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- Title
FRMPD4 mutations cause X-linked intellectual disability and disrupt dendritic spine morphogenesis.
- Authors
Piard, Juliette; Jia-Hua Hu; Campeau, Philippe M.; Rzońca, Sylwia; Van Esch, Hilde; Vincent, Elizabeth; Mei Han; Rossignol, Elsa; Castaneda, Jennifer; Chelly, Jamel; Skinner, Cindy; Kalscheuer, Vera M.; Ruihua Wang; Lemyre, Emmanuelle; Kosińska, Joanna; Stawinski, Piotr; Bal, Jerzy; Hoffman, Dax A.; Schwartz, Charles E.; Van Maldergem, Lionel
- Abstract
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
- Publication
Human Molecular Genetics, 2018, Vol 27, Issue 4, p589
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddx426