title: First case of aplastic anemia in a Japanese child with a homozygous missense mutation in the NBS1 gene (I171V) associated with genomic instability.
abstract: The NBS1 gene is strongly linked to several factors involved in genome integrity. Functional disruption of NBS1 could therefore induce genomic instability and carcinogenesis. Four children with acute lymphoblastic leukemia have been reported to be heterozygous for a germline and/or somatic missense mutation in NBS1, leading to the I171V substitution. We screened healthy controls and pediatric patients with hematological malignancies and aplastic anemia (AA) for the presence of I171V. Of the 62 patients, one individual with AA was confirmed to harbor a homozygous I171V mutation. Genetic analysis of NBS1 in this patient and her healthy parents indicated that she inherited the germline I171V mutation from her father and the wild-type allele from her mother, and that the second I171V hit occurred on the wild-type allele early in embryonic development. Furthermore, cytogenetic analysis of lymphoblastic cell lines from the patient indicated a remarkable increase in numerical and structural chromosomal aberrations in the absence of clastogens, suggesting that she potentially carried genomic instability. This is the first report of AA with a homozygous I171V mutation. We hypothesize that NBS1 may play an important role in the pathogenesis of AA.
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.forename: Kimiko
authors.initials: K
authors.lastname: Shimizu
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Mimaki
authors.forename: Tokuki
authors.initials: T
authors.lastname: Sakiyama
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mori
authors.forename: Noriko
authors.initials: N
authors.lastname: Shimasaki
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
authors.forename: Kei
authors.initials: K
authors.lastname: Nakachi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ohta
authors.forename: Misao
authors.initials: M
authors.lastname: Ohki
mesh_terms: D000741:Anemia, Aplastic / Q000235:genetics*; D044466:Asian People; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D002869:Chromosome Aberrations; D005260:Female; D042822:Genomic Instability; D006801:Humans; D007621:Karyotyping; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins