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Relevance to Autism

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.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Deficiency of FRMD5 results in neurodevelopmental dysfunction and autistic-like behavior in mice
ASD
Support
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
ASD
Support
De novo variants in FRMD5 are associated with developmental delay, intellectual disability, ataxia, and abnormalities of eye movement
Neurodevelopmental disorder with eye movement abno
ASD, epilepsy/seizures
Support
Integrating de novo and inherited variants in 42
ASD
Support
Recent ultra-rare inherited variants implicate new autism candidate risk genes
ASD
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1434R001 
 missense_variant 
 c.953G>A 
 p.Arg318Gln 
 De novo 
  
  
 GEN1434R002 
 synonymous_variant 
 c.1446G>A 
 p.Leu482= 
 De novo 
  
  
 GEN1434R003 
 frameshift_variant 
 c.1491del 
 p.Phe497LeufsTer3 
 Familial 
  
 Simplex 
 GEN1434R004 
 frameshift_variant 
 c.1536_1539del 
 p.Val514CysfsTer5 
 Familial 
  
 Simplex 
 GEN1434R005 
 missense_variant 
 c.340T>C 
 p.Phe114Leu 
 De novo 
  
  
 GEN1434R006 
 missense_variant 
 c.1051A>G 
 p.Ser351Gly 
 De novo 
  
  
 GEN1434R007 
 missense_variant 
 c.1053C>G 
 p.Ser351Arg 
 De novo 
  
  
 GEN1434R008 
 missense_variant 
 c.1054T>C 
 p.Cys352Arg 
 De novo 
  
 Simplex 
 GEN1434R009 
 missense_variant 
 c.1054T>C 
 p.Cys352Arg 
 De novo 
  
 Simplex 
 GEN1434R010 
 missense_variant 
 c.1060T>C 
 p.Ser354Pro 
 De novo 
  
 Simplex 
 GEN1434R011 
 missense_variant 
 c.1045A>C 
 p.Ser349Arg 
 Unknown 
 Not maternal 
 Unknown 
 GEN1434R012 
 missense_variant 
 c.1637A>G 
 p.Tyr546Cys 
 Unknown 
 Not maternal 
 Simplex 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
15
Duplication
 89
  construct

Model Summary

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.

References

Type
Title
Author, Year
Primary
Deficiency of FRMD5 results in neurodevelopmental dysfunction and autistic-like behavior in mice
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
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Dendritic architecture: spine morphology1
Abnormal
 Fluorescence microscopy
 8-12 weeks
Object recognition memory1
Decreased
 Novel object recognition test
 8-12 weeks
Spatial reference memory1
Decreased
 Y-maze test
 8-12 weeks
Object recognition memory1
Decreased
 Object-place recognition test
 8-12 weeks
Ultrasonic vocalization: isolation induced1
 No change
 Monitoring ultrasonic vocalizations
 P7
Anxiety1
 No change
 Elevated zero maze test
 8-12 weeks
Anxiety1
 No change
 Light-dark exploration test
 8-12 weeks
Anxiety1
 No change
 Open field test
 8-12 weeks
Procedural learning1
 No change
 Morris water maze
 8-12 weeks
Spatial learning1
 No change
 Morris water maze
 8-12 weeks
Spatial reference memory1
 No change
 Morris water maze
 8-12 weeks
Spatial working memory1
 No change
 Y-maze test
 8-12 weeks
Climbing1
 No change
 Open field test
 8-12 weeks
General locomotor activity: ambulatory activity1
 No change
 Open field test
 8-12 weeks
Motor coordination and balance1
 No change
 Accelerating rotarod test
 8-12 weeks
Rearing behavior1
 No change
 Open field test
 8-12 weeks
Dendritic architecture: dendritic length1
 No change
 Golgi-Cox staining
 8-12 weeks
Dendritic architecture: dendritic tree complexity1
 No change
 Sholl analysis
 8-12 weeks
Dendritic architecture: spine density1
 No change
 Fluorescence microscopy
 8-12 weeks
Repetitive digging1
 No change
 Marble-burying test
 8-12 weeks
Self grooming1
 No change
 Novel cage test
 8-12 weeks
Pain or nociception: thermal1
 No change
 Hot plate test
 8-12 weeks
Touch1
 No change
 Von Frey filament test
 8-12 weeks
Social approach1
 No change
 Three-chamber social approach test
 8-12 weeks
Social interaction1
 No change
 Home cage behavior
 8-12 weeks
Social interaction1
 No change
 Reciprocal social interaction test
 8-12 weeks
Social memory1
 No change
 Three-chamber social approach test
 8-12 weeks
 Not Reported:

 

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