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

作者:Kato Koji; Miya Fuyuki; Hori Ikumi; Ieda Daisuke; Ohashi Kei; Negishi Yutaka; Hattori Ayako; Okamoto Nobuhiko; Kato Mitsuhiro; Tsunoda Tatsuhiko; Yamasaki Mami; Kanemura Yonehiro; Kosaki Kenjiro; Saitoh Shinji*
来源:Journal of Human Genetics, 2017, 62(9): 861-863.
DOI:10.1038/jhg.2017.53

摘要

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.

  • 出版日期2017-9
  • 单位RIKEN