ArticleHuman molecular genetics2018
FRMPD4 mutations cause X-linked intellectual disability and disrupt dendritic spine morphogenesis.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 34 citations in OpenAlex.
- Identifying SHROOM4 as a novel X-linked susceptibility gene for cerebral palsy in Chinese males.BMC pediatrics · 2026Article
- Human-specific multicopy gene FRMPD2 promotes synapse formation via recruitment of neuroligin 1.bioRxiv : the preprint server for biology · 2026Article
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- Change of Spiny Neuron Structure in the Basal Ganglia Song Circuit and Its Regulation by miR-9 during Song Development.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- X-chromosome-wide association study for Alzheimer's disease.Molecular psychiatry · 2025Article
- Aging activates escape of the silent X chromosome in the female mouse hippocampus.Science advances · 2025Article
- Mapping the topography of spatial gene expression with interpretable deep learning.Nature methods · 2025Article
- Genomic insights into runs of homozygosity, effective population size and selection signatures in Iranian meat and dairy sheep breeds.PloS one · 2025Article
- Human-unique brain cell clusters are associated with learning disorders and human episodic memory activity.Molecular psychiatry · 2025Article
- Genetic analysis of a child with severe intellectual disability caused by a novel variant in the FERM domain of the FRMPD4 protein.Journal of genetics · 2024Article
- Mapping the topography of spatial gene expression with interpretable deep learning.bioRxiv : the preprint server for biology · 2023Article
- Expanding the genetics and phenotypic spectrum of Lysine-specific demethylase 5C (KDM5C): a report of 13 novel variants.European journal of human genetics : EJHG · 2023Article
- Synaptic proteomics reveal distinct molecular signatures of cognitive change and C9ORF72 repeat expansion in the human ALS cortex.Acta neuropathologica communications · 2022Article
- Complex Diagnostics of Non-Specific Intellectual Developmental Disorder.International journal of molecular sciences · 2022Article
- Neuronal-glial communication perturbations in murine SOD1Communications biology · 2022Article
- ADeditome provides the genomic landscape of A-to-I RNA editing in Alzheimer's disease.Briefings in bioinformatics · 2021Article
- The Complex Formed by Group I Metabotropic Glutamate Receptor (mGluR) and Homer1a Plays a Central Role in Metaplasticity and Homeostatic Synaptic Scaling.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Review
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Authors and funding
22 authors at 10 institutions in 6 countries.
Funding
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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