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Current Molecular Medicine

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ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

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Research Article

A COL4A5 Missense Variant in a Han-Chinese Family with X-linked Alport Syndrome

Author(s): Yuan Wu, Yi Guo, Jinzhong Yuan, Hongbo Xu, Yong Chen, Hao Zhang, Mingyang Yuan, Hao Deng and Lamei Yuan*

Volume 19, Issue 10, 2019

Page: [758 - 765] Pages: 8

DOI: 10.2174/1566524019666190906144214

Price: $65

Abstract

Background: Alport syndrome (AS) is an inherited familial nephropathy, characterized by progressive hematuric nephritis, bilateral sensorineural hypoacusis and ocular abnormalities. X-linked AS (XLAS) is the major AS form and is clinically heterogeneous, and it is associated with defects in the collagen type IV alpha 5 chain gene (COL4A5).

Objective: The purpose of this research is to detect the genetic defect responsible for renal disorder in a 3-generation Han-Chinese pedigree.

Methods: Detailed family history and clinical data of the family members were collected and recorded. Whole exome sequencing (WES) was applied in the proband to screen potential genetic variants, and then Sanger sequencing was used to verify the variant within the family. Two hundred unrelated ethnically matched normal individuals (male/female: 100/100, age 37.5 ± 5.5 years) without renal disorder were recruited as controls.

Results: Three patients (I:1, II:1 and II:2) presented microscopic hematuria and proteinuria, and the patient I:1 developed uremia and end stage renal disease (ESRD) by age 55 and showed sensorineural hearing loss. Patient II:2 developed mild left ear hearing loss. Cataracts were present in patients I:1 and II:1. A COL4A5 gene missense variant, c.2156G>A (p.G719E), located in the Gly-X-Y repeats of exon 28, was identified to co-segregate with the renal disorder in this family. The variant was absent in 200 ethnically matched controls.

Conclusion: By conducting WES and Sanger sequencing, a COL4A5 missense variant, c.2156G>A (p.G719E), was identified to co-segregate with the renal disorder, and it is possible that this variant is the genetic cause of the disorder in this family. Our study may extend the mutation spectrum of XLAS and may be useful for genetic counseling of this family. Further functional studies associated with genetic deficiency are warranted in the following research.

Keywords: X-linked Alport syndrome, the COL4A5 gene, type IV collagen, α3α4α5 network, WES, Sanger sequencing.

« Previous Next »
[1]
Cosgrove D. Glomerular pathology in Alport syndrome: a molecular perspective. Pediatr Nephrol 2012; 27(6): 885-90.
[http://dx.doi.org/10.1007/s00467-011-1868-z] [PMID: 21455721]
[2]
Cervera-Acedo C, Coloma A, Huarte-Loza E, Sierra-Carpio M, Domínguez-Garrido E. Phenotype variability in a large Spanish family with Alport syndrome associated with novel mutations in COL4A3 gene. BMC Nephrol 2017; 18(1): 325.
[http://dx.doi.org/10.1186/s12882-017-0735-y] [PMID: 29089023]
[3]
Liu JH, Wei XX, Li A, et al. Novel mutations in COL4A3, COL4A4, and COL4A5 in Chinese patients with Alport Syndrome. PLoS One 2017; 12(5)e0177685
[http://dx.doi.org/10.1371/journal.pone.0177685] [PMID: 28542346]
[4]
Guo Y, Yuan J, Liang H, et al. Identification of a novel COL4A5 mutation in a Chinese family with X-linked Alport syndrome using exome sequencing. Mol Biol Rep 2014; 41(6): 3631-5.
[http://dx.doi.org/10.1007/s11033-014-3227-1] [PMID: 24522658]
[5]
Jais JP, Knebelmann B, Giatras I, 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 2003; 14(10): 2603-10.
[http://dx.doi.org/10.1097/01.ASN.0000090034.71205.74] [PMID: 14514738]
[6]
Savige J. Alport syndrome: its effects on the glomerular filtration barrier and implications for future treatment. J Physiol 2014; 592(18): 4013-23.
[http://dx.doi.org/10.1113/jphysiol.2014.274449] [PMID: 25107927]
[7]
Mao M, Alavi MV, Labelle-Dumais C, Gould DB. Type IV collagens and basement membrane diseases: cell biology and pathogenic mechanisms. Curr Top Membr 2015; 76: 61-116.
[http://dx.doi.org/10.1016/bs.ctm.2015.09.002] [PMID: 26610912]
[8]
Haas M. Alport syndrome and thin glomerular basement membrane nephropathy: a practical approach to diagnosis. Arch Pathol Lab Med 2009; 133(2): 224-32.
[http://dx.doi.org/10.1043/1543-2165-133.2.224] [PMID: 19195966]
[9]
Xiao H, Guo Y, Yi J, et al. Identification of a novel keratin 9 missense mutation in a Chinese family with epidermolytic palmoplantar keratoderma. Cell Physiol Biochem 2018; 46(5): 1919-29.
[http://dx.doi.org/10.1159/000489381] [PMID: 29719290]
[10]
Xiao H, Yuan L, Xu H, et al. Novel and recurring disease-causing NF1 variants in two Chinese families with neurofibromatosis type 1. J Mol Neurosci 2018; 65(4): 557-63.
[http://dx.doi.org/10.1007/s12031-018-1128-9] [PMID: 30046999]
[11]
Chen Q, Yuan L, Deng X, et al. A missense variant p.Ala117Ser in the transthyretin gene of a Han Chinese family with familial amyloid polyneuropathy. Mol Neurobiol 2018; 55(6): 4911-7.
[http://dx.doi.org/10.1007/s12035-017-0694-0] [PMID: 28762097]
[12]
Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009; 25(14): 1754-60.
[http://dx.doi.org/10.1093/bioinformatics/btp324] [PMID: 19451168]
[13]
Xiao H, Deng S, Deng X, et al. Mutation analysis of the ATP7B gene in seven Chinese families with Wilson’s disease. Digestion 2019; 99(4): 319-26.
[http://dx.doi.org/10.1159/000493314] [PMID: 30384382]
[14]
Wu Y, Hu P, Xu H, et al. A novel heterozygous COL4A4 missense mutation in a Chinese family with focal segmental glomerulosclerosis. J Cell Mol Med 2016; 20(12): 2328-32.
[http://dx.doi.org/10.1111/jcmm.12924] [PMID: 27469977]
[15]
Xiu X, Yuan J, Deng X, et al. A novel COL4A5 mutation identified in a Chinese Han family using exome sequencing. BioMed Res Int 2014; 2014186048
[http://dx.doi.org/10.1155/2014/186048] [PMID: 25110662]
[16]
Savige J, Sheth S, Leys A, Nicholson A, Mack HG, Colville D. Ocular features in Alport syndrome: pathogenesis and clinical significance. Clin J Am Soc Nephrol 2015; 10(4): 703-9.
[http://dx.doi.org/10.2215/CJN.10581014] [PMID: 25649157]
[17]
Miner JH. The glomerular basement membrane. Exp Cell Res 2012; 318(9): 973-8.
[http://dx.doi.org/10.1016/j.yexcr.2012.02.031] [PMID: 22410250]
[18]
Kashtan C. Alport syndrome: facts and opinions. F1000 Res 2017; 6: 50.
[http://dx.doi.org/10.12688/f1000research.9636.1] [PMID: 28163907]
[19]
Kashtan CE, Kim Y. Distribution of the alpha 1 and alpha 2 chains of collagen IV and of collagens V and VI in Alport syndrome. Kidney Int 1992; 42(1): 115-26.
[http://dx.doi.org/10.1038/ki.1992.269] [PMID: 1635341]
[20]
Abrahamson DR, Prettyman AC, Robert B, St John PL. Laminin-1 reexpression in Alport mouse glomerular basement membranes. Kidney Int 2003; 63(3): 826-34.
[http://dx.doi.org/10.1046/j.1523-1755.2003.00800.x] [PMID: 12631063]
[21]
Kashtan CE, Kim Y, Lees GE, Thorner PS, Virtanen I, Miner JH. Abnormal glomerular basement membrane laminins in murine, canine, and human Alport syndrome: aberrant laminin alpha2 deposition is species independent. J Am Soc Nephrol 2001; 12(2): 252-60.
[PMID: 11158215]
[22]
Meehan DT, Delimont D, Cheung L, et al. Biomechanical strain causes maladaptive gene regulation, contributing to Alport glomerular disease. Kidney Int 2009; 76(9): 968-76.
[http://dx.doi.org/10.1038/ki.2009.324] [PMID: 19710627]
[23]
Jais JP, Knebelmann B, Giatras I, et al. X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males. J Am Soc Nephrol 2000; 11(4): 649-57.
[PMID: 10752524]
[24]
Rheault MN. Women and Alport syndrome. Pediatr Nephrol 2012; 27(1): 41-6.
[http://dx.doi.org/10.1007/s00467-011-1836-7] [PMID: 21380623]
[25]
Bekheirnia MR, Reed B, Gregory MC, et al. Genotype-phenotype correlation in X-linked Alport syndrome. J Am Soc Nephrol 2010; 21(5): 876-83.
[http://dx.doi.org/10.1681/ASN.2009070784] [PMID: 20378821]
[26]
Wang F, Zhao D, Ding J, et al. Skin biopsy is a practical approach for the clinical diagnosis and molecular genetic analysis of X-linked Alport’s syndrome. J Mol Diagn 2012; 14(6): 586-93.
[http://dx.doi.org/10.1016/j.jmoldx.2012.06.005] [PMID: 22921432]
[27]
Zhou J, Hertz JM, Leinonen A, Tryggvason K. Complete amino acid sequence of the human alpha 5 (IV) collagen chain and identification of a single-base mutation in exon 23 converting glycine 521 in the collagenous domain to cysteine in an Alport syndrome patient. J Biol Chem 1992; 267(18): 12475-81.
[PMID: 1352287]
[28]
Gross O, Netzer KO, Lambrecht R, Seibold S, Weber M. Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling. Nephrol Dial Transplant 2002; 17(7): 1218-27.
[http://dx.doi.org/10.1093/ndt/17.7.1218] [PMID: 12105244]
[29]
Lemmink HH, Schröder CH, Monnens LA, Smeets HJ. The clinical spectrum of type IV collagen mutations. Hum Mutat 1997; 9(6): 477-99.
[http://dx.doi.org/10.1002/(SICI)1098-1004(1997)9:6<477:AID-HUMU1>3.0.CO;2-#] [PMID: 9195222]
[30]
Kruegel J, Rubel D, Gross O. Alport syndrome--insights from basic and clinical research. Nat Rev Nephrol 2013; 9(3): 170-8.
[http://dx.doi.org/10.1038/nrneph.2012.259] [PMID: 23165304]
[31]
Richards S, Aziz N, Bale S, 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 2015; 17(5): 405-24.
[http://dx.doi.org/10.1038/gim.2015.30] [PMID: 25741868]
[32]
Ma J, Pan X, Wang Z, et al. Twenty-one novel mutations identified in the COL4A5 gene in Chinese patients with X-linked Alport’s syndrome confirmed by skin biopsy. Nephrol Dial Transplant 2011; 26(12): 4003-10.
[http://dx.doi.org/10.1093/ndt/gfr184] [PMID: 21505094]
[33]
Barker DF, Denison JC, Atkin CL, Gregory MC. Efficient detection of Alport syndrome COL4A5 mutations with multiplex genomic PCR-SSCP. Am J Med Genet 2001; 98(2): 148-60.
[http://dx.doi.org/10.1002/1096-8628(20010115)98:2<148:AID-AJMG1024>3.0.CO;2-W] [PMID: 11223851]
[34]
Kashtan CE. Animal models of Alport syndrome. Nephrol Dial Transplant 2002; 17(8): 1359-62.
[http://dx.doi.org/10.1093/ndt/17.8.1359] [PMID: 12147777]
[35]
Zheng K, Thorner PS, Marrano P, Baumal R, McInnes RR. Canine X chromosome-linked hereditary nephritis: a genetic model for human X-linked hereditary nephritis resulting from a single base mutation in the gene encoding the alpha 5 chain of collagen type IV. Proc Natl Acad Sci USA 1994; 91(9): 3989-93.
[http://dx.doi.org/10.1073/pnas.91.9.3989] [PMID: 8171024]
[36]
Cox ML, Lees GE, Kashtan CE, Murphy KE. Genetic cause of X-linked Alport syndrome in a family of domestic dogs. Mamm Genome 2003; 14(6): 396-403.
[http://dx.doi.org/10.1007/s00335-002-2253-9] [PMID: 12879362]
[37]
Rheault MN, Kren SM, Thielen BK, et al. Mouse model of X-linked Alport syndrome. J Am Soc Nephrol 2004; 15(6): 1466-74.
[http://dx.doi.org/10.1097/01.ASN.0000130562.90255.8F] [PMID: 15153557]
[38]
Hashikami K, Asahina M, Nozu K, Iijima K, Nagata M, Takeyama M. Establishment of X-linked alport syndrome model mice with a Col4a5 R471X mutation. Biochem Biophys Rep 2018; 17: 81-6.
[http://dx.doi.org/10.1016/j.bbrep.2018.12.003] [PMID: 30582011]
[39]
Kashtan CE, Ding J, Gregory M, et al. Clinical practice recommendations for the treatment of Alport syndrome: a statement of the Alport Syndrome Research Collaborative. Pediatr Nephrol 2013; 28(1): 5-11.
[http://dx.doi.org/10.1007/s00467-012-2138-4] [PMID: 22461141]
[40]
Katayama K, Nomura S, Tryggvason K, Ito M. Searching for a treatment for Alport syndrome using mouse models. World J Nephrol 2014; 3(4): 230-6.
[http://dx.doi.org/10.5527/wjn.v3.i4.230] [PMID: 25374816]
[41]
Parpala-Spårman T, Lukkarinen O, Heikkilä P, Tryggvason K. A novel surgical organ perfusion method for effective ex vivo and in vivo gene transfer into renal glomerular cells. Urol Res 1999; 27(2): 97-102.
[http://dx.doi.org/10.1007/s002400050094] [PMID: 10424390]
[42]
Heikkilä P, Tibell A, Morita T, et al. Adenovirus-mediated transfer of type IV collagen alpha5 chain cDNA into swine kidney in vivo: deposition of the protein into the glomerular basement membrane. Gene Ther 2001; 8(11): 882-90.
[http://dx.doi.org/10.1038/sj.gt.3301342] [PMID: 11423936]
[43]
Prodromidi EI, Poulsom R, Jeffery R, et al. Bone marrow-derived cells contribute to podocyte regeneration and amelioration of renal disease in a mouse model of Alport syndrome. Stem Cells 2006; 24(11): 2448-55.
[http://dx.doi.org/10.1634/stemcells.2006-0201] [PMID: 16873763]
[44]
LeBleu V, Sugimoto H, Mundel TM, et al. Stem cell therapies benefit Alport syndrome. J Am Soc Nephrol 2009; 20(11): 2359-70.
[http://dx.doi.org/10.1681/ASN.2009010123] [PMID: 19833902]

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