A missense mutation in the alpha-actinin 1 gene (ACTN1) is the cause of autosomal dominant macrothrombocytopenia in a large French family.
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.
Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France ; Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France ; Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire (CHU) Brest, Hôpital Morvan, Brest, France.
Paul
P
Guéguen
Karen
K
Rouault
Jian-Min
JM
Chen
Odile
O
Raguénès
Yann
Y
Fichou
Elisabeth
E
Hardy
Eric
E
Gobin
Brigitte
B
Pan-Petesch
Mathieu
M
Kerbiriou
Pascal
P
Trouvé
Pascale
P
Marcorelles
Jean-Francois
JF
Abgrall
Cédric
C
Le Maréchal
Claude
C
Férec
D000185:Actinin / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001792:Blood Platelets / Q000473:pathology* / Q000648:ultrastructure; D001853:Bone Marrow / Q000473:pathology; D019556:COS Cells; D002522:Chlorocebus aethiops; D005190:Family; D005260:Female; D005602:France; D015870:Gene Expression; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010974:Platelet Aggregation; D010976:Platelet Count; D017422:Sequence Analysis, DNA; D013921:Thrombocytopenia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult
C526905:ACTN1 protein, human; D000185:Actinin