title: Biallelic truncating mutations in FMN2, encoding the actin-regulatory protein Formin 2, cause nonsyndromic autosomal-recessive intellectual disability.
abstract: Dendritic spines represent the major site of neuronal activity in the brain; they serve as the receiving point for neurotransmitters and undergo rapid activity-dependent morphological changes that correlate with learning and memory. Using a combination of homozygosity mapping and next-generation sequencing in two consanguineous families affected by nonsyndromic autosomal-recessive intellectual disability, we identified truncating mutations in formin 2 (FMN2), encoding a protein that belongs to the formin family of actin cytoskeleton nucleation factors and is highly expressed in the maturing brain. We found that FMN2 localizes to punctae along dendrites and that germline inactivation of mouse Fmn2 resulted in animals with decreased spine density; such mice were previously demonstrated to have a conditioned fear-learning defect. Furthermore, patient neural cells derived from induced pluripotent stem cells showed correlated decreased synaptic density. Thus, FMN2 mutations link intellectual disability either directly or indirectly to the regulation of actin-mediated synaptic spine density.
authors.affiliation: The Campbell Family Mental Health Research Institute, The Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Law
authors.affiliation: Department of Neuroscience, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Tracy
authors.initials: T
authors.lastname: Dixon-Salazar
authors.affiliation: Department of Neuroscience, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Julie
authors.initials: J
authors.lastname: Jerber
authors.affiliation: Department of Neuroscience, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Na
authors.initials: N
authors.lastname: Cai
authors.affiliation: Department of Zoology, University of Azad Jammu and Kashmir, 13100 Muzaffarabad, Pakistan.
authors.forename: Ansar A
authors.initials: AA
authors.lastname: Abbasi
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.affiliation: The Campbell Family Mental Health Research Institute, The Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada.
authors.forename: Kirti
authors.initials: K
authors.lastname: Mittal
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.affiliation: The Campbell Family Mental Health Research Institute, The Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada.
authors.forename: Muhammad Arshad
authors.initials: MA
authors.lastname: Rafiq
authors.affiliation: Department of Biochemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
authors.forename: Valeed
authors.initials: V
authors.lastname: Khan
authors.affiliation: Department of Neuroscience, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Maria
authors.initials: M
authors.lastname: Nguyen
authors.affiliation: Department of Biotechnology, University of Azad Jammu and Kashmir, 13100 Muzaffarabad, Pakistan.
authors.forename: Ghazanfar
authors.initials: G
authors.lastname: Ali
authors.affiliation: Department of Neuroscience, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Brett
authors.initials: B
authors.lastname: Copeland
authors.affiliation: Department of Neuroscience, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Eric
authors.initials: E
authors.lastname: Scott
authors.affiliation: The Campbell Family Mental Health Research Institute, The Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada.
authors.forename: Nasim
authors.initials: N
authors.lastname: Vasli
authors.affiliation: The Campbell Family Mental Health Research Institute, The Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Mikhailov
authors.affiliation: Department of Biotechnology, University of Azad Jammu and Kashmir, 13100 Muzaffarabad, Pakistan.
authors.forename: Muhammad Nasim
authors.initials: MN
authors.lastname: Khan
authors.affiliation: Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario M5S 2J7, Canada; Krembil Neuroscience Centre, Toronto Western Research Institute, Toronto, Ontario M5S 2J7, Canada.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Andrade
authors.affiliation: Lahore Institute of Research and Development, Lahore 51000, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ayaz
authors.affiliation: Department of Biochemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.affiliation: Lahore Institute of Research and Development, Lahore 51000, Pakistan; Department of Psychiatry, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ayub
authors.affiliation: The Campbell Family Mental Health Research Institute, The Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario M5T 1R8, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Electronic address: john.vincent@camh.ca.
authors.forename: John B
authors.initials: JB
authors.lastname: Vincent
authors.affiliation: Department of Neuroscience, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute. Electronic address: jogleeson@rockefeller.edu.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D025063:Chromosome Disorders / Q000235:genetics* / Q000503:physiopathology; D015331:Cohort Studies; D003241:Consanguinity; D004534:Egypt; D059472:Exome / Q000235:genetics; D005260:Female; D000080865:Formins; D005808:Genes, Recessive; D008040:Genetic Linkage; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010154:Pakistan; D010375:Pedigree; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: C587953:Fmn2 protein, human; D000080865:Formins; D008840:Microfilament Proteins; D009687:Nuclear Proteins