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Hum Mol Genet. 2018 Feb 15;27(4):589-600. doi: 10.1093/hmg/ddx426.

FRMPD4 mutations cause X-linked intellectual disability and disrupt dendritic spine morphogenesis.

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Centre de Génétique Humaine and Integrative and Cognitive Neuroscience Research Unit EA481, Université de Franche-Comté, Besançon, France.
Department of Neuroscience, Department of Pediatrics, Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Program in Developmental Neuroscience, Molecular Neurophysiology and Biophysics Section, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Department of Pediatrics, University of Montreal, Montreal, QC, Canada.
Institute of Mother and Child, Warsaw, Poland.
Department of Human Genetics, University Hospitals Leuven, Belgium.
Department of Neurosciences, University of Montreal, Montreal, QC, Canada.
CNRS UMR7104, Institut de Génétique, Biologie Moléculaire et Cellulaire, Illkirch, France.
Greenwood Genetic Center, Greenwood, SC, USA.
Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Centre of Clinical Investigation 1431, National Institute for Health and Medical Research (INSERM), Université de Franche-Comté, Besançon, France.


FRMPD4 (FERM and PDZ Domain Containing 4) is a neural scaffolding protein that interacts with PSD-95 to positively regulate dendritic spine morphogenesis, and with mGluR1/5 and Homer to regulate mGluR1/5 signaling. We report the genetic and functional characterization of 4 FRMPD4 deleterious mutations that cause a new X-linked intellectual disability (ID) syndrome. These mutations were found to be associated with ID in ten affected male patients from four unrelated families, following an apparent X-linked mode of inheritance. Mutations include deletion of an entire coding exon, a nonsense mutation, a frame-shift mutation resulting in premature termination of translation, and a missense mutation involving a highly conserved amino acid residue neighboring FRMPD4-FERM domain. Clinical features of these patients consisted of moderate to severe ID, language delay and seizures alongside with behavioral and/or psychiatric disturbances. In-depth functional studies showed that a frame-shift mutation, FRMPD4p.Cys618ValfsX8, results in a disruption of FRMPD4 binding with PSD-95 and HOMER1, and a failure to increase spine density in transfected hippocampal neurons. Behavioral studies of frmpd4-KO mice identified hippocampus-dependent spatial learning and memory deficits in Morris Water Maze test. These findings point to an important role of FRMPD4 in normal cognitive development and function in humans and mice, and support the hypothesis that FRMPD4 mutations cause ID by disrupting dendritic spine morphogenesis in glutamatergic neurons.

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