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Novel ACTN1 variants in cases of thrombocytopenia

Anne Vincenot 1 Paul Saultier 2 Shinji Kunishima 3 Marjorie Poggi 2 Marie-Françoise Hurtaud-Roux 1 Alain Roussel 4 Christine Biron-Andreani 5 Jean-François Claisse 6 Remy Dulery 7 Eric Durot 8 Véronique Fiore 9 Rémi Favier 10 Pierre Fenaux 11 Felipe Guerrero 12 Véronique Le Cam-Duchez 13 Elisabeth Mazoyer 14 Stephanie Müller 15 Benedicte Neven 16 Catherine Pouymayou 17 Bruno Royer 6 Pierre Sie 18 Sandrine Thouvenin 19 Catherine Trichet 20 Nathalie Trillot 21 Karima Yakouben 1 Schlegel Nicole 1 Marie-Christine Alessi 2
1 CHU Robert Debré
2 C2VN - Centre recherche en CardioVasculaire et Nutrition
3 Gifu University of Medical Science
4 AFMB - Architecture et fonction des macromolécules biologiques
5 UM - Université de Montpellier
6 CHU Amiens-Picardie
7 CHU Saint-Antoine [AP-HP]
8 CHU Reims - Centre Hospitalier Universitaire de Reims
9 CHU Bordeaux [Bordeaux]
10 CHU Armand Trousseau
11 CHU Saint Louis [APHP]
12 CHU Toulouse [Toulouse]
13 CHU Rouen
14 Hôpital Avicenne [AP-HP]
15 CH Rambouillet
16 CHU Necker - Enfants Malades [AP-HP]
17 TIMONE - Hôpital de la Timone [CHU - APHM]
18 UT3 - Université Toulouse III - Paul Sabatier
19 CHU Saint-Etienne
20 HUPNVS - Hôpitaux Universitaires Paris Nord Val-de-Seine
21 CHU de Lille - Centre Hospitalier Universitaire de Lille
Abstract : The ACTN1 gene has been implicated in inherited macrothrombocytopenia. To decipher the spectrum of variants and phenotype of ACTN1-related thrombocytopenia, we sequenced the ACTN1 gene in 272 cases of unexplained chronic or familial thrombocy-topenia. We identified 15 rare, monoallelic, nonsynonymous and likely pathogenic ACTN1 variants in 20 index cases from 20 unrelated families. Thirty-one family members exhibited thrombocytopenia. Targeted sequencing was carried out on 12 affected relatives, which confirmed presence of the variant. Twenty-eight of 32 cases with monoallelic ACTN1 variants had mild to no bleeding complications. Eleven cases harbored 11 different unreported ACTN1 variants that were monoallelic and likely pathogenic. Nine variants were located in the α-actinin-1 (ACTN1) rod domain and were predicted to hinder dimer formation. These variants displayed a smaller increase in platelet size compared with variants located outside the rod domain. In vitro expression of the new ACTN1 variants induced actin network disorganization and led to increased thickness of actin fibers. These findings expand the repertoire of ACTN1 variants associated with thrombocytopenia and highlight the high frequency of ACTN1-related thrombocytopenia cases. The rod domain, like other ACTN1 functional domains, may be mutated resulting in actin disorganization in vitro and thrombocytopenia with normal platelet size in most cases.
Keywords : ALPHA-ACTININ actin actinin ACTN1 constitutional platelet rod domain thrombocytopenia ACTIN-BINDING DOMAIN MUTATIONS MACROTHROMBOCYTOPENIA ALPHA-ACTININ-4
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UNIV-AMU | UNIV-TLSE3 | COMUE-NORMANDIE | UNIV-MONTPELLIER | CNRS | INRAE

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Anne Vincenot, Paul Saultier, Shinji Kunishima, Marjorie Poggi, Marie-Françoise Hurtaud-Roux, et al.. Novel ACTN1 variants in cases of thrombocytopenia. Human Mutation, Wiley, 2019, 40 (12), pp.2258-2269. ⟨10.1002/humu.23840⟩. ⟨hal-02556150⟩

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