TY - JOUR
T1 - FRMPD4 mutations cause X-linked intellectual disability and disrupt dendritic spine morphogenesis
AU - Piard, Juliette
AU - Hu, Jia Hua
AU - Campeau, Philippe M.
AU - Rzońca, Sylwia
AU - Esch, Hilde Van
AU - Vincent, Elizabeth
AU - Han, Mei
AU - Rossignol, Elsa
AU - Castaneda, Jennifer
AU - Chelly, Jamel
AU - Skinner, Cindy
AU - Kalscheuer, Vera M.
AU - Wang, Ruihua
AU - Lemyre, Emmanuelle
AU - Kosińska, Joanna
AU - Stawinski, Piotr
AU - Bal, Jerzy
AU - Hoffman, Dax A.
AU - Schwartz, Charles E.
AU - Maldergem, Lionel Van
AU - Wang, Tao
AU - Worley, Paul F.
N1 - Funding Information:
National Institute of Health (GM110265) to P.W. and T.W.; (MH100024) to P.W.; (NS073854) to C.E.S. and T.W.; the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health to D.H.; NARSAD Young Investigator Grant (#21203) to J.H. National Science Centre in Poland (2012/07/B/NZ4/01764). Department of Disabilities and Special Needs of South Carolina and Greenwood Genetic Center Foundation.
Publisher Copyright:
© The Author(s) 2017.
PY - 2018/2/15
Y1 - 2018/2/15
N2 - 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.
AB - 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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U2 - 10.1093/hmg/ddx426
DO - 10.1093/hmg/ddx426
M3 - Article
C2 - 29267967
AN - SCOPUS:85041519267
SN - 0964-6906
VL - 27
SP - 589
EP - 600
JO - Human molecular genetics
JF - Human molecular genetics
IS - 4
M1 - ddx426
ER -