Biallelic truncating mutations in FMN2, encoding the actin-regulatory protein Formin 2, cause nonsyndromic autosomal-recessive intellectual disability

Am J Hum Genet. 2014 Dec 4;95(6):721-8. doi: 10.1016/j.ajhg.2014.10.016.

Rosalind Law ¹, Tracy Dixon-Salazar ², Julie Jerber ², Na Cai ², Ansar A Abbasi ³, Maha S Zaki ⁴, Kirti Mittal ¹, Stacey B Gabriel ⁵, Muhammad Arshad Rafiq ¹, Valeed Khan ⁶, Maria Nguyen ², Ghazanfar Ali ⁷, Brett Copeland ², Eric Scott ², Nasim Vasli ¹, Anna Mikhailov ¹, Muhammad Nasim Khan ⁷, Danielle M Andrade ⁸, Muhammad Ayaz ⁹, Muhammad Ansar ⁶, Muhammad Ayub ¹⁰, John B Vincent ¹¹, Joseph G Gleeson ¹²

Affiliations

1 The Campbell Family Mental Health Research Institute, The Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada.
2 Department of Neuroscience, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
3 Department of Zoology, University of Azad Jammu and Kashmir, 13100 Muzaffarabad, Pakistan.
4 Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
5 Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
6 Department of Biochemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
7 Department of Biotechnology, University of Azad Jammu and Kashmir, 13100 Muzaffarabad, Pakistan.
8 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.
9 Lahore Institute of Research and Development, Lahore 51000, Pakistan.
10 Lahore Institute of Research and Development, Lahore 51000, Pakistan; Department of Psychiatry, Queen's University, Kingston, Ontario K7L 3N6, Canada.
11 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: [email protected].
12 Department of Neuroscience, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute. Electronic address: [email protected].

PMID: 25480035 DOI: 10.1016/j.ajhg.2014.10.016

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.

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