title: ACTN1 rod domain mutation associated with congenital macrothrombocytopenia.
abstract: Mutations in ACTN1, the gene encoding the actin-crosslinking protein α-actinin-1, cause autosomal dominant macrothrombocytopenia. α-Actinin-1 exists as antiparallel dimers, composed of an N-terminal actin-binding domain (ABD), four spectrin-like repeats (SLRs), which form the spacer rod, and a C-terminal calmodulin-like (CaM) domain. All of the previously reported ACTN1 mutations associated with macrothrombocytopenia reside within the ABD and the CaM domain and not within the SLR domain. In this report, we describe a mutation in SLR2 of α-actinin-1 (p.Leu395Gln) associated with familial macrothrombocytopenia. A 3-year-old boy and his mother both had this mutation. They showed a mild form of thrombocytopenia without severe bleeding, accompanied by an elevated mean platelet volume. Consistent with the previous reports of mutations that reside in the ABD or the CaM domain, immunofluorescence examination revealed disorganization of the actin cytoskeleton in Gln395 mutant-transduced Chinese hamster ovary cells. Our findings suggest a novel mechanism for the pathogenesis of ACTN1-related macrothrombocytopenia that does not involve functional domain mutations.
authors.affiliation: Department of Pediatrics, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaizuki, Matsuoka, Eiheiji, Yoshida, Fukui, 9101193, Japan. yasutomi@u-fukui.ac.jp.
authors.forename: Motoko
authors.initials: M
authors.lastname: Yasutomi
authors.affiliation: Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, 4-1-1 Sannomaru, Naka-ku, Nagoya, 4600001, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kunishima
authors.affiliation: Department of Pediatrics, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaizuki, Matsuoka, Eiheiji, Yoshida, Fukui, 9101193, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Okazaki
authors.affiliation: Department of Pediatrics, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaizuki, Matsuoka, Eiheiji, Yoshida, Fukui, 9101193, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Tanizawa
authors.affiliation: Tsuchida Pediatrics Clinic, 11-10-2 Yoshimasa, Maruoka, Sakai, Fukui, 9100372, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Tsuchida
authors.affiliation: Department of Pediatrics, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaizuki, Matsuoka, Eiheiji, Yoshida, Fukui, 9101193, Japan.
authors.forename: Yusei
authors.initials: Y
authors.lastname: Ohshima
mesh_terms: D000185:Actinin / Q000737:chemistry / Q000235:genetics*; D000818:Animals; D016466:CHO Cells; D002675:Child, Preschool; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D017433:Protein Structure, Secondary; D013921:Thrombocytopenia / Q000175:diagnosis* / Q000235:genetics*
chemical_list: C526905:ACTN1 protein, human; D000185:Actinin
keywords: ACTN1; Macrothrombocytopenia; Rod; Spectrin-like repeat; α-actinin-1