Identification of four novel mutations in the COL4A5 gene identified in Chinese patients with X‑linked Alport syndrome

Zhao,Xuechao; Shang,Xueliang; Chen,Chen; Liu,Lina; Wang,Conghui; Zhao,Ganye; Zhang,Junjun; Kong,Xiangdong

doi:10.3892/br.2020.1311

Identification of four novel mutations in the COL4A5 gene identified in Chinese patients with X‑linked Alport syndrome

Authors:
- Xuechao Zhao
- Xueliang Shang
- Chen Chen
- Lina Liu
- Conghui Wang
- Ganye Zhao
- Junjun Zhang
- Xiangdong Kong
View Affiliations

Affiliations: Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University, Henan Engineering Research Center for Gene Editing of Human Genetic Disease, Zhengzhou, Henan 450052, P.R. China, School of Psychology, North China University of Science and Technology, Tang'shan, Hebei 063210, P.R. China, Research Institute of Nephrology, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
Published online on: June 9, 2020 https://doi.org/10.3892/br.2020.1311
Article Number: 4
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Alport syndrome (AS) is an inherited progressive nephropathy caused by mutations in one or two of the type IV collagen novel chains (α3, α4 and α5), which are encoded by COL4A3, COL4A4 and COL4A5, respectively. To date, three genetic forms of AS have been reported, including X‑linked AS, autosomal recessive AS, and autosomal dominant AS, and ~80% of patients have X‑linked AS caused by mutations in COL4A5. In the present study, four novel and one previously reported COL4A5 mutations were identified using targeted next‑generation sequencing in Chinese patients suspected of having AS. The results were confirmed by Sanger sequencing, which revealed two novel missense mutations resulting in the substitution of various glycine residues in a collagenous domain containing Gly‑X‑Y triplet sequence repeats [c.4198G>C, p.(Gly1400Arg) and c.3428G>T, p.(Gly1143Val)], a previously reported missense mutation [c.3071G>A, p.(Gly1024Glu)], a splice site mutation (c.2146+2T>A) and one frameshift mutation [c.1810delC (p.Thr605Ilefs*13)]. After analyzing the affected family members, it was shown that the identified mutations were associated with severe clinical phenotypes. These results broaden the known spectrum of mutations of the COL4A5 gene associated with AS and may have implications for genetic diagnosis, therapy and genetic counseling of affected families.

View Figures

View References

1	Gubler MC: Inherited diseases of the glomerular basement membrane. Nat Clin Prac Nephrol. 4:24–37. 2008.PubMed/NCBI View Article : Google Scholar
2	Hudson BG, Tryggvason K, Sundaramoorthy M and Neilson EG: Alport's syndrome, Goodpasture's syndrome, and type IV collagen. N Engl J Med. 348:2543–2556. 2003.PubMed/NCBI View Article : Google Scholar
3	Alport AC: Hereditary familial congenital haemorrhagic nephritis. Br Med J. 1:504–506. 1927.PubMed/NCBI View Article : Google Scholar
4	Han KH, Park JE and Ki CS: De novo mutations in COL4A5 identified by whole exome sequencing in 2 girls with Alport syndrome in Korea. Korean J Pediatr. 62:193–197. 2019.PubMed/NCBI View Article : Google Scholar
5	Behjati S and Tarpey PS: What is next generation sequencing? Arch Dis Child Educ Pract Ed. 98:236–238. 2013.PubMed/NCBI View Article : Google Scholar
6	Wei G, Zhihong L, Huiping C, Caihong Z, Zhaohong C and Leishi L: Spectrum of clinical features and type IV collagen alpha-chain distribution in Chinese patients with Alport syndrome. Nephrology, dialysis, transplantation: Official publication of the European Dialysis and Transplant Association. European Renal Association. 21:3146–3154. 2006.
7	Barker DF, Hostikka SL, Zhou J, Chow LT, Oliphant AR, Gerken SC, Gregory MC, Skolnick MH, Atkin CL and Tryggvason K: Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science. 248:1224–1227. 1990.PubMed/NCBI View Article : Google Scholar
8	Kashtan CE: Alport syndromes: Phenotypic heterogeneity of progressive hereditary nephritis. Pediatr Nephrol. 14:502–512. 2000.PubMed/NCBI View Article : Google Scholar
9	Meleg-Smith S, Magliato S, Cheles M, Garola RE and Kashtan CE: X-linked Alport syndrome in females. Hum Pathol. 29:404–408. 1998.PubMed/NCBI View Article : Google Scholar
10	Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer KO, Flinter F, et al: X-linked Alport syndrome: Natural history and genotype-phenotype correlations in girls and women belonging to 195 families: A ‘European community Alport syndrome concerted action’ study. J Am Soc Nephrol. 14:2603–2610. 2003.PubMed/NCBI View Article : Google Scholar
11	Tsiakkis D, Pieri M, Koupepidou P, Demosthenous P, Panayidou K and Deltas C: Genotype-phenotype correlation in X-linked Alport syndrome patients carrying missense mutations in the collagenous domain of COL4A5. Clin Genet. 82:297–299. 2012.PubMed/NCBI View Article : Google Scholar
12	Zhao X, Chen C, Wei Y, Zhao G, Liu L, Wang C Zhang J and Kong X: Novel mutations of COL4A3, COL4A4, and COL4A5 genes in Chinese patients with Alport syndrome using next generation sequence technique. Mol Genet Genomic Med. 7(e653)2019.PubMed/NCBI View Article : Google Scholar
13	Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al: Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 17:405–424. 2015.PubMed/NCBI View Article : Google Scholar
14	Wang YF, Ding J, Wang F and Bu DF: Effect of glycine substitutions on alpha5(IV) chain structure and structure-phenotype correlations in Alport syndrome. Biochem Biophys Res Commun. 316:1143–1149. 2004.PubMed/NCBI View Article : Google Scholar
15	Hudson BG: The molecular basis of Goodpasture and Alport syndromes: Beacons for the discovery of the collagen IV family. J Am Soc Nephrol. 15:2514–2527. 2004.PubMed/NCBI View Article : Google Scholar
16	Kashtan CE: Alport Syndrome and thin basement membrane nephropathy. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al, editors. GeneReviews((R)). Seattle (WA) 1993.
17	Slajpah M, Gorinsek B, Berginc G, Vizjak A, Ferluga D, Hvala A, Meglic A, Jaksa I, Furlan P, Gregoric A, et al: Sixteen novel mutations identified in COL4A3, COL4A4, and COL4A5 genes in Slovenian families with Alport syndrome and benign familial hematuria. Kidney Int. 71:1287–1295. 2007.PubMed/NCBI View Article : Google Scholar
18	Demosthenous P, Voskarides K, Stylianou K, Hadjigavriel M, Arsali M, Patsias C, Georgaki E, Zirogiannis P, Stavrou C, Daphnis E, et al: X-linked Alport syndrome in Hellenic families: Phenotypic heterogeneity and mutations near interruptions of the collagen domain in COL4A5. Clin Genet. 81:240–248. 2012.PubMed/NCBI View Article : Google Scholar
19	Xiu X, Yuan J, Deng X, Xiao J, Xu H, Zeng Z, Guan L, Xu F and Deng S: A novel COL4A5 mutation identified in a Chinese Han family using exome sequencing. Biomed Res Int. 2014(186048)2014.PubMed/NCBI View Article : Google Scholar
20	Morinière V, Dahan K, Hilbert P, Lison M, Lebbah S, Topa A, Bole-Feysot C, Pruvost S, Nitschke P, Plaisier E, et al: Improving mutation screening in familial hematuric nephropathies through next generation sequencing. J Am Soc Nephrol. 25:2740–2751. 2014.PubMed/NCBI View Article : Google Scholar
21	Zhou J, Hertz JM and Tryggvason K: Mutation in the alpha 5(IV) collagen chain in juvenile-onset Alport syndrome without hearing loss or ocular lesions: Detection by denaturing gradient gel electrophoresis of a PCR product. Am J Hum Genet. 50:1291–1300. 1992.PubMed/NCBI