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01-09-2014 | Original Article

Natural history of genetically proven autosomal recessive Alport syndrome

Authors: Masafumi Oka, Kandai Nozu, Hiroshi Kaito, Xue Jun Fu, Koichi Nakanishi, Yuya Hashimura, Naoya Morisada, Kunimasa Yan, Masafumi Matsuo, Norishige Yoshikawa, Igor Vorechovsky, Kazumoto Iijima

Published in: Pediatric Nephrology | Issue 9/2014

Abstract

Background

Autosomal recessive Alport syndrome (ARAS) is a rare hereditary disease caused by homozygous or compound heterozygous mutations in either the COL4A3 or COL4A4 genes. Failure to diagnose ARAS cases is common, even if detailed clinical and pathological examinations are carried out. As the mutation detection rate for ARAS is unsatisfactory, we sought to develop more reliable diagnostic methods and provide a better description of the clinicopathological characteristics of this disorder.

Methods

A retrospective analysis of 30 genetically diagnosed patients with ARAS in 24 pedigrees was conducted. The mutation detection strategy comprised three steps: (1) genomic DNA analysis using polymerase chain reaction (PCR) and direct sequencing; (2) mRNA analysis using reverse transcription (RT)-PCR to detect RNA processing abnormalities; (3) semi-quantitative PCR using capillary electrophoresis to detect large heterozygous deletions.

Results

Using the three-step analysis, we identified homozygous or compound heterozygous mutations in all patients. Interestingly, 20 % of our ARAS patients showed normal expression of α5 in kidney tissue. The median age of developing end-stage renal disease was 21 years.

Conclusions

The strategy described in this study improves the diagnosis for ARAS families. Although immunohistochemical analysis of α5 can provide diagnostic information, normal distribution does not exclude the diagnosis of ARAS.

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Kashtan CE (1999) Alport syndrome. An inherited disorder of renal, ocular, and cochlear basement membranes. Medicine (Baltimore) 78:338–360CrossRef

Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F (2013) Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol 24:364–375PubMedCrossRef

Hashimura Y, Nozu K, Kaito H, Nakanishi K, Fu XJ, Ohtsubo H, Hashimoto F, Oka M, Ninchoji T, Ishimori S, Morisada N, Matsunoshita N, Kamiyoshi N, Yoshikawa N, Iijima K (2013) Milder clinical aspects of X-linked Alport syndrome in men positive for the collagen IV alpha5 chain. Kidney Int. doi:10.1038/ki.2013.479 PubMed

Storey H, Savige J, Sivakumar V, Abbs S, Flinter FA (2013) COL4A3/COL4A4 mutations and features in individuals with autosomal recessive Alport syndrome. J Am Soc Nephrol 24:1945–1954PubMedCrossRef

Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41PubMedCrossRef

Schwartz GJ, Gauthier B (1985) A simple estimate of glomerular filtration rate in adolescent boys. J Pediatr 106:522–526PubMedCrossRef

Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A (1976) A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 58:259–263PubMed

Kagawa M, Kishiro Y, Naito I, Nemoto T, Nakanishi H, Ninomiya Y, Sado Y (1997) Epitope-defined monoclonal antibodies against type-IV collagen for diagnosis of Alport’s syndrome. Nephrol Dial Transplant 12:1238–1241PubMedCrossRef

Voskarides K, Damianou L, Neocleous V, Zouvani I, Christodoulidou S, Hadjiconstantinou V, Ioannou K, Athanasiou Y, Patsias C, Alexopoulos E, Pierides A, Kyriacou K, Deltas C (2007) COL4A3/COL4A4 mutations producing focal segmental glomerulosclerosis and renal failure in thin basement membrane nephropathy. J Am Soc Nephrol 18:3004–3016PubMedCrossRef

10.

Kaito H, Nozu K, Fu XJ, Kamioka I, Fujita T, Kanda K, Krol RP, Suminaga R, Ishida A, Iijima K, Matsuo M (2007) Detection of a transcript abnormality in mRNA of the SLC12A3 gene extracted from urinary sediment cells of a patient with Gitelman’s syndrome. Pediatr Res 61:502–505PubMedCrossRef

11.

Nozu K, Iijima K, Kawai K, Nozu Y, Nishida A, Takeshima Y, Fu XJ, Hashimura Y, Kaito H, Nakanishi K, Yoshikawa N, Matsuo M (2009) In vivo and in vitro splicing assay of SLC12A1 in an antenatal salt-losing tubulopathy patient with an intronic mutation. Hum Genet 126:533–538PubMedCrossRef

12.

Nozu K, Fu XJ, Nakanishi K, Yoshikawa N, Kaito H, Kanda K, Krol RP, Miyashita R, Kamitsuji H, Kanda S, Hayashi Y, Satomura K, Shimizu N, Iijima K, Matsuo M (2007) Molecular analysis of patients with type III Bartter syndrome: picking up large heterozygous deletions with semiquantitative PCR. Pediatr Res 62:364–369PubMedCrossRef

13.

Nozu K, Przybyslaw Krol R, Ohtsuka Y, Nakanishi K, Yoshikawa N, Nozu Y, Kaito H, Kanda K, Hashimura Y, Hamasaki Y, Iijima K, Matsuo M (2008) Detection of large deletion mutations in the COL4A5 gene of female Alport syndrome patients. Pediatr Nephrol 23:2085–2090PubMedCrossRef

14.

Ding J, Stitzel J, Berry P, Hawkins E, Kashtan CE (1995) Autosomal recessive Alport syndrome: mutation in the COL4A3 gene in a woman with Alport syndrome and posttransplant antiglomerular basement membrane nephritis. J Am Soc Nephrol 5:1714–1717PubMed

15.

Artuso R, Fallerini C, Dosa L, Scionti F, Clementi M, Garosi G, Massella L, Epistolato MC, Mancini R, Mari F, Longo I, Ariani F, Renieri A, Bruttini M (2012) Advances in Alport syndrome diagnosis using next-generation sequencing. Eur J Hum Genet 20:50–57PubMedCentralPubMedCrossRef

16.

Boye E, Mollet G, Forestier L, Cohen-Solal L, Heidet L, Cochat P, Grunfeld JP, Palcoux JB, Gubler MC, Antignac C (1998) Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport syndrome. Am J Hum Genet 63:1329–1340PubMedCentralPubMedCrossRef

17.

Gross O, Netzer KO, Lambrecht R, Seibold S, Weber M (2003) Novel COL4A4 splice defect and in-frame deletion in a large consanguine family as a genetic link between benign familial haematuria and autosomal Alport syndrome. Nephrol Dial Transplant 18:1122–1127PubMedCrossRef

18.

Heidet L, Arrondel C, Forestier L, Cohen-Solal L, Mollet G, Gutierrez B, Stavrou C, Gubler MC, Antignac C (2001) Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome. J Am Soc Nephrol 12:97–106PubMed

19.

Longo I, Porcedda P, Mari F, Giachino D, Meloni I, Deplano C, Brusco A, Bosio M, Massella L, Lavoratti G, Roccatello D, Frasca G, Mazzucco G, Muda AO, Conti M, Fasciolo F, Arrondel C, Heidet L, Renieri A, De Marchi M (2002) COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. Kidney Int 61:1947–1956PubMedCrossRef

20.

Longo I, Scala E, Mari F, Caselli R, Pescucci C, Mencarelli MA, Speciale C, Giani M, Bresin E, Caringella DA, Borochowitz ZU, Siriwardena K, Winship I, Renieri A, Meloni I (2006) Autosomal recessive Alport syndrome: an in-depth clinical and molecular analysis of five families. Nephrol Dial Transplant 21:665–671PubMedCrossRef

21.

Rana K, Tonna S, Wang YY, Sin L, Lin T, Shaw E, Mookerjee I, Savige J (2007) Nine novel COL4A3 and COL4A4 mutations and polymorphisms identified in inherited membrane diseases. Pediatr Nephrol 22:652–657PubMedCrossRef

22.

Sakai K, Muramatsu M, Ogiwara H, Kawamura T, Arai K, Aikawa A, Ohara T, Mizuiri S, Joh K, Naito I, Hasegawa A (2003) Living related kidney transplantation in a patient with autosomal-recessive Alport syndrome. Clin Transplant 17[Suppl 10]:4–8PubMedCrossRef

23.

Shaw EA, Colville D, Wang YY, Zhang KW, Dagher H, Fassett R, Guymer R, Savige J (2007) Characterization of the peripheral retinopathy in X-linked and autosomal recessive Alport syndrome. Nephrol Dial Transplant 22:104–108PubMedCrossRef

24.

Temme J, Peters F, Lange K, Pirson Y, Heidet L, Torra R, Grunfeld JP, Weber M, Licht C, Muller GA, Gross O (2012) Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations. Kidney Int 81:779–783PubMedCrossRef

25.

Torra R, Badenas C, Cofan F, Callis L, Perez-Oller L, Darnell A (1999) Autosomal recessive Alport syndrome: linkage analysis and clinical features in two families. Nephrol Dial Transplant 14:627–630PubMedCrossRef

26.

Wang Y, Sivakumar V, Mohammad M, Colville D, Storey H, Flinter F, Dagher H, Savige J (2013) Clinical and genetic features in autosomal recessive and X-linked Alport syndrome. Pediatr Nephrol 29:391–396PubMedCrossRef

27.

Webb B, Brandt T, Liu L, Jalas C, Liao J, Fedick A, Linderman M, Diaz G, Kornreich R, Trachtman H, Mehta L, Edelmann L (2013) A founder mutation in COL4A3 causes autosomal recessive Alport syndrome in the Ashkenazi Jewish population. Clin Genet. doi:10.1111/cge.12247 PubMed

28.

Zhang Y, Wang F, Ding J, Zhang H, Zhao D, Yu L, Xiao H, Yao Y, Zhong X, Wang S (2012) Genotype-phenotype correlations in 17 Chinese patients with autosomal recessive Alport syndrome. Am J Med Genet A 158A:2188–2193PubMedCrossRef

29.

Crovetto F, Moroni G, Zaina B, Acaia B, Ossola MW, Fedele L (2013) Pregnancy in women with Alport syndrome. Int Urol Nephrol 45:1223–1227

30.

Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer KO, Flinter F, Pirson Y, Verellen C, Wieslander J, Persson U, Tryggvason K, Martin P, Hertz JM, Schroder C, Sanak M, Krejcova S, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler MC (2000) X-linked Alport syndrome: natural history in 195 families and genotype-phenotype correlations in males. J Am Soc Nephrol 11:649–657PubMed

31.

Gubler MC, Knebelmann B, Beziau A, Broyer M, Pirson Y, Haddoum F, Kleppel MM, Antignac C (1995) Autosomal recessive Alport syndrome: immunohistochemical study of type IV collagen chain distribution. Kidney Int 47:1142–1147PubMedCrossRef

32.

Tazon Vega B, Badenas C, Ars E, Lens X, Mila M, Darnell A, Torra R (2003) Autosomal recessive Alport’s syndrome and benign familial hematuria are collagen type IV diseases. Am J Kidney Dis 42:952–959PubMedCrossRef

33.

King K, Flinter FA, Nihalani V, Green PM (2002) Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome. Hum Genet 111:548–554PubMedCrossRef

34.

Lo YF, Nozu K, Iijima K, Morishita T, Huang CC, Yang SS, Sytwu HK, Fang YW, Tseng MH, Lin SH (2011) Recurrent deep intronic mutations in the SLC12A3 gene responsible for Gitelman’s syndrome. Clin J Am Soc Nephrol 6:630–639PubMedCentralPubMedCrossRef

35.

Nozu K, Iijima K, Nozu Y, Ikegami E, Imai T, Fu XJ, Kaito H, Nakanishi K, Yoshikawa N, Matsuo M (2009) A deep intronic mutation in the SLC12A3 gene leads to Gitelman syndrome. Pediatr Res 66:590–593PubMedCrossRef

36.

Chatterjee R, Hoffman M, Cliften P, Seshan S, Liapis H, Jain S (2013) Targeted exome sequencing integrated with clinicopathological information reveals novel and rare mutations in atypical, suspected and unknown cases of Alport syndrome or proteinuria. PloS one 8:e76360PubMedCentralPubMedCrossRef

37.

Fallerini C, Dosa L, Tita R, Del Prete D, Feriozzi S, Gai G, Clementi M, La Manna A, Miglietti N, Mancini R, Mandrile G, Ghiggeri G, Piaggio G, Brancati F, Diano L, Frate E, Pinciaroli A, Giani M, Castorina P, Bresin E, Giachino D, De Marchi M, Mari F, Bruttini M, Renieri A, Ariani F (2013) Unbiased next generation sequencing analysis confirms the existence of autosomal dominant Alport syndrome in a relevant fraction of cases. Clin Genet. doi:10.1111/cge.12258 PubMed

38.

Beicht S, Strobl-Wildemann G, Rath S, Wachter O, Alberer M, Kaminsky E, Weber LT, Hinrichsen T, Klein HG, Hoefele J (2013) Next generation sequencing as a useful tool in the diagnostics of mosaicism in Alport syndrome. Gene 526:474–477PubMedCrossRef

Title: Natural history of genetically proven autosomal recessive Alport syndrome
Authors: Masafumi Oka
Kandai Nozu
Hiroshi Kaito
Xue Jun Fu
Koichi Nakanishi
Yuya Hashimura
Naoya Morisada
Kunimasa Yan
Masafumi Matsuo
Norishige Yoshikawa
Igor Vorechovsky
Kazumoto Iijima
Publication date: 01-09-2014
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 9/2014
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-014-2797-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Natural history of genetically proven autosomal recessive Alport syndrome

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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