Lyu et al., 2024 demonstrated that Frmd5-deficient mice displayed morphological abnormalities in neurons and synaptic dysfunction, learning and memory dysfunction, impaired social function, and increased repetitive stereotyped behavior; tandem mass tag-labeled quantitative proteomics found that FRMD5 deletion affected the distribution of synaptic proteins implicated in ASD pathogenesis. De novo variants in the FRMD5 gene, including a de novo missense variant that was predicted to be deleterious and a de novo coding-synonymous variant, have been identified in ASD probands (Satterstrom et al., 2020; Zhou et al., 2022). Wilfert et al., 2021 identified FRMD5 as an ASD candidate gene based on the transmission of private likely gene-disruptive (LGD) variants exclusively to probands in two or more unrelated families. Lu et al., 2022 described eight probands with rare heterozygous missense variants in FRMD5 who presented with developmental delay, intellectual disability, ataxia, seizures, and abnormalities of eye movement; one of these probands also presented with autism spectrum disorder. Additional functional characterization of six FRMD5 missense variants, including the c.1637A>G missense variant identified in the proband with ASD, in Drosophila in Lu et al., 2022 demonstrated partial loss-of-function effects.
Molecular Function
Enables integrin binding activity and protein kinase binding activity. Involved in negative regulation of cell motility; positive regulation of cell adhesion; and regulation of cell migration. Located in adherens junction.
Haploinsufficiency of Frmd5 leads to changes in spine morphology and spatial novelty and object novelty recognition. A Frmd5 knockout model shows additional ASD-like phenotypes, including deficiency in social memory and social interactions, and an increase in repetitive behaviors such as repetitive grooming and increased climbing and jumping behavior. The Frmd5 knockout also shows a decrease in dendritic length in basal dendrites from the CA1 region of the hippocampus, and deficits spontaneous post-synaptic excitatory current frequency in neurons from the dentate gyrus region of the hippocampus.
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Frmd5 knockout allele was generated with site-specific transcription activator-like effector nuclease (TALEN) technology. Several TALEN target site was designed on exon 6 of the Frmd5 gene. Knockout of Frmd5 was achieved by a frameshift mutation in Frmd5 with a 1-bp or 2-bp deletion, which resulted in premature termination of the transcription translation process. The heterozygous mouse has one copy of the knockout allele.
Allele Type: Knockout
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: Not applicable
Mutant ES Cell Line: Model Source: Hong-Quan Zhang
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Frmd5 knockout allele was generated with site-specific transcription activator-like effector nuclease (TALEN) technology. Several TALEN target site was designed on exon 6 of the Frmd5 gene. Knockout of Frmd5 was achieved by a frameshift mutation in Frmd5 with a 1-bp or 2-bp deletion, which resulted in premature termination of the transcription translation process. The homozygous mouse has two copies of the knockout allele, making it a full knockout.
Allele Type: Knockout
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: Not applicable
Mutant ES Cell Line: Model Source: Hong-Quan Zhang
Description: Frmd5 heterozygous mice show a decreased number of entries to novel arm, and the percent of time in novel arm shows a nonsignificant decrease (p=0.11).
Description: Frmd5 heterozygous mice show no significant difference in exploration time for novel and familiar placement, whereas wildtype mice show a preference for a novel placement.
Description: Frmd5 heterozygous mice show no significant difference in exploration time for novel and familiar objects, whereas wildtype mice show a preference for a novel object.
Description: Frmd5 knockout mice show a decrease in total dendritic length of basal dendrites on CA1 pyramidal neurons but no changes in the dendritic length of apical dendrites on CA1 pyramidal neurons or dentate gyrus neurons.
Description: Frmd5 knockout mice show an increased number of stubby spines, an increased size of mushroom spine head and length, and an increased size in long/thin spine head.
Dendritic architecture: dendritic tree complexity1
Decreased
Description: Frmd5 knockout mice show a decrease in dendritic complexity of basal dendrites on CA1 pyramidal neurons but no changes in the dendritic complexity of apical dendrites on CA1 pyramidal neurons or dentate gyrus neurons, measured by number of dendritic branches and Sholl analysis intersections.
Description: Frmd5 knockout mice show in lower injected current an increased number of spikes and in higher injected current decreased responsivity, in the dentate gyrus.
Exp Paradigm: dentate gyrus
Description: Frmd5 knockout mice show a decrease in reciprocal social interactions, measured by time engaging in nose-to-nose sniffing and anogenital sniffing.
Description: Frmd5 knockout mice show a decreased percent of time in novel arm, and the number of entries to novel arm shows a nonsignificant decrease (p=0.10).
Description: Frmd5 knockout mice show no significant difference in exploration time for novel and familiar placement, whereas wildtype mice show a preference for a novel placement.
Description: Frmd5 knockout mice show no significant difference in exploration time for novel and familiar objects, whereas wildtype mice show a preference for a novel object.
Description: Frmd5 knockout mice show a decrease in many ASD risk gene products, including SHANK3, also increase in some proteins, in the synaptosomal fraction of hippocampus tissue.
Exp Paradigm: synaptosomes
Tandem mass tag (TMT)-labeled quantitative proteomics
Description: Western blot analysis verified that Frmd5 deficiency leads to reduced expression of the SHANK3 and CAMK family scaffolding proteins, in the synaptosomal fraction of hippocampus tissue.
Exp Paradigm: synaptosomes
