title: ACTN1 mutations cause congenital macrothrombocytopenia.
abstract: Congenital macrothrombocytopenia (CMTP) is a heterogeneous group of rare platelet disorders characterized by a congenital reduction of platelet counts and abnormally large platelets, for which CMTP-causing mutations are only found in approximately half the cases. We herein performed whole-exome sequencing and targeted Sanger sequencing to identify mutations that cause CMTP, in which a dominant mode of transmission had been suspected but for which no known responsible mutations have been documented. In 13 Japanese CMTP-affected pedigrees, we identified six (46%) affected by ACTN1 variants cosegregating with CMTP. In the entire cohort, ACNT1 variants accounted for 5.5% of the dominant forms of CMTP cases and represented the fourth most common cause in Japanese individuals. Individuals with ACTN1 variants presented with moderate macrothrombocytopenia with anisocytosis but were either asymptomatic or had only a modest bleeding tendency. ACTN1 encodes α-actinin-1, a member of the actin-crosslinking protein superfamily that participates in the organization of the cytoskeleton. In vitro transfection experiments in Chinese hamster ovary cells demonstrated that altered α-actinin-1 disrupted the normal actin-based cytoskeletal structure. Moreover, transduction of mouse fetal liver-derived megakaryocytes with disease-associated ACTN1 variants caused a disorganized actin-based cytoskeleton in megakaryocytes, resulting in the production of abnormally large proplatelet tips, which were reduced in number. Our findings provide an insight into the pathogenesis of CMTP.
authors: Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan. kunishis@nnh.hosp.go.jp
authors: Shinji
authors: S
authors: Kunishima
authors: Yusuke
authors: Y
authors: Okuno
authors: Kenichi
authors: K
authors: Yoshida
authors: Yuichi
authors: Y
authors: Shiraishi
authors: Masashi
authors: M
authors: Sanada
authors: Hideki
authors: H
authors: Muramatsu
authors: Kenichi
authors: K
authors: Chiba
authors: Hiroko
authors: H
authors: Tanaka
authors: Koji
authors: K
authors: Miyazaki
authors: Michio
authors: M
authors: Sakai
authors: Masatoshi
authors: M
authors: Ohtake
authors: Ryoji
authors: R
authors: Kobayashi
authors: Akihiro
authors: A
authors: Iguchi
authors: Gen
authors: G
authors: Niimi
authors: Makoto
authors: M
authors: Otsu
authors: Yoshiyuki
authors: Y
authors: Takahashi
authors: Satoru
authors: S
authors: Miyano
authors: Hidehiko
authors: H
authors: Saito
authors: Seiji
authors: S
authors: Kojima
authors: Seishi
authors: S
authors: Ogawa
mesh_terms: D000185:Actinin / Q000235:genetics*; D000818:Animals; D044466:Asian People / Q000235:genetics; D001792:Blood Platelets / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods; D013921:Thrombocytopenia / Q000097:blood / Q000235:genetics* / Q000378:metabolism
chemical_list: C526905:ACTN1 protein, human; D000185:Actinin