ADAMTS13 Gene Mutations Influence ADAMTS13 Conformation and Disease Age-Onset in the French Cohort of Upshaw–Schulman Syndrome

Bérangère S. Joly; Pierre Boisseau; Elien Roose; Alain Stepanian; Nathalie Biebuyck; Julien Hogan; François Provot; Yahsou Delmas; Céline Garrec; Karen Vanhoorelbeke; Paul Coppo; Agnès Veyradier; on behalf of the French Reference Center for Thrombotic Microangiopathies

doi:10.1055/s-0038-1673686

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2018; 118(11): 1902-1917
DOI: 10.1055/s-0038-1673686

Cellular Haemostasis and Platelets

Georg Thieme Verlag KG Stuttgart · New York

ADAMTS13 Gene Mutations Influence ADAMTS13 Conformation and Disease Age-Onset in the French Cohort of Upshaw–Schulman Syndrome

Bérangère S. Joly^*

¹Institut Universitaire d'Hématologie, Université Paris Diderot, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France

²Service d'Hématologie Biologique, Université Paris Diderot, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France

,

Pierre Boisseau^*

³Service de Génétique Médicale, Hôpital Hôtel-Dieu, CHU de Nantes, Nantes, France

,

Elien Roose

⁴Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Kulak Campus Kortrijk, KU Leuven, Kortrijk, Belgium

,

Alain Stepanian

¹Institut Universitaire d'Hématologie, Université Paris Diderot, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France

²Service d'Hématologie Biologique, Université Paris Diderot, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France

,

Nathalie Biebuyck

⁵Service de Néphrologie Pédiatrique, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France

,

Julien Hogan

⁶Service de Néphrologie Pédiatrique, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, Paris, France

,

François Provot

⁷Service de néphrologie, CHRU de Lille, Lille, France

,

Yahsou Delmas

⁸Service de Néphrologie, CHU Pellegrin, Bordeaux, France

,

Céline Garrec

³Service de Génétique Médicale, Hôpital Hôtel-Dieu, CHU de Nantes, Nantes, France

,

Karen Vanhoorelbeke

⁴Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Kulak Campus Kortrijk, KU Leuven, Kortrijk, Belgium

,

Paul Coppo

⁹Département d'Hématologie Clinique, Université Pierre et Marie Curie, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France

,

Agnès Veyradier

¹Institut Universitaire d'Hématologie, Université Paris Diderot, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France

²Service d'Hématologie Biologique, Université Paris Diderot, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France

,

on behalf of the French Reference Center for Thrombotic Microangiopathies

› Institutsangaben

Abstract

Background Congenital thrombotic thrombocytopaenic purpura (TTP) or Upshaw–Schulman syndrome (USS) is a rare, life-threatening, inherited thrombotic microangiopathy (TMA). USS is mostly due to bi-allelic recessive sequence variations of the a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) gene inducing a severe ADAMTS13 deficiency (activity < 10 IU/dL). In healthy individuals, ADAMTS13 circulates in a folded conformation where CUB domains interact with the spacer domain. The spacer–CUB interaction is abrogated when ADAMTS13 is conformationally activated.

Objective This article evaluates the influence of ADAMTS13 sequence variations on both clinical/biological phenotype and ADAMTS13 conformation in USS.

Patients and Methods All USS patients from the French registry for TMAs (1 January 2000 to 1 June 2017) were investigated for ADAMTS13 genotype, phenotype (activity, antigen and autoantibodies) and conformation. Clinical records were analysed (inaugural acute TTP and follow-up). Child-onset USS was compared with adult-onset USS.

Results Fifty-six USS patients from 51 families (34 child-onset and 22 adult-onset cases) were enrolled. Child-onset USS was characterized by a large panel of ADAMTS13 sequence variations (n = 43), spread all over ADAMTS13 gene and not correlated with either clinical features or plasmatic ADAMTS13 parameters. In contrast, adult-onset USS, consisting exclusively in pregnancy-induced TTP, included a smaller and distinct panel of ADAMTS13 sequence variations (n = 20) because of one mutation (p.Arg1060Trp) present in 82% of patients. ADAMTS13 conformation was studied in 16 USS patients (5 child-onset and 11 adult-onset USS, encompassing 16 distinct ADAMTS13 sequence variations) whose ADAMTS13 antigen levels were detectable: 14 of 16 patients (87.5%) exhibited abnormalities of ADAMTS13 conformation.

Conclusion In USS, age-onset defines two entities and ADAMTS13 sequence variations modify ADAMTS13 conformation.

Keywords

ADAMTS13 - thrombotic thrombocytopenic purpura - Upshaw–Schulman syndrome - von Willebrand factor - rare disease

Volltext

Referenzen

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