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01-01-2012 | Original Article

Manifestation of atypical hemolytic uremic syndrome caused by novel mutations in MCP

Authors: Dana Provaznikova, Simon Rittich, Michal Malina, Tomas Seeman, Iuri Marinov, Magdalena Riedl, Ingrid Hrachovinova

Published in: Pediatric Nephrology | Issue 1/2012

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Mutations in genes encoding regulators of the alternative complement pathway (CFH, MCP, C3, CFI, CFB, THBD, and CFHR1-5) are connected with this disease. Polymorphisms (SNPs) in these genes might also influence the manifestation of aHUS. We have analyzed the genes of CFH, CFI, MCP, and C3 in a cohort of 10 unrelated Czech patients with clinically diagnosed familial aHUS. Surprisingly, 4 patients had mutations only in MCP, without mutations in any of the other genes that cause aHUS. Mutations, as yet unpublished, were widely distributed over the gene (SCR2 domain, signal peptide, and cytoplasmic region). The phenotype of the patients and their close relatives (14 individuals) was also investigated. Functional examination of MCP was also provided and proved lower expression on granulocytes in all mutations. Severity of disease varied, but onset was never earlier than 5 years of age. Penetrance of disease was 50% among carriers. We found that the severity and recurrence of the disease within families varied and might also be dependent on SNPs. Mutations in the MCP gene seems to be a common etiology of aHUS in Czech patients.

Moake JL (2002) Thrombotic microangiopathies. N Engl J Med 347:589–600PubMedCrossRef

Boyle TG, Swerdlow DL, Griffin PM (1995) Escherichia coli 0157:H7 and the haemolytic uremic syndrome. N Engl J Med 333:364–368CrossRef

Noris M, Remuzzi G (2005) Hemolytic uremic syndrome. J Am Soc Nephrol 16:1035–1050PubMedCrossRef

Fitzpatrick MM, Walters MD, Trompeter RS, Dillon MI, Barratt TM (1993) Atypical (non-diarrhea-associated) hemolytic-uremic syndrome in childhood. J Pediatr 122:532–537PubMedCrossRef

Hellwage J, Jokiranta T, Koistinen V, Vaarala O, Meri S, Zipfel P (1999) Functional properties of complement factor H/related proteins FHR3 and FHR4: binding to the C3d region of C3b and differential regulation by heparin. FEBS Lett 462:345–352PubMedCrossRef

Józsi M, Licht C, Strobel S, Zipfel SLH, Richter H, Heinen S, Zipfel PF, Skerka C (2008) Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood 111:1512–1514PubMedCrossRef

Warwicker P, Goodship TH, Donne RL, Pirson Y, Nicholls A, Ward RM, Turnpenny P, Goodship JA (1998) Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int 53:836–844PubMedCrossRef

Noris M, Brioschi S, Caprioli J, Todeschini M, Bresin E, Porrati F, Gamba S, Remuzzi G (2003) Familial haemolytic uremic syndrome and an MCP mutation. Lancet 362:1542–1547PubMedCrossRef

Richards A, Kemp EJ, Liszewski MK, Goodship JA, Lampe AK, Decorte R, Muslumanoglu MH, Kavukcu S, Filler G, Pirson Y, Wen LS, Atkinson JP, Goodship TH (2003) Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc Natl Acad Sci USA 100:12966–12971PubMedCrossRef

10.

Fremeaux-Bacchi V, Dragon-Durey MA, Blouin J, Vigneau C, Kuypers D, Boudailliez B, Loirat C, Rondeau E, Fridman WH (2004) Complement factor I: a susceptibility gene for atypical haemolytic uremic syndrome. J Med Genet 41:1–5CrossRef

11.

Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero J, Plaisance S, Claes B, Lambrechts D, Zoja C, Remuzzi G, Conway EM (2009) Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 361:345–357PubMedCrossRef

12.

Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJH (2010) Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat 31:1445–1460CrossRef

13.

Sullivan M, Erlic Z, Hoffmann MM, Arbeiter K, Patzer L, Budde K, Hoppe B, Zeier M, Lhotta K, Rybicki LA, Bock A, Berisha G, Neumann HPH (2010) Mutations in hemolytic uremic syndrome. Ann Hum Genet 74:17–26PubMedCrossRef

14.

Liszewski MK, Leung M, Cui W, Subramanian VB, Parkinson J, Barlow PN, Manchester M, Atkinson JP (2000) Dissecting sites important for complement regulator activity in membrane cofactor protein (MCP; CD46). J Biol Chem 275:37692–37701PubMedCrossRef

15.

Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F, Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G (2006) Genetics of HUS: the impact of MCP, CFH and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108:1267–1279PubMedCrossRef

16.

Johns MB Jr, Paulus-Thomas JE (1989) Purification of human genomic DNA from whole blood using sodium perchlorate in place of phenol. Anal Biochem 180(2):276–278PubMedCrossRef

17.

Fremeaux-Bacchi V, Moulton EA, Kavanagh D, Dragon-Durey MA, Blouin J, Caudy A, Arzouk N, Cleper R, Francois M, Guest G, Pourrat J, Seligman R, Fridman WH, Loirat C, Atkinson JP (2006) Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome. J Am Soc Nephrol 17:2017–2025PubMedCrossRef

18.

Richards A, Buddles MR, Donne RL, Kaplan BS, Kirk E, Venning MC, Tielemans CL, Goodship JA, Goodship TH (2001) Factor H mutations in hemolytic uremic syndrome cluster in exons 18–20, a domain important for host cell recognition. Am J Hum Genet 68:485–490PubMedCrossRef

19.

Dragon-Durey M, Lorait C, Cloarec S, Macher MA, Blouin J, Nivet H, Weiss L, Fridman WH, Fremeaux-Bacchi V (2005) Anti-factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol 16:555–563PubMedCrossRef

20.

Saunders RE, Abarrategui-Garrido C, Fremeaux-Bacchi V, Goicoechea de Jorge E, Goodship THJ, Lopez Trascasa M, Noris M, Ponce Castro IM, Remuzzi G, Rodriguez de Cordoba S, Sanchez-Corral P, Skerka C, Zipfel PF, Perkins SJ (2007) The interactive Factor H-atypical hemolytic uremic syndrome mutation database and website: update and integration of membrane cofactor protein and Factor I mutations with structural models. Hum Mutat 28(3):222–234PubMedCrossRef

21.

Westra D, Volokhina E, van der Heijden E, Vos A, Huigen M, Jansen J, van Kaauwen E, van der Velden T, van de Kar N, van den Heuvel L (2010) Genetic disorders in complement (regulating) genes in patients with atypical haemolytic uremic syndrome (aHUS). Nephrol Dial Transplant 25:2195–2202PubMedCrossRef

22.

Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, Daina E, Fenili C, Castelletti F, Sorosina A, Piras R, Donadelli R, Maranta R, van der Meer I, Conway EM, Zipfel PF, Goodship TH, Remuzzi G (2010) Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 5:1844–1859PubMedCrossRef

23.

Wang G, Liszewski MK, Chan AC, Atkinson JP (2000) Membrane cofactor protein (MCP; CD46): isoform-specific tyrosine phosphorylation. J Immunol 164:1839–1846PubMed

24.

Fang CJ, Fremeaux-Bacchi V, Liszewski MK, Pianetti G, Noris M, Goodship THJ, Atkinson JP (2008) Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood 111:624–632PubMedCrossRef

25.

Schwarz JM, Rödelsperger C, Schuelke M, Seelow D (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7(8):575–576PubMedCrossRef

26.

Loirat C, Fremeaux-Bacchi V (2008) Hemolytic uremic syndrome recurrence after renal transplantation. Pediatr Transplant 12(6):619–629PubMedCrossRef

27.

Esparza-Gordillo J, Goicoechea de Jorge E, Buil A, Carreras Berges L, López-Trascasa M, Sánchez-Corral P, Rodríguez de Córdoba S (2005) Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. Hum Mol Genet 14(5):703–712PubMedCrossRef

Title: Manifestation of atypical hemolytic uremic syndrome caused by novel mutations in MCP
Authors: Dana Provaznikova
Simon Rittich
Michal Malina
Tomas Seeman
Iuri Marinov
Magdalena Riedl
Ingrid Hrachovinova
Publication date: 01-01-2012
Publisher: Springer-Verlag
Published in: Pediatric Nephrology / Issue 1/2012
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-011-1943-5

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Manifestation of atypical hemolytic uremic syndrome caused by novel mutations in MCP

Abstract

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Abstract

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