Neurodevelopmental abnormalities associated with severe congenital neutropenia due to the R86X mutation in the HAX1 gene

Ishikawa, Nobutsune; Okada, Satoshi; Miki, Manabu; Shirao, Kenichiro; Kihara, Hajime; Tsumura, Miyuki; Nakamura, Kazuhiro; Kawaguchi, Hiroshi; Ohtsubo, Motoaki; Yasunaga, Shin’ichiro; Matsubara, Kousaku; Shinoda, Masahiro; Hara, Junichi; Shiohara, Masaaki; Kojima, Seiji; Sato, Takashi; Takihara, Yoshihiro; Kobayashi, Masao

doi:10.1136/jmg.2008.058297

Cited by 48 publications

(52 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[4][5][6] A correlation between genotype and phenotype was observed in these patients, suggesting that mutations affecting transcript variant 1 of HAX1 were associated with CN alone, whereas mutations affecting both transcripts caused CN and neurological symptoms. [6][7][8] This finding implies isoform b of the HAX1 protein is critical for neuronal function, which has also been confirmed in an animal experiment. 9 The present study describes the first Chinese autosomal recessive SCN patient with chronic myelomonocytic leukemia (CMML) transformation, who carries a novel compound heterozygous mutation in the HAX1 gene that affects both transcripts without neurodevelopmental abnormalities.…”

mentioning

confidence: 94%

“…Both drugs have shown efficacy in improving the clinical condition of patients with POEMS syndrome. [5][6][7] Lenalidomide has the additional advantage of being associated with a much lower risk of peripheral neuropathy than thalidomide. Similarly, concerns about exacerbating neuropathy also arise when other new therapeutic agents, such as bortezomib, are taken into consideration.…”

mentioning

confidence: 99%

See 1 more Smart Citation

A novel compound heterozygous HAX1 mutation in a Chinese patient with severe congenital neutropenia and chronic myelomonocytic leukemia transformation but without neurodevelopmental abnormalities

Xue¹,

Li²,

Zou³

et al. 2011

Haematologica

View full text Add to dashboard Cite

mentioning

confidence: 94%

mentioning

confidence: 99%

A novel compound heterozygous HAX1 mutation in a Chinese patient with severe congenital neutropenia and chronic myelomonocytic leukemia transformation but without neurodevelopmental abnormalities

Xue¹,

Li²,

Zou³

et al. 2011

Haematologica

View full text Add to dashboard Cite

“…[3][4][5] Five Japanese SCN patients are described 6 and only a few cases of true European descent have been documented so far. 3,5,7 In the present study we describe the first 2 Italian SCN patients carrying two novel HAX1 mutations associated to neurodevelopment abnormalities.…”

mentioning

confidence: 99%

Novel HAX1 gene mutations associated to neurodevelopment abnormalities in two Italian patients with severe congenital neutropenia

Lanciotti¹,

Indaco²,

Bonanomi³

et al. 2010

Haematologica

View full text Add to dashboard Cite

“…Many types of inherited bone marrow failure syndrome were characterized by multisystem developmental defects that affected the heart, kidney, skeletomuscular system, and central nervous system. Among these, neurological symptoms were frequently seen in SCN patients with HAX1 gene deficiency, 19,23,34 suggesting that a loss in HAX1 may also affect neural development. Indeed, our patient also presented for epilepsy and severe delays in motor, cognitive, and intellectual development.…”

Section: Discussionmentioning

confidence: 99%

Genetic correction of HAX1 in induced pluripotent stem cells from a patient with severe congenital neutropenia improves defective granulopoiesis

et al. 2013

View full text Add to dashboard Cite

T. Morishima et al. 20haematologica | 2014; 99(1) tion system from human iPS cells 17 as well as a serum-and feeder-free monolayer hematopoietic culture system from human ES and iPS cells. 18 In this study, we generate iPS cell lines from an SCN patient with HAX1 gene deficiency and differentiate them into neutrophils in vitro. Furthermore, we corrected for the HAX1 gene deficiency in HAX1-iPS cells by lentiviral transduction with HAX1 cDNA and analyzed the neutrophil differentiation potential of these cells. Thus, this in vitro neutrophil differentiation system from patient-derived iPS cells may be a useful model for future studies in SCN patients with HAX1 gene deficiency. Methods Human iPS cell generationSkin biopsy specimens were obtained from an 11-year old male SCN patient with HAX1 gene deficiency. 19 This study was approved by the Ethics Committee of Kyoto University, and informed consent was obtained from the patient's guardians in accordance with the Declaration of Helsinki. Fibroblasts were expanded in DMEM (Nacalai Tesque, Inc., Kyoto, Japan) containing 10% FBS (vol/vol, Invitrogen, Carlsbad, CA, USA) and 0.5% penicillin and streptomycin (wt/vol, Invitrogen). Generation of iPS cells was performed as described previously. 12 In brief, we introduced OCT3/4, SOX2, KLF4, and cMYC using ecotropic retroviral transduction into patient's fibroblasts expressing mouse Slc7a1. Six days after transduction, cells were harvested and re-plated onto mitotically inactive SNL feeder cells. On the following day, DMEM was replaced with primate ES cell medium (ReproCELL, Kanagawa, Japan) supplemented with basic fibroblast growth factor (5 ng/mL, R&D Systems, Minneapolis, MN, USA). Three weeks later, individual colonies were isolated and expanded. Maintenance of cellsControl ES (KhES-1) and control iPS (253G4 and 201B6) cells were kindly provided by Drs. Norio Nakatsuji and Shinya Yamanaka (Kyoto University, Kyoto, Japan), respectively. These human ES and iPS cell lines were maintained on mitomycin-C (Kyowa Hakko Kirin, Tokyo, Japan)-treated SNL feeder cells as described previously 17 and subcultured onto new SNL feeder cells every seven days. Flow cytometric analysisCells were stained with antibodies as reported previously. 17Samples were analyzed using an LSR flow cytometer and Cell Quest software (Becton-Dickinson). Neutrophil differentiation of iPS cellsIn a previous study, we established a serum and feeder-free monolayer hematopoietic culture system from human ES and iPS cells. 18 In this study, we modified this culture system to direct neutrophil differentiation. iPS cell colonies were cultured on growth factor-reduced Matrigel (Becton-Dickinson)-coated cell culture dishes in Stemline II hematopoietic stem cell expansion medium (Sigma-Aldrich, St. Louis, MO, USA) containing the insulin-transferrin-selenium (ITS) supplement (Invitrogen) and cytokines. iPS cells were treated with cytokines as follows: bone morphogenetic protein (BMP) 4 (20 ng/mL, R&D Systems) was added for four days and then replaced with vas...

show abstract

Neurodevelopmental abnormalities associated with severe congenital neutropenia due to the R86X mutation in the HAX1 gene

Abstract: 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.

Cited by 48 publications

References 21 publications

A novel compound heterozygous HAX1 mutation in a Chinese patient with severe congenital neutropenia and chronic myelomonocytic leukemia transformation but without neurodevelopmental abnormalities

A novel compound heterozygous HAX1 mutation in a Chinese patient with severe congenital neutropenia and chronic myelomonocytic leukemia transformation but without neurodevelopmental abnormalities

Novel HAX1 gene mutations associated to neurodevelopment abnormalities in two Italian patients with severe congenital neutropenia

Genetic correction of HAX1 in induced pluripotent stem cells from a patient with severe congenital neutropenia improves defective granulopoiesis

Contact Info

Product

Resources

About