Abstract
Background
Hemolytic uremic syndrome (HUS) secondary to homozygous mutations in CD46 is uncommon. While heterozygous individuals may remain asymptomatic, homozygous mutations with severely depleted CD46 surface expression without disease manifestation is rare.
Methods
We report on two siblings with features suggestive of hemolytic uremic syndrome. Estimation of CD46 expression by flow cytometry and gene sequencing were performed in members of this family.
Results
Three siblings, two of whom were symptomatic, had markedly decreased (<10 %) cell surface expression of CD46 and homozygous splice site mutation (IVS2 + 2 T > G) in the CD46 gene; the other 10-year-old sibling was asymptomatic. The illness was preceded by dengue shock syndrome in the index case. Both parents and two other siblings were heterozygous for this CD46 mutation.
Conclusions
Homozygous IVS2 + 2 T > G mutation in CD46 gene, similar to heterozygous mutation, may be clinically silent at least during childhood. The role of antecedent infections in triggering the disease requires further examination.
Similar content being viewed by others
References
Loirat C, Fremeaux-Bacchi V (2011) Atypical hemolytic uremic syndrome. Orphanet J Rare Dis 6:60
Kavanagh D, Goodship TH, Richards A (2013) Atypical hemolytic uremic syndrome. Semin Nephrol 33:508–530
Richards A, Kathryn Liszewski M, Kavanagh D, Fang CJ, Moulton E, Fremeaux-Bacchi V, Remuzzi G, Noris M, Goodship TH, Atkinson JP (2007) Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome. Mol Immunol 44:111–122
Sinha A, Gulati A, Saini S, Blanc C, Gupta A, Gurjar BS, Saini H, Kotresh ST, Ali U, Bhatia D, Ohri A, Kumar M, Agarwal I, Gulati S, Anand K, Vijayakumar M, Sinha R, Sethi S, Salmona M, George A, Bal V, Singh G, Dinda AK, Hari P, Rath S, Dragon-Durey MA, Bagga A, Registry IH (2014) Prompt plasma exchanges and immunosuppressive treatment improves the outcomes of anti-factor H autoantibody-associated hemolytic uremic syndrome in children. Kidney Int 85:1151–1160
Moore I, Strain L, Pappworth I, Kavanagh D, Barlow PN, Herbert AP, Schmidt CQ, Staniforth SJ, Holmes LV, Ward R, Morgan L, Goodship TH, Marchbank KJ (2010) Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. Blood 115:379–387
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 17:2017–2025
Bresin E, Rurali E, Caprioli J, Sanchez-Corral P, Fremeaux-Bacchi V, Rodriguez de Cordoba S, Pinto S, Goodship TH, Alberti M, Ribes D, Valoti E, Remuzzi G, Noris M, European Working Party on Complement Genetics in Renal D (2013) Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. J Am Soc Nephrol 24:475–486
Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaime F, Dragon-Durey MA, Ngo S, Moulin B, Servais A, Provot F, Rostaing L, Burtey S, Niaudet P, Deschenes G, Lebranchu Y, Zuber J, Loirat C (2013) Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol 8:554–562
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 5:1844–1859
Couzi L, Contin-Bordes C, Marliot F, Sarrat A, Grimal P, Moreau JF, Merville P, Fremeaux-Bacchi V (2008) Inherited deficiency of membrane cofactor protein expression and varying manifestations of recurrent atypical hemolytic uremic syndrome in a sibling pair. Am J Kidney Dis 52:e5–9
Fremeaux-Bacchi V, Arzouk N, Ferlicot S, Charpentier B, Snanoudj R, Durrbach A (2007) Recurrence of HUS due to CD46/MCP mutation after renal transplantation: a role for endothelial microchimerism. Am J Transplant 7:2047–2051
Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ (2010) Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat 31:E1445–1460
Brocklebank V, Wong EK, Fielding R, Goodship TH, Kavanagh D (2014) Atypical haemolytic uremic syndrome associated with a CD46 mutation triggered by Shigella flexneri. Clin Kidney J 7:286–288
Alberti M, Valoti E, Piras R, Bresin E, Galbusera M, Tripodo C, Thaiss F, Remuzzi G, Noris M (2013) Two patients with history of STEC-HUS, posttransplant recurrence and complement gene mutations. Am J Transplant 13:2201–2206
Le Friec G, Sheppard D, Whiteman P, Karsten CM, Shamoun SA, Laing A, Bugeon L, Dallman MJ, Melchionna T, Chillakuri C, Smith RA, Drouet C, Couzi L, Fremeaux-Bacchi V, Kohl J, Waddington SN, McDonnell JM, Baker A, Handford PA, Lea SM, Kemper C (2012) The CD46–Jagged1 interaction is critical for human TH1 immunity. Nat Immunol 13:1213–1221
Fuchs A, Atkinson JP, Fremeaux-Bacchi V, Kemper C (2009) CD46-induced human Treg enhance B-cell responses. Eur J Immunol 39:3097–3109
Wiersinga WJ, Scheepstra CG, Kasanardjo JS, de Vries PJ, Zaaijer H, Geerlings SE (2006) Dengue fever-induced hemolytic uremic syndrome. Clin Infect Dis 43:800–801
Nascimento EJ, Silva AM, Cordeiro MT, Brito CA, Gil LH, Braga-Neto U, Marques ET (2009) Alternative complement pathway deregulation is correlated with dengue severity. PLoS One 4, e6782
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 uraemic syndrome (aHUS). Nephrol Dial Transplant 25:2195–2202
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 HP (2010) Epidemiological approach to identifying genetic predispositions for atypical hemolytic uremic syndrome. Ann Hum Genet 74:17–26
Acknowledgments
The study was supported by the Department of Biotechnology, Government of India (102/IFD/SAN/PR2624/2010-11), Indo-French Centre for Promotion of Advanced Research (CEFIPRA) Project 4703 and a grant from the Korean Health Technology R & D Project, Ministry of Health and Welfare, Republic of Korea (HI12C0014).
Conflict of interest
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bhatia, D., Khandelwal, P., Sinha, A. et al. Incomplete penetrance of CD46 mutation causing familial atypical hemolytic uremic syndrome. Pediatr Nephrol 30, 2215–2220 (2015). https://doi.org/10.1007/s00467-015-3189-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-015-3189-0