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A novel de novo FEM1C variant as a potential cause of neurodevelopmental disorder with absent speech, pyramidal signs, and limb ataxia

View ORCID ProfileAbhishek Anil Dubey, View ORCID ProfileMagdalena Krygier, View ORCID ProfileNatalia A. Szulc, View ORCID ProfileKarolina Rutkowska, View ORCID ProfileJoanna Kosińska, View ORCID ProfileAgnieszka Pollak, View ORCID ProfileMałgorzata Rydzanicz, View ORCID ProfileTomasz Kmieć, View ORCID ProfileMaria Mazurkiewicz-Bełdzińska, View ORCID ProfileWojciech Pokrzywa, View ORCID ProfileRafał Płoski
doi: https://doi.org/10.1101/2022.04.24.489208
Abhishek Anil Dubey
1Laboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in Warsaw, 4 Ks. Trojdena Str., 02-109 Warsaw, Poland
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Magdalena Krygier
2Department of Developmental Neurology, Medical University of Gdansk, ul. Debinki 7, 80-952, Gdansk, Poland
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  • ORCID record for Magdalena Krygier
Natalia A. Szulc
1Laboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in Warsaw, 4 Ks. Trojdena Str., 02-109 Warsaw, Poland
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Karolina Rutkowska
3Department of Medical Genetics, Medical University of Warsaw, Pawinskiego 3c, 02-106 Warsaw, Poland
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Joanna Kosińska
3Department of Medical Genetics, Medical University of Warsaw, Pawinskiego 3c, 02-106 Warsaw, Poland
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  • ORCID record for Joanna Kosińska
Agnieszka Pollak
3Department of Medical Genetics, Medical University of Warsaw, Pawinskiego 3c, 02-106 Warsaw, Poland
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  • ORCID record for Agnieszka Pollak
Małgorzata Rydzanicz
3Department of Medical Genetics, Medical University of Warsaw, Pawinskiego 3c, 02-106 Warsaw, Poland
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  • ORCID record for Małgorzata Rydzanicz
Tomasz Kmieć
4Department of Neurology and Epileptology, The Children’s Memorial Health Institute, aleja Dzieci Polskich 20, 04-730 Warsaw, Poland
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Maria Mazurkiewicz-Bełdzińska
2Department of Developmental Neurology, Medical University of Gdansk, ul. Debinki 7, 80-952, Gdansk, Poland
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Wojciech Pokrzywa
1Laboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in Warsaw, 4 Ks. Trojdena Str., 02-109 Warsaw, Poland
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  • For correspondence: rafal.ploski@wum.edu.pl wpokrzywa@iimcb.gov.pl
Rafał Płoski
3Department of Medical Genetics, Medical University of Warsaw, Pawinskiego 3c, 02-106 Warsaw, Poland
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  • ORCID record for Rafał Płoski
  • For correspondence: rafal.ploski@wum.edu.pl wpokrzywa@iimcb.gov.pl
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Abstract

Maintaining protein homeostasis (proteostasis) requires the degradation of damaged or unwanted proteins and plays a crucial role in cellular function. The principal proteolytic component of the proteostasis network is the ubiquitin-proteasome system (UPS) which orchestrates protein degradation through ubiquitination of appropriate targets. Ubiquitination is mediated by an enzymatic cascade involving, i.e., E3 ubiquitin ligases, many of which belong to the cullin-RING ligases (CRLs) family. Genetic defects of the UPS are known causes of neurodevelopmental disorders, with >60 entities described so far. Using exome sequencing (ES) to diagnose a pediatric patient with global developmental delay, pyramidal signs, and limb ataxia, we identified a de novo missense variant c.376G>C; p.(Asp126His) in the FEM1C gene, which encodes a CRL substrate receptor. The p.(Asp126His) variant, which alters a conserved amino acid (phyloP100way = 7.9), is located within a highly constrained coding region (CCR=98.6) and is predicted to be pathogenic by the majority (13/19) of in silico tools. To further assess its pathogenicity, we employed Caenorhabditis elegans nematode as a disease model. We found that the mutant vs. wild-type worms had impaired mobility as assessed by track length (p=0.0001), turn counts (p=0.0001), and omega bend counts (p=0.038). Furthermore, mutant worms had histologically normal muscle architecture but were sensitive to an acetylcholinesterase inhibitor - aldicarb which indicates that their locomotion defects result from synaptic defects rather than muscle dysfunction. We conclude that the disease in our patient may be the first reported case of a neurodevelopmental disorder caused by the FEM1C genetic defect.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    ADHD
    attention deficit hyperactivity disorder
    ADS
    amplicon deep sequencing
    ASD
    autism spectrum disorder
    CCR
    constrained coding region
    CP
    cerebral palsy
    CRLs
    cullin-RING ligases
    DD
    developmental delay
    E1
    ubiquitin-activating enzyme
    E2
    ubiquitin-conjugating enzyme
    E3
    ubiquitin ligase
    ES
    exome sequencing
    ID
    intellectual disability
    NDDs
    neurodevelopmental disorders
    NGM
    nematode growth medium
    UPS
    ubiquitin-proteasome system
    WES
    whole exome sequencing
  • Copyright 
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    Posted April 24, 2022.
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    A novel de novo FEM1C variant as a potential cause of neurodevelopmental disorder with absent speech, pyramidal signs, and limb ataxia
    Abhishek Anil Dubey, Magdalena Krygier, Natalia A. Szulc, Karolina Rutkowska, Joanna Kosińska, Agnieszka Pollak, Małgorzata Rydzanicz, Tomasz Kmieć, Maria Mazurkiewicz-Bełdzińska, Wojciech Pokrzywa, Rafał Płoski
    bioRxiv 2022.04.24.489208; doi: https://doi.org/10.1101/2022.04.24.489208
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    A novel de novo FEM1C variant as a potential cause of neurodevelopmental disorder with absent speech, pyramidal signs, and limb ataxia
    Abhishek Anil Dubey, Magdalena Krygier, Natalia A. Szulc, Karolina Rutkowska, Joanna Kosińska, Agnieszka Pollak, Małgorzata Rydzanicz, Tomasz Kmieć, Maria Mazurkiewicz-Bełdzińska, Wojciech Pokrzywa, Rafał Płoski
    bioRxiv 2022.04.24.489208; doi: https://doi.org/10.1101/2022.04.24.489208

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