Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome

Shuju Feng; Stephen J Eyler; Yuzhou Zhang; Tara Maga; Carla M Nester; Michael H Kroll; Richard J Smith; Vahid Afshar-Kharghan

doi:10.1182/blood-2013-03-492421

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Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome

Journal article

Open access

Peer reviewed

Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome

Shuju Feng, Stephen J Eyler, Yuzhou Zhang, Tara Maga, Carla M Nester, Michael H Kroll, Richard J Smith and Vahid Afshar-Kharghan

Blood, Vol.122(8), pp.1487-1493

08/22/2013

DOI: 10.1182/blood-2013-03-492421

PMCID: PMC3750341

PMID: 23847193

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Abstract

Reduction in ADAMTS13 function and complement dysregulation coexist in a significant number of patients with aHUS. Variations in the ADAMTS13 gene (polymorphisms and rare variants) are partly responsible for the reduced ADAMTS13 function in aHUS. Complement dysregulation leads to atypical hemolytic uremic syndrome (aHUS), while ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura. We investigated whether genetic variations in the ADAMTS13 gene partially explain the reduced activity known to occur in some patients with aHUS. We measured complement activity and ADAMTS13 function, and completed mutation screening of multiple complement genes and ADAMTS13 in a large cohort of aHUS patients. In over 50% of patients we identified complement gene mutations. Surprisingly, 80% of patients also carried at least 1 nonsynonymous change in ADAMTS13, and in 38% of patients, multiple ADAMTS13 variations were found. Six of the 9 amino acid substitutions in ADAMTS13 were common single nucleotide polymorphisms; however, 3 variants—A747V, V832M, and R1096H— were rare, with minor allele frequencies of 0.0094%, 0.5%, and 0.32%, respectively. Reduced complement and ADAMTS13 activity (<60% of normal activity) were found in over 60% and 50% of patients, respectively. We concluded that partial ADAMTS13 deficiency is a common finding in aHUS patients and that genetic screening and functional tests of ADAMTS13 should be considered in these patients.

Thrombosis and Hemostasis

Details

Title: Subtitle: Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome
Creators: Shuju Feng - Division of Internal Medicine, Benign Hematology, University of Texas MD Anderson Cancer Center, Houston, TX; and
Stephen J Eyler - Molecular Otolaryngology and Renal Research Laboratories and the
Yuzhou Zhang - Molecular Otolaryngology and Renal Research Laboratories and the
Tara Maga - Molecular Otolaryngology and Renal Research Laboratories and the
Carla M Nester - Molecular Otolaryngology and Renal Research Laboratories and the
Michael H Kroll - Division of Internal Medicine, Benign Hematology, University of Texas MD Anderson Cancer Center, Houston, TX; and
Richard J Smith - Molecular Otolaryngology and Renal Research Laboratories and the
Vahid Afshar-Kharghan - Division of Internal Medicine, Benign Hematology, University of Texas MD Anderson Cancer Center, Houston, TX; and
Resource Type: Journal article
Publication Details: Blood, Vol.122(8), pp.1487-1493
DOI: 10.1182/blood-2013-03-492421
PMID: 23847193
PMCID: PMC3750341
NLM abbreviation: Blood
ISSN: 0006-4971
eISSN: 1528-0020
Publisher: American Society of Hematology; Washington, DC
Grant note: 1R21AI101932 / National Institutes of Health
Language: English
Date published: 08/22/2013
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
Record Identifier: 9984006354302771

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