A novel missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria and cleft palate

Journal of Human Genetics volume 62, pages861–863(2017)Cite this article

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  • A Correction to this article was published on 26 April 2019

Abstract

We identified a novel de novo heterozygous missense mutation in the NEDD4L gene (NM_015277: c.2617G>A; p.Glu873Lys) through whole-exome sequencing in a 3-year-old girl showing severe global developmental delay, infantile spasms, cleft palate, periventricular nodular heterotopia and polymicrogyria. Mutations in the HECT domain of NEDD4L have been reported in patients with a neurodevelopmental disorder along with similar brain malformations. All patients reported with NEDD4L HECT domain mutations showed periventricular nodular heterotopia, and most had seizures, cortex anomalies, cleft palate and syndactyly. The unique constellation of clinical features in patients with NEDD4L mutations might help clinically distinguish them from patients with other genetic mutations including FLNA, which is a well-known causative gene of periventricular nodular heterotopia. Although mutations in the HECT domain of NEDD4L that lead to AKT-mTOR pathway deregulation in forced expression system were reported, our western blot analysis did not show an increased level of AKT-mTOR activity in lymphoblastoid cell lines (LCLs) derived from the patient. In contrast to the forced overexpression system, AKT-mTOR pathway deregulation in LCLs derived from our patient seems to be subtle.

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Author notes

  1. Koji Kato and Fuyuki Miya: These authors contributed equally to this work.

Affiliations

  1. Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    • Koji Kato
    • , Ikumi Hori
    • , Daisuke Ieda
    • , Kei Ohashi
    • , Yutaka Negishi
    • , Ayako Hattori
    •  & Shinji Saitoh

  2. Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    • Koji Kato

  3. Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

    • Fuyuki Miya
    •  & Tatsuhiko Tsunoda

  4. Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    • Fuyuki Miya
    •  & Tatsuhiko Tsunoda

  5. Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan

    • Nobuhiko Okamoto

  6. Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan

    • Mitsuhiro Kato

  7. Department of Neurosurgery, Takatsuki General Hospital, Osaka, Japan

    • Mami Yamasaki

  8. Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan

    • Yonehiro Kanemura

  9. Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, Osaka, Japan

    • Yonehiro Kanemura

  10. Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan

    • Kenjiro Kosaki

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Corresponding author

Correspondence to Shinji Saitoh.

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The authors declare no conflict of interest.

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Kato, K., Miya, F., Hori, I. et al. A novel missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria and cleft palate. J Hum Genet 62, 861–863 (2017) doi:10.1038/jhg.2017.53

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