Inherited Deficiency of Membrane Cofactor Protein Expression and Varying Manifestations of Recurrent Atypical Hemolytic Uremic Syndrome in a Sibling Pair

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathic disorder that may be familial or sporadic. Complement factor H (CFH), factor I, and membrane cofactor protein (MCP; CD46), 3 regulators of the alternative pathway of the complement system activation, have been implicated in this pathological state. To date, 29 different mutations of CD46 have been reported, with incomplete penetrance and better clinical outcome compared with CFH mutations. Of those mutations, only 6 were found to be homozygous (accounting for 8 patients), and 5 resulted in a lack of or dramatically decreased cell-surface CD46 expression. We report here the seventh patient with a null mutation associated with recurrent aHUS. This mutation, a guanine to cytosine substitution in the first nucleotide of intron 2, disrupts a splice donor site. Interestingly, the patient's disease-free sister showed the same homozygous mutation. Extensive analysis of other complement regulatory protein- and polymorphism-associated risk factors did not uncover a difference between the patient and his sister. In conclusion, we describe for the first time a disease-free individual with complete CD46 deficiency, confirming the extremely variable penetrance and genetic complexity of aHUS.