OTUD7A Regulates Neurodevelopmental Phenotypes in the 15q13.3 Microdeletion Syndrome

Mohammed Uddin; Brianna K Unda; Vickie Kwan; Nicholas T Holzapfel; Sean H White; Leon Chalil; Marc Woodbury-Smith; Karen S Ho; Erin Harward; Nadeem Murtaza; Biren Dave; Giovanna Pellecchia; Lia D'Abate; Thomas Nalpathamkalam; Sylvia Lamoureux; John Wei; Marsha Speevak; James Stavropoulos; Kristin J Hope; Brad W Doble; Jacob Nielsen; E Robert Wassman; Stephen W Scherer; Karun K Singh

doi:10.1016/j.ajhg.2018.01.006

OTUD7A Regulates Neurodevelopmental Phenotypes in the 15q13.3 Microdeletion Syndrome

Am J Hum Genet. 2018 Feb 1;102(2):278-295. doi: 10.1016/j.ajhg.2018.01.006.

Authors

Mohammed Uddin¹, Brianna K Unda², Vickie Kwan², Nicholas T Holzapfel², Sean H White², Leon Chalil², Marc Woodbury-Smith³, Karen S Ho⁴, Erin Harward⁴, Nadeem Murtaza², Biren Dave², Giovanna Pellecchia⁵, Lia D'Abate⁶, Thomas Nalpathamkalam⁵, Sylvia Lamoureux⁵, John Wei⁵, Marsha Speevak⁷, James Stavropoulos⁸, Kristin J Hope², Brad W Doble², Jacob Nielsen⁹, E Robert Wassman⁴, Stephen W Scherer¹⁰, Karun K Singh¹¹

Affiliations

¹ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE.
² Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
³ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Institute of Neuroscience, Newcastle University, UK.
⁴ Lineagen Inc., Salt Lake City, UT 84109, USA.
⁵ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁶ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁷ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON L5M 2N1, Canada.
⁸ Genome Diagnostics, Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁹ Synaptic Transmission, In Vitro, Neuroscience Research DK, H. Lundbeck A/S, Ottiliaavej 9, Valby 2500, Denmark.
¹⁰ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Program in Genetics and Genome Biology (GGB), The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; McLaughlin Centre, University of Toronto, Toronto, ON M5G 0A4, Canada. Electronic address: stephen.scherer@sickkids.ca.
¹¹ Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada. Electronic address: singhk2@mcmaster.ca.

Abstract

Copy-number variations (CNVs) are strong risk factors for neurodevelopmental and psychiatric disorders. The 15q13.3 microdeletion syndrome region contains up to ten genes and is associated with numerous conditions, including autism spectrum disorder (ASD), epilepsy, schizophrenia, and intellectual disability; however, the mechanisms underlying the pathogenesis of 15q13.3 microdeletion syndrome remain unknown. We combined whole-genome sequencing, human brain gene expression (proteome and transcriptome), and a mouse model with a syntenic heterozygous deletion (Df(h15q13)/+ mice) and determined that the microdeletion results in abnormal development of cortical dendritic spines and dendrite outgrowth. Analysis of large-scale genomic, transcriptomic, and proteomic data identified OTUD7A as a critical gene for brain function. OTUD7A was found to localize to dendritic and spine compartments in cortical neurons, and its reduced levels in Df(h15q13)/+ cortical neurons contributed to the dendritic spine and dendrite outgrowth deficits. Our results reveal OTUD7A as a major regulatory gene for 15q13.3 microdeletion syndrome phenotypes that contribute to the disease mechanism through abnormal cortical neuron morphological development.

Keywords: 15q13.3 microdeletion syndrome; OTUD7A; autism spectrum disorder; copy-number variation; dendrite; dendritic spine; deubiquitinase; neurodevelopmental disorder; schizophrenia; synapse.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autism Spectrum Disorder / genetics
Chromosome Deletion
Chromosome Disorders / enzymology*
Chromosome Disorders / genetics*
Chromosomes, Human, Pair 15 / enzymology
Chromosomes, Human, Pair 15 / genetics
Dendritic Spines / metabolism
Deubiquitinating Enzymes / genetics
Deubiquitinating Enzymes / physiology*
Endopeptidases / genetics*
Endopeptidases / metabolism
Female
Gene Deletion
Genetic Association Studies
Humans
Intellectual Disability / enzymology*
Intellectual Disability / genetics*
Male
Mice
Neurodevelopmental Disorders / enzymology*
Neurodevelopmental Disorders / genetics*
Phenotype
Prosencephalon / pathology
Seizures / enzymology*
Seizures / genetics*

Substances

Endopeptidases
Deubiquitinating Enzymes
OTUD7A protein, human
Otud7a protein, mouse

Supplementary concepts

Chromosome 15q13.3 Microdeletion Syndrome

Grants and funding

CIHR/Canada