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Transfus Apher Sci. 2016 Apr;54(2):212-9. doi: 10.1016/j.transci.2016.04.011. Epub 2016 May 2.

Defining the genetics of thrombotic microangiopathies.

Author information

1
Assistance Publique - Hopitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France.
2
Assistance Publique - Hopitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France; INSERM UMRS 1138, Cordeliers Research Center, Paris, France. Electronic address: veronique.fremeaux-bacchi@aphp.fr.

Abstract

The spectrum of the thrombotic microangiopathies (TMA) encompasses a heterogeneous group of disorders with hereditary and acquired forms. Endothelial cell injury in the microvasculature is common to all TMAs, whatever the pathophysiological process. In this review we describe genetic mutations characteristic of certain TMAs and review their contributions to disease. Recent identification of novel pathologic mutations has been enabled by exome studies. The monogenic forms of TMA are more frequently caused by recessive alterations in von Willebrand factor cleaving protease ADAMST13, leading to congenital thrombotic thrombocytopenic purpura, or cobalamine C and DGKE genes, leading to an atypical hemolytic-uremic syndrome (aHUS)-like TMA. aHUS, whether idiopathic or linked to a known complement amplifying condition, is a TMA that primarily affects kidney function. It often results from a combination of an underlying genetic susceptibility with environmental factors activating the alternative complement pathway. Pathogenic variants in at least five complement genes coding for complement factor H (CFH) complement factor I (CFI), MCP (CD46), C3 and complement factor B (CFB) have been demonstrated to increase the risk of developing aHUS, but several more genes have been implicated. A new challenge is to separate disease-associated genetic variants from the broader background of variants or polymorphisms present in all human genomes that are rare, potentially functional, but may or may not be pathogenic.

KEYWORDS:

Complement; Thrombotic microangiopathy; Variant

PMID:
27177491
DOI:
10.1016/j.transci.2016.04.011
[Indexed for MEDLINE]

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