title: Defining the genetics of thrombotic microangiopathies.
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.
authors.affiliation: Assistance Publique - Hopitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Paula
authors.initials: P
authors.lastname: Vieira-Martins
authors.affiliation: Assistance Publique - Hopitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Carine
authors.initials: C
authors.lastname: El Sissy
authors.affiliation: Assistance Publique - Hopitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Bordereau
authors.affiliation: Assistance Publique - Hopitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Gruber
authors.affiliation: Assistance Publique - Hopitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Rosain
authors.affiliation: 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.
authors.forename: Veronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
mesh_terms: D000071120:ADAMTS13 Protein / Q000235:genetics*; D000818:Animals; D065766:Atypical Hemolytic Uremic Syndrome / Q000235:genetics*; D003165:Complement System Proteins / Q000235:genetics*; D015894:Genome, Human; D006801:Humans; D051916:Membrane Cofactor Protein / Q000235:genetics*; D011110:Polymorphism, Genetic; D057049:Thrombotic Microangiopathies / Q000235:genetics*
chemical_list: C497857:CD46 protein, human; D051916:Membrane Cofactor Protein; D003165:Complement System Proteins; D000071120:ADAMTS13 Protein
keywords: Complement; Thrombotic microangiopathy; Variant