A missense mutation in the alpha-actinin 1 gene (ACTN1) is the cause of autosomal dominant macrothrombocytopenia in a large French family

PLoS One. 2013 Sep 17;8(9):e74728. doi: 10.1371/journal.pone.0074728. eCollection 2013.

Abstract

Inherited thrombocytopenia is a heterogeneous group of disorders characterized by a reduced number of blood platelets. Despite the identification of nearly 20 causative genes in the past decade, approximately half of all subjects with inherited thrombocytopenia still remain unexplained in terms of the underlying pathogenic mechanisms. Here we report a six-generation French pedigree with an autosomal dominant mode of inheritance and the identification of its genetic basis. Of the 55 subjects available for analysis, 26 were diagnosed with isolated macrothrombocytopenia. Genome-wide linkage analysis mapped a 10.9 Mb locus to chromosome 14 (14q22) with a LOD score of 7.6. Candidate gene analysis complemented by targeted next-generation sequencing identified a missense mutation (c.137GA; p.Arg46Gln) in the alpha-actinin 1 gene (ACTN1) that segregated with macrothrombocytopenia in this large pedigree. The missense mutation occurred within actin-binding domain of alpha-actinin 1, a functionally critical domain that crosslinks actin filaments into bundles. The evaluation of cultured mutation-harboring megakaryocytes by electron microscopy and the immunofluorescence examination of transfected COS-7 cells suggested that the mutation causes disorganization of the cellular cytoplasm. Our study concurred with a recently published whole-exome sequence analysis of six small Japanese families with congenital macrothrombocytopenia, adding ACTN1 to the growing list of thrombocytopenia genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actinin / genetics*
  • Actinin / metabolism
  • Adolescent
  • Adult
  • Aged
  • Animals
  • Blood Platelets / pathology*
  • Blood Platelets / ultrastructure
  • Bone Marrow / pathology
  • COS Cells
  • Chlorocebus aethiops
  • Family
  • Female
  • France
  • Gene Expression
  • Genes, Dominant*
  • Humans
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Pedigree
  • Platelet Aggregation
  • Platelet Count
  • Sequence Analysis, DNA
  • Thrombocytopenia / genetics*
  • Thrombocytopenia / metabolism
  • Thrombocytopenia / pathology*
  • Young Adult

Substances

  • ACTN1 protein, human
  • Actinin

Grant support

This work was partly supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), France. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.