Loss-of-Function Mutation in APC2 Causes Sotos Syndrome Features
Mariam Almuriekhi,
Takafumi Shintani,
Somayyeh Fahiminiya,
Akihiro Fujikawa,
Kazuya Kuboyama,
Yasushi Takeuchi,
Zafar Nawaz,
Javad Nadaf,
Hussein Kamel,
Abu Khadija Kitam,
Zaineddin Samiha,
Laila Mahmoud,
Tawfeg Ben-Omran,
Jacek Majewski,
Masaharu Noda
Affiliations
Mariam Almuriekhi
Section of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
Takafumi Shintani
Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan
Somayyeh Fahiminiya
Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, QC H3A 1B1, Canada
Akihiro Fujikawa
Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan
Kazuya Kuboyama
Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan
Yasushi Takeuchi
Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan
Zafar Nawaz
Cytogenetic and Molecular Cytogenetic Laboratory, Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
Javad Nadaf
Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, QC H3A 1B1, Canada
Hussein Kamel
Department of Radiology, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
Abu Khadija Kitam
Cytogenetic and Molecular Cytogenetic Laboratory, Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
Zaineddin Samiha
Cytogenetic and Molecular Cytogenetic Laboratory, Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
Laila Mahmoud
Section of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
Tawfeg Ben-Omran
Section of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
Jacek Majewski
Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, QC H3A 1B1, Canada
Masaharu Noda
Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan
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.
