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A novel PAK1 variant causative of neurodevelopmental disorder with postnatal macrocephaly

Journal of Human Genetics volume 65, pages 481–485 (2020)Cite this article

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Abstract

p21-activated kinases (PAKs) are protein serine/threonine kinases stimulated by Rho-family p21 GTPases such as CDC42 and RAC. PAKs have been implicated in several human disorders, with pathogenic variants in PAK3 associated with intellectual disability and several PAK members, especially PAK1 and PAK4, overexpressed in human cancer. Recently, de novo PAK1 variants were reported to be causative of neurodevelopmental disorder (ND) with secondary macrocephaly in three patients. We herein report a fourth patient with ND, epilepsy, and macrocephaly caused by a de novo PAK1 missense variant. Two previously reported missense PAK1 variants functioned as activating alleles by reducing PAK1 homodimerization. To examine the pathogenicity of the identified novel p.Ser110Thr variant, we carried out in silico structural analysis. Our findings suggest that this variant also prevents PAK1 homodimerization, leading to constitutive PAK1 activation.

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Acknowledgements

We thank all patients and family members for participating in this study. This work was supported by JSPS KAKENHI, under grant numbers JP19K07977 and JP17H01539; and AMED under grant numbers JP18ek0109280, JP18dm0107090, JP18ek0109301, JP18ek0109348, and JP18kk020501. We thank Sarah Williams, PhD, from Edanz Group (www.edanzediting.com) for editing a draft of this manuscript.

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Authors and Affiliations

  1. Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan

    Sachiko Ohori, Satomi Mitsuhashi & Naomichi Matsumoto

  2. Pediatric Neurology and Development Center, Shamir Medical Center, 70300, Tzrifin, Beer Yaakov, Israel

    Revital Ben-Haim & Eli Heyman

  3. Department of Biochemistry, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan

    Toru Sengoku & Kazuhiro Ogata

Authors
  1. Sachiko Ohori
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  2. Satomi Mitsuhashi
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  3. Revital Ben-Haim
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  4. Eli Heyman
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  6. Kazuhiro Ogata
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  7. Naomichi Matsumoto
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Correspondence to Satomi Mitsuhashi or Naomichi Matsumoto.

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Ohori, S., Mitsuhashi, S., Ben-Haim, R. et al. A novel PAK1 variant causative of neurodevelopmental disorder with postnatal macrocephaly. J Hum Genet 65, 481–485 (2020). https://doi.org/10.1038/s10038-020-0728-8

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