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

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.

Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features

“…Moreover, FMRP was shown to increase DLG4 mRNA stability, which could contribute to Fragile X Syndrome pathogenesis . FRMPD4 gene whose protein product interacts with PSD‐95 with a crucial role for the formation of the excitatory synapses and dendritic spines was recently described as associated with X‐linked ID in 10 affected male patients from 4 families and functional data of one of the frameshift pathogenic variant showed decreased spine density in transfected hippocampal neurons . Different knock‐out mouse models have been described.…”

“…22 FRMPD4 gene whose protein product interacts with PSD-95 with a crucial role for the formation of the excitatory synapses and dendritic spines 23 was recently described as associated with X-linked ID in 10 affected male patients from 4 families and functional data of one of the frameshift pathogenic variant showed decreased spine density in transfected hippocampal neurons. 24 Different knock-out mouse models have been described. One of them concerned Dlg4 −/− mice generated by deletion of the GUK domain resulting in undetectable protein with unaffected levels of other MAGUK proteins.…”

Structure of the FERM domain of a neural scaffold protein FRMPD4 implicated in X-linked intellectual disability

“…You are encouraged to use the Version of Record that, when published, will replace this version. The most up-to-date-version is available at https://doi.org/10.1042/BCJ20200857 learning and memory, highlighting a critical role of FRMPD4 in normal cognitive function of brain [18]. Importantly, genetic studies have identified several mutations of FRMPD4 in the patients with X-linked intellectual disability [18][19][20][21].…”

“…The most up-to-date-version is available at https://doi.org/10.1042/BCJ20200857 learning and memory, highlighting a critical role of FRMPD4 in normal cognitive function of brain [18]. Importantly, genetic studies have identified several mutations of FRMPD4 in the patients with X-linked intellectual disability [18][19][20][21]. X-linked intellectual disability is a neurodevelopmental disorder defined by significant limitations in intellectual functions and adaptive behaviors, which affects approximately 1%-3% of the general population [5,22].…”

“…The interaction between FRMPD4 PBM and PSD-95 positively regulated dendritic spine morphogenesis [17]. Importantly, an X-linked intellectual disability-causing mutation of FRMPD4 that results in a disruption of FRMPD4-PSD-95 interaction failed to display increased spine density [18]. The FERM domain in FRMPD4 mediates the interaction with the cytoplasmic tails (CTs) of group I mGluRs (mGluR1/5) [16].…”