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Mutations in membrane cofactor protein (CD46) gene in Indian children with hemolytic uremic syndrome.

ABSTRACT: Background:Mutations in the CD46 gene account for an important proportion of patients with atypical hemolytic uremic syndrome (aHUS) who characteristically show multiple relapses, no response to plasma exchange and low recurrence risk in allograft. We screened for mutations in CD46 in patients with and without circulating anti-factor H (FH) antibodies-associated aHUS. Methods:We estimated CD46 surface expression by flow cytometry and sequenced the CD46 gene in 23 and 56 patients with and without circulating anti-FH antibodies, respectively. Human Splicing Finder and PolyPhen2 were used for in silico prediction of pathogenicity. Results:Two novel and three known (c.286?+2T?>?G, c.104G?>?A and c.565T?>?G) mutations in CD46 were found in nine (11.4%) patients; one patient had a variant of unknown significance and two patients presented during the first year of life. Novel intronic (c.1127?+?46C?>?G) and exonic (c.911C?>?T) mutations are proposed to activate cryptic splicing sites or alter protein conformation. Markedly reduced CD46 surface expression was found in homozygous states in five patients. Conclusion:Patients with mutations in CD46 present at all ages, including the first year of life. Mutations in intron 2, (c.286?+2T?>?G) may be a potential hot spot in Indian children. Flow cytometry for CD46 expression is a satisfactory screening tool enabling early diagnosis.

SUBMITTER: Khandelwal P

PROVIDER: S-EPMC5888602 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Mutations in <i>membrane cofactor protein</i> (<i>CD46</i>) gene in Indian children with hemolytic uremic syndrome.

Khandelwal Priyanka P Birla Shweta S Bhatia Divya D Puraswani Mamta M Saini Himanshi H Sinha Aditi A Hari Pankaj P Sharma Arundhati A Bagga Arvind A

Clinical kidney journal 20170810 2

<h4>Background</h4>Mutations in the <i>CD46</i> gene account for an important proportion of patients with atypical hemolytic uremic syndrome (aHUS) who characteristically show multiple relapses, no response to plasma exchange and low recurrence risk in allograft. We screened for mutations in <i>CD46</i> in patients with and without circulating anti-factor H (FH) antibodies-associated aHUS.<h4>Methods</h4>We estimated <i>CD46</i> surface expression by flow cytometry and sequenced the <i>CD46</i> ...[more]

PMID: 29644059

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Project description:The hemolytic-uremic syndrome consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. The common form of the syndrome is triggered by infection with Shiga toxin-producing bacteria and has a favorable outcome. The less common form of the syndrome, called atypical hemolytic-uremic syndrome, accounts for about 10% of cases, and patients with this form of the syndrome have a poor prognosis. Approximately half of the patients with atypical hemolytic-uremic syndrome have mutations in genes that regulate the complement system. Genetic factors in the remaining cases are unknown. We studied the role of thrombomodulin, an endothelial glycoprotein with anticoagulant, antiinflammatory, and cytoprotective properties, in atypical hemolytic-uremic syndrome.We sequenced the entire thrombomodulin gene (THBD) in 152 patients with atypical hemolytic-uremic syndrome and in 380 controls. Using purified proteins and cell-expression systems, we investigated whether thrombomodulin regulates the complement system, and we characterized the mechanisms. We evaluated the effects of thrombomodulin missense mutations associated with atypical hemolytic-uremic syndrome on complement activation by expressing thrombomodulin variants in cultured cells.Of 152 patients with atypical hemolytic-uremic syndrome, 7 unrelated patients had six different heterozygous missense THBD mutations. In vitro, thrombomodulin binds to C3b and factor H (CFH) and negatively regulates complement by accelerating factor I-mediated inactivation of C3b in the presence of cofactors, CFH or C4b binding protein. By promoting activation of the plasma procarboxypeptidase B, thrombomodulin also accelerates the inactivation of anaphylatoxins C3a and C5a. Cultured cells expressing thrombomodulin variants associated with atypical hemolytic-uremic syndrome had diminished capacity to inactivate C3b and to activate procarboxypeptidase B and were thus less protected from activated complement.Mutations that impair the function of thrombomodulin occur in about 5% of patients with atypical hemolytic-uremic syndrome.

Dataset Information

Mutations in membrane cofactor protein (CD46) gene in Indian children with hemolytic uremic syndrome.

Publications

Mutations in <i>membrane cofactor protein</i> (<i>CD46</i>) gene in Indian children with hemolytic uremic syndrome.

Similar Datasets

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