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Neurodevelopmental abnormalities associated with severe congenital neutropenia due to the R86X mutation in the HAX1 gene
  1. Nobutsune Ishikawa (ishikan{at}hiroshima-u.ac.jp)
  1. Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Japan
    1. Satoshi Okada
    1. Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Japan
      1. Mizuka Miki
      1. Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Japan
        1. Kenichiro Shirao
        1. Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Japan
          1. Hirotaka Kihara
          1. Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Japan
            1. Miyuki Tsumura
            1. Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Japan
              1. Kazuhiro Nakamura
              1. Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Japan
                1. Hiroshi Kawaguchi
                1. Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Japan
                  1. Motoaki Ohtsubo
                  1. Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Japan
                    1. Shin'ichiro Yasunaga
                    1. Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Japan
                      1. Kousaku Matsubara
                      1. Department of Pediatrics, Nishi-Kobe Medical Center, Japan
                        1. Masahiro Sako
                        1. Department of Pediatric Hematology/Oncology, Children's Medical Center, Osaka City General Hospital, Japan
                          1. Junichi Hara
                          1. Department of Pediatric Hematology/Oncology, Children's Medical Center, Osaka City General Hospital, Japan
                            1. Masaaki Shiohara
                            1. Department of Pediatrics, Shinshu University Faculty of Medicine, Japan
                              1. Seiji Kojima
                              1. Department of Pediatrics, Nagoya University School of Medicine, Japan
                                1. Yoshihiro Takihara
                                1. Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Japan
                                  1. Masao Kobayashi
                                  1. Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Japan

                                    Abstract

                                    OBJECTIVE: Severe congenital neutropenia (SCN), also known as Kostmann syndrome (SCN3, OMIM 610738), includes a variety of hematological disorders caused by different genetic abnormalities. Mutations in ELA2 are most often the cause in autosomal dominant or sporadic forms. Recently, mutations in HAX1 have been identified as the cause of some autosomal recessive forms of SCN, including those present in the original pedigree first reported by Kostmann. We sought to determine the relationship between HAX1 gene mutations and the clinical characteristics of Japanese cases of SCN.

                                    METHODS: The genes implicated in SCN (ELA2, HAX1, Gfi-1, WAS, and P14) were analyzed in 18 Japanese patients with SCN. The clinical features of these patients were obtained from medical records. Immunoblotting of HAX1 was performed on cell extracts from peripheral blood leukocytes from patients and/or their parents.

                                    RESULTS: We found five patients with HAX1 deficiency and 11 patients with mutations in the ELA2 gene. In HAX1 deficiency, a homozygous single base-pair substitution (256C>T), which causes the nonsense change R86X, was identified in three affected individuals. Two sibling patients showed a compound heterozygous mutation consisting of a single base pair substitution (256C>T) and a 59-bp deletion at nucleotides 376-434. There was no detectable phenotype in any heterozygous carrier. All patients with HAX1 deficiency had experienced developmental delay. Three patients carrying R86X also suffered from epileptic seizures. In contrast, no SCN patient with heterozygous mutations in the ELA2 gene suffered from any neurodevelopmental abnormality.

                                    CONCLUSIONS: These findings suggest that the R86X mutation in the HAX1 gene is an abnormality in Japanese SCN patients with HAX1 deficiency and may lead to neurodevelopmental abnormalities and severe myelopoietic defects.

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