A novel COL4A4 gene variant (c.1856G>A): from a focal segmental glomerulosclerosis case to a family with Alport syndrome

Sibel Ersan Health Sciences University, Izmir Tepecik Training and Research Hospital, Department of Nephrology, Izmir
Ozgur Kirbiyik Health Sciences University, Izmir Tepecik Training and Research Hospital, Department of Medical Genetics, Izmir
Turker Sarikaya Health Sciences University, Izmir Tepecik Training and Research Hospital, Department of Internal Medicine, Izmir
Merve Saka Guvenc Health Sciences University, Izmir Tepecik Training and Research Hospital, Department of Medical Genetics, Izmir
Tugba Karadeniz Health Sciences University, Izmir Tepecik Training and Research Hospital, Department of Pathology, Izmir

Keywords: Alport syndrome, COL4A4 mutations, focal segmental glomerulosclerosis

Abstract

Alport syndrome, also known as hereditary nephritis, is an inherited progressive form of glomerular disease that is often associated with sensorineural hearing loss and ocular abnormalities. It is caused by mutations in genes encoding several members of type IV colagen proteins primarily found in basement membranes. Genetic analyses of affected families have identified four different modes of transmission in patients with Alport syndrome. X-linked form of the syndrome arises from mutations of COL4A5 and COL4A6 on chromosome X, whereas autosomal forms result from genetic defects in either the COL4A3 or COL4A4 genes at chromosome 2q35-37. Digenic forms include patients with coexisting mutations in COL4A3, COL4A4, and COL4A5. The long-term clinical outcome in AS patients with heterozygous COL4A3/A4 mutations is generally unpredictable. Focal segmental glomerulosclerosis usually develops in classical AS at later stages and presents predominantly with proteinuria associated with hematuria. The index case presented in this report, a 26-year-old man, had kidney biopsy because of nephrotic proteinuria and microscopic hematuria accompanied by impaired renal function. He diagnosed focal segmental glomerulosclerosis. As he had progressive hearing loss since chidhood we conducted a genetic study for mutations in COL4A3 and COL4A4 genes. A novel mutation in COL4A4 gene (c.1804-7T>C) was detected. As his parents had consanguineous marriage we investigated the rest of the family for the same variant. His parents, and his sister were found to be heterozygote, and homozygote for the same variant, respectively. In this report we demonstrated an Alport syndrome family with a novel mutation in COL4A4 gene (c.1856G>A) that has been first reported to our best knowledge.

References

Gast C, Pengelly RJ, Lyon M, Bunyan DJ, Seaby EG, Graham N, et al. Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis. Nephrol Dial Transplant. 2016;31(6):961-70.

Haas M. Alport syndrome and thin glomerular basement membrane nephropathy: a practical approach to diagnosis. Arch Pathol Lab Med. 2009;133(2):224-32.

Deltas C, Savva I, Voskarides K, Papazachariou L, Pierides A. Carriers of Autosomal Recessive Alport Syndrome with Thin Basement Membrane Nephropathy Presenting as Focal Segmental Glomerulosclerosis in Later Life. Nephron. 2015;130(4):271-80.

Fogo AB. Causes nd pathogenesis of focal segmental glomerulosclerosis. Nat Rev Nephrol. 2015;11(2):76-87.

Hines SL, Agarwal A, Ghandour M, Nabeel A, Mohammad AN, Atwal PS. Novel variants in COL4A4 and COL4A5 are rare causes of FSGS in two unrelated families. Hum Genome Var. 2018;5:15.

Voskarides K, Pierides A, Deltas C. COL4A3/COL4A4 mutations link familial hematuria and focal segmental glomerulosclerosis. glomerular epithelium destruction via basement membrane thinning? Connect Tissue Res. 2008;49(3):283-8.

Malone AF, Phelan PJ, Hall G, Cetincelik U, Homstad A, Alonso AS, et al. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int. 2014;86(6):1253-9.

Xie J, Wu X, Ren H, Wang W, Wang Z, Pan X, et al. COL4A3 mutations cause focal segmental glomerulosclerosis. J Mol Cell Biol. 2014;6(6):498-505.

Li A, Gao EZ, Cui YX, Liu JH, Lv X, Wei XX, et al. Three Novel Heterozygous COL4A4 Mutations Result in Three Different Collagen Type IV Kidney Disease Phenotypes. Cytogenet Genome Res. 2018;154(1):30-6.

Papazachariou L, Papagregoriou G, Hadjipanagi D, Demosthenous P, Voskarides K, Koutsofti C, et al. Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis. Clin Genet. 2017;92(5):517-27.

Miner JH. Pathology vs. molecular genetics: (re)defining the spectrum of Alport syndrome. Kidney Int. 2014;86(6):1081-3.

D'Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med. 2011;365(25):2398-411.

Wu Y, Hu P, Xu H, Yuan J, Yuan L, Xiong W, 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.

Slajpah M, Gorinsek B, Berginc G, Vizjak A, Ferluga D, Hvala 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. 2007;71(12):1287-95.

Longo I, Porcedda P, Mari F, Giachino D, Meloni I, Deplano C, et al. COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. Kidney Int. 2002;61(6):1947-56.

Published

2019-07-16

How to Cite

Ersan S, Kirbiyik O, Sarikaya T, Guvenc MS, Karadeniz T. A novel COL4A4 gene variant (c.1856G>A): from a focal segmental glomerulosclerosis case to a family with Alport syndrome. Rev Nefrol Dial Traspl. [Internet]. 2019Jul.16 [cited 2024Jul.16];39(2):120-5. Available from: http://revistarenal.org.ar/index.php/rndt/article/view/436