnormalities. Our finding broadens mutation spectrum of the COL4A4 gene and extends the phenotypic spectrum of collagen IV nephropathies. Our study suggests that exome sequencing is a cost‐effective and efficient approach for identification of disease‐causing mutations in phenotypically complex or equivocal disorders. Timely screening for COL4A3/COL4A4 mutations in patients with familial FSGS may help both accurately diagnose and treat these patients.

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COL4A3 mutations cause focal segmental glomerulosclerosis

Cited by 15 publications

References 0 publications

Genotype‐phenotype correlation and prognostic impact in Chinese patients with Alport Syndrome

Genotype‐phenotype correlation and prognostic impact in Chinese patients with Alport Syndrome

Novel mutations in COL4A3, COL4A4, and COL4A5 in Chinese patients with Alport Syndrome

A novel heterozygous COL4A4 missense mutation in a Chinese family with focal segmental glomerulosclerosis

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