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

Piard, J., Hu, J. H., Campeau, P. M., Rzonca, S., Van Esch, H., Vincent, E., et al. (2018). FRMPD4 mutations cause X-linked intellectual disability and disrupt dendritic spine morphogenesis. Human Molecular Genetics, 27(4), 589-600. doi:10.1093/hmg/ddx426.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-CE3F-3 Version Permalink: http://hdl.handle.net/21.11116/0000-0000-CE40-0
Genre: Journal Article

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 Creators:
Piard, J., Author
Hu, J. H., Author
Campeau, P. M., Author
Rzonca, S., Author
Van Esch, H., Author
Vincent, E., Author
Han, M., Author
Rossignol, E., Author
Castaneda, J., Author
Chelly, J., Author
Skinner, C., Author
Kalscheuer, V. M.1, Author              
Wang, R., Author
Lemyre, E., Author
Kosinska, J., Author
Stawinski, P., Author
Bal, J., Author
Hoffman, D. A., Author
Schwartz, C. E., Author
Van Maldergem, L., Author
Wang, T., AuthorWorley, P. F., Author more..
Affiliations:
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385702              

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 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 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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Language(s): eng - English
 Dates: 2017-12-182018-02-15
 Publication Status: Published in print
 Pages: 12
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1093/hmg/ddx426
ISSN: 1460-2083 (Electronic)0964-6906 (Print)
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Title: Human Molecular Genetics
Source Genre: Journal
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Publ. Info: Oxford, England : IRL Press
Pages: - Volume / Issue: 27 (4) Sequence Number: - Start / End Page: 589 - 600 Identifier: ISSN: 0964-6906
CoNE: /journals/resource/954925581153