A large family with a gain-of-function mutation of complement C3 predisposing to atypical hemolytic uremic syndrome, microhematuria, hypertension and chronic renal failure.
OBJECTIVE
Atypical hemolytic uremic syndrome (aHUS) is associated with mutations in genes encoding complement-regulatory proteins factor H, I and B and membrane cofactor protein. Recently, heterozygous gain-of-function mutations in the complement C3 gene have been found in patients with aHUS.


METHODS
A large family with a C3 R570Q mutation is described. Clinical and laboratory findings of carriers of the mutation and unaffected family members are reported.


RESULTS
The index patient suffered from recurrent aHUS at age 22 and developed end-stage renal failure. Of 24 family members, nine harbored the C3 R570Q mutation. Carriers showed reduced or borderline C3 levels. Arterial hypertension was found in six family members, microhematuria in five and chronic kidney disease stage 3 in two elderly carrier patients. Despite marked consumption of C3, serum terminal complement complex levels were not elevated in carriers compared with other family members.


CONCLUSIONS
The penetrance of the C3 R570Q mutation to induce aHUS is incomplete and lower compared with mutations in other genes predisposing to the disease. The mutation is possibly also associated with hypertension, hematuria and chronic kidney disease, all of which may represent consequences of long-term complement activation in the renal vasculature.
Lhotta
Karl
K
Department of Nephrology and Hypertension, Academic Teaching Hospital Feldkirch, Carinagasse 47, A-6800 Feldkirch, Austria. Karl.lhotta@lkhf.at
Janecke
Andreas R
AR
Scheiring
Johanna
J
Petzlberger
Barbara
B
Giner
Thomas
T
Fally
Verena
V
Würzner
Reinhard
R
Zimmerhackl
Lothar B
LB
Mayer
Gert
G
Fremeaux-Bacchi
Veronique
V
D000328:Adult; D000368:Aged; D002648:Child; D003176:Complement C3 / Q000235:genetics* / Q000276:immunology; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006417:Hematuria / Q000235:genetics* / Q000276:immunology; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics* / Q000276:immunology; D006579:Heterozygote; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000276:immunology; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
D003176:Complement C3