title: Complement mutations in diacylglycerol kinase-ε-associated atypical hemolytic uremic syndrome.
abstract: OBJECTIVE
  Atypical hemolytic uremic syndrome is characterized by vascular endothelial damage caused by complement dysregulation. Consistently, complement inhibition therapies are highly effective in most patients with atypical hemolytic uremic syndrome. Recently, it was shown that a significant percentage of patients with early-onset atypical hemolytic uremic syndrome carry mutations in diacylglycerol kinase-ε, an intracellular protein with no obvious role in complement. These data support an alternative, complement-independent mechanism leading to thrombotic microangiopathy that has implications for treatment of early-onset atypical hemolytic uremic syndrome. To get additional insights into this new form of atypical hemolytic uremic syndrome, the diacylglycerol kinase-ε gene in a cohort with atypical hemolytic uremic syndrome was analyzed.
  
  
  METHODS
  Eighty-three patients with early-onset atypical hemolytic uremic syndrome (<2 years) enrolled in the Spanish atypical hemolytic uremic syndrome registry between 1999 and 2013 were screened for mutations in diacylglycerol kinase-ε. These patients were also fully characterized for mutations in the genes encoding factor H, membrane cofactor protein, factor I, C3, factor B, and thrombomodulin CFHRs copy number variations and rearrangements, and antifactor H antibodies.
  
  
  RESULTS
  Four patients carried mutations in diacylglycerol kinase-ε, one p.H536Qfs*16 homozygote and three compound heterozygotes (p.W322*/p.P498R, two patients; p.Q248H/p.G484Gfs*10, one patient). Three patients also carried heterozygous mutations in thrombomodulin or C3. Extensive plasma infusions controlled atypical hemolytic uremic syndrome recurrences and prevented renal failure in the two patients with diacylglycerol kinase-ε and thrombomodulin mutations. A positive response to plasma infusions and complement inhibition treatment was also observed in the patient with concurrent diacylglycerol kinase-ε and C3 mutations.
  
  
  CONCLUSIONS
  Data suggest that complement dysregulation influences the onset and disease severity in carriers of diacylglycerol kinase-ε mutations and that treatments on the basis of plasma infusions and complement inhibition are potentially useful in patients with combined diacylglycerol kinase-ε and complement mutations. A comprehensive understanding of the genetic component predisposing to atypical hemolytic uremic syndrome is, therefore, critical to guide an effective treatment.
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain; Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain;
authors.forename: Daniel
authors.initials: D
authors.lastname: Sánchez Chinchilla
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain; Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain;
authors.forename: Sheila
authors.initials: S
authors.lastname: Pinto
authors.affiliation: Department of Pediatrics, Division of Pediatric Nephrology, University of Bonn, Bonn, Germany;
authors.forename: Bernd
authors.initials: B
authors.lastname: Hoppe
authors.affiliation: Department of Nephrology, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina;
authors.forename: Marta
authors.initials: M
authors.lastname: Adragna
authors.affiliation: Department of Nephrology, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina;
authors.forename: Laura
authors.initials: L
authors.lastname: Lopez
authors.affiliation: Servicio de Nefrología Pediátrica, Hospital Universitario Infantil Miguel Servet, Zaragoza, Spain; and.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Justa Roldan
authors.affiliation: Servicio de Nefrología Pediátrica.
authors.forename: Antonia
authors.initials: A
authors.lastname: Peña
authors.affiliation: Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain; Unidad de Inmunología, and.
authors.forename: Margarita
authors.initials: M
authors.lastname: Lopez Trascasa
authors.affiliation: Unidad de Investigación, Hospital Universitario La Paz/Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain;
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Corral
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain; Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain;
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodríguez de Córdoba
mesh_terms: D000293:Adolescent; D065766:Atypical Hemolytic Uremic Syndrome / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003165:Complement System Proteins / Q000235:genetics*; D019852:Diacylglycerol Kinase / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree
chemical_list: D003165:Complement System Proteins; C526464:DGKE protein, human; D019852:Diacylglycerol Kinase
keywords: complement; genetic renal disease; hemolytic uremic syndrome