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Updated: Aug 26, 2025
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
De novo variants in FRMD5 are associated with developmental delay, intellectual disability, ataxia, and abnormalities
Shenzhao Lu1, Mengqi Ma1, Xiao Mao2
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
Abstract:
Proteins containing the FERM (four-point-one, ezrin, radixin, and moesin) domain link the plasma membrane with cytoskeletal structures at specific cellular locations and have been implicated in the localization of cell-membrane-associated proteins and/or phosphoinositides. FERM domain-containing protein 5 (FRMD5) localizes at cell adherens junctions and stabilizes cell-cell contacts. To date, variants in FRMD5 have not been associated with a Mendelian disease in OMIM. Here, we describe eight probands with rare heterozygous missense variants in FRMD5 who present with developmental delay, intellectual disability, ataxia, seizures, and abnormalities of eye movement. The variants are de novo in all for whom parental testing was available (six out of eight probands), and human genetic datasets suggest that FRMD5 is intolerant to loss of function (LoF). We found that the fly ortholog of FRMD5, CG5022 (dFrmd), is expressed in the larval and adult central nervous systems where it is present in neurons but not in glia. dFrmd LoF mutant flies are viable but are extremely sensitive to heat shock, which induces severe seizures. The mutants also exhibit defective responses to light. The human FRMD5 reference (Ref) cDNA rescues the fly dFrmd LoF phenotypes. In contrast, all the FRMD5 variants tested in this study (c.340T>C, c.1051A>G, c.1053C>G, c.1054T>C, c.1045A>C, and c.1637A>G) behave as partial LoF variants. In addition, our results indicate that two variants that were tested have dominant-negative effects. In summary, the evidence supports that the observed variants in FRMD5 cause neurological symptoms in humans.
Insights
Genetic variants in FRMD5 cause developmental disorders, intellectual disability, ataxia, and seizures. This study links FRMD5 mutations to neurological symptoms in humans and flies, revealing its critical role in nervous system function.
Area of Science:
- Human Genetics
- Neuroscience
- Molecular Biology
Background:
- FERM domain proteins link the plasma membrane to the cytoskeleton, influencing protein and phosphoinositide localization.
- FRMD5 (FERM domain-containing protein 5) localizes to adherens junctions, stabilizing cell-cell contacts.
- No prior association of FRMD5 variants with Mendelian diseases was reported in OMIM.
Purpose of the Study:
- To investigate the role of FRMD5 in human neurological disorders.
- To characterize the functional impact of identified FRMD5 variants.
- To explore the conserved function of FRMD5 in a model organism.
Main Methods:
- Clinical evaluation of eight probands with rare heterozygous FRMD5 missense variants.
- De novo variant testing and analysis of human genetic datasets for loss-of-function intolerance.
- Functional characterization of the fly ortholog CG5022 (dFrmd) in loss-of-function mutants and rescue experiments with human FRMD5.
Main Results:
- Eight probands presented with developmental delay, intellectual disability, ataxia, seizures, and abnormal eye movements due to de novo FRMD5 variants.
- FRMD5 is intolerant to loss of function, and tested human variants act as partial loss-of-function or dominant-negative alleles.
- Fly dFrmd loss-of-function mutants exhibit heat shock sensitivity and defective phototaxis, which are rescued by human FRMD5.
Conclusions:
- Heterozygous variants in FRMD5 cause a novel neurodevelopmental disorder characterized by intellectual disability, ataxia, and seizures.
- FRMD5 plays a conserved role in neuronal function, essential for preventing heat-induced seizures and ensuring proper light responses.
- The findings establish FRMD5 as a disease-causing gene for human neurological symptoms.
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