2. Academic Validation
  3. Loss-of-Function Mutation in APC2 Causes Sotos Syndrome Features

Loss-of-Function Mutation in APC2 Causes Sotos Syndrome Features

  • Cell Rep. 2015 Mar 10;10(9):1585-1598. doi: 10.1016/j.celrep.2015.02.011.
Mariam Almuriekhi 1,  Takafumi Shintani 2,  Somayyeh Fahiminiya 3,  Akihiro Fujikawa 4,  Kazuya Kuboyama 4,  Yasushi Takeuchi 4,  Zafar Nawaz 5,  Javad Nadaf 3,  Hussein Kamel 6,  Abu Khadija Kitam 5,  Zaineddin Samiha 5,  Laila Mahmoud 1,  Tawfeg Ben-Omran 1,  Jacek Majewski 3,  Masaharu Noda 7
Affiliations

Affiliations

  • 1 Section of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.
  • 2 Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan; School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan.
  • 3 Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Génome Québec Innovation Centre, Montreal, QC H3A 0G1, Canada.
  • 4 Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan.
  • 5 Cytogenetic and Molecular Cytogenetic Laboratory, Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.
  • 6 Department of Radiology, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.
  • 7 Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan; School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan. Electronic address: madon@nibb.ac.jp.
PMID: 25753423 DOI: 10.1016/j.celrep.2015.02.011
Abstract

Sotos syndrome, characterized by intellectual disability and characteristic facial features, is caused by haploinsufficiency in the NSD1 gene. We conducted an etiological study on two siblings with Sotos features without mutations in NSD1 and detected a homozygous frameshift mutation in the APC2 gene by whole-exome Sequencing, which resulted in the loss of function of cytoskeletal regulation in neurons. Apc2-deficient (Apc2-/-) mice exhibited impaired learning and memory abilities along with an abnormal head shape. Endogenous Apc2 expression was downregulated by the knockdown of Nsd1, indicating that APC2 is a downstream effector of NSD1 in neurons. Nsd1 knockdown in embryonic mouse brains impaired the migration and laminar positioning of cortical neurons, as observed in Apc2-/- mice, and this defect was rescued by the forced expression of Apc2. Thus, APC2 is a crucial target of NSD1, which provides an explanation for the intellectual disability associated with Sotos syndrome.

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