{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T15:04:30Z","timestamp":1787843070993,"version":"build-2784847793"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T00:00:00Z","timestamp":1667779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"National Science Centre","doi-asserted-by":"publisher","award":["2021\/41\/N\/NZ1\/03473"],"award-info":[{"award-number":["2021\/41\/N\/NZ1\/03473"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004281","name":"National Science Centre","doi-asserted-by":"publisher","award":["2019\/34\/H\/NZ3\/00691"],"award-info":[{"award-number":["2019\/34\/H\/NZ3\/00691"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The principal component of the protein homeostasis network is the ubiquitin-proteasome system. Ubiquitination is mediated by an enzymatic cascade involving, i.e. E3 ubiquitin ligases, many of which belong to the cullin-RING ligases family. Genetic defects in the ubiquitin-proteasome system components, including cullin-RING ligases, are known causes of neurodevelopmental disorders. Using exome sequencing to diagnose a pediatric patient with developmental delay, pyramidal signs and limb ataxia, we identified a de novo missense variant c.376G&amp;gt;C; p.(Asp126His) in the FEM1C gene encoding a cullin-RING ligase substrate receptor. This variant alters a conserved amino acid located within a highly constrained coding region and is predicted as pathogenic by most in silico tools. In addition, a de novo FEM1C mutation of the same residue p.(Asp126Val) was associated with an undiagnosed developmental disorder, and the relevant variant (FEM1CAsp126Ala) was found to be functionally compromised in vitro. Our computational analysis showed that FEM1CAsp126His hampers protein substrate binding. To further assess its pathogenicity, we used the nematode Caenorhabditis elegans. We found that the FEM-1Asp133His animals (expressing variant homologous to the FEM1C p.(Asp126His)) had normal muscle architecture yet impaired mobility. Mutant worms were sensitive to the acetylcholinesterase inhibitor aldicarb but not levamisole (acetylcholine receptor agonist), showing that their disabled locomotion is caused by synaptic abnormalities and not muscle dysfunction. In conclusion, we provide the first evidence from an animal model suggesting that a mutation in the evolutionarily conserved FEM1C Asp126 position causes a neurodevelopmental disorder in humans.<\/jats:p>","DOI":"10.1093\/hmg\/ddac276","type":"journal-article","created":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T07:28:26Z","timestamp":1667806106000},"page":"1152-1161","source":"Crossref","is-referenced-by-count":3,"title":["A novel <i>de novo FEM1C<\/i> variant is linked to neurodevelopmental disorder with absent speech, pyramidal signs and limb ataxia"],"prefix":"10.1093","volume":"32","author":[{"given":"Abhishek Anil","family":"Dubey","sequence":"first","affiliation":[{"name":"International Institute of Molecular and Cell Biology in Warsaw Laboratory of Protein Metabolism, , 02-109 Warsaw , Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Krygier","sequence":"additional","affiliation":[{"name":"Medical University of Gda\u0144sk Department of Developmental Neurology, , 80-952 Gda\u0144sk , Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia A","family":"Szulc","sequence":"additional","affiliation":[{"name":"International Institute of Molecular and Cell Biology in Warsaw Laboratory of Protein Metabolism, , 02-109 Warsaw , Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina","family":"Rutkowska","sequence":"additional","affiliation":[{"name":"Medical University of Warsaw Department of Medical Genetics, , 02-106 Warsaw , Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Kosi\u0144ska","sequence":"additional","affiliation":[{"name":"Medical University of Warsaw Department of Medical Genetics, , 02-106 Warsaw , Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Pollak","sequence":"additional","affiliation":[{"name":"Medical University of Warsaw Department of Medical Genetics, , 02-106 Warsaw , Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u0142gorzata","family":"Rydzanicz","sequence":"additional","affiliation":[{"name":"Medical University of Warsaw Department of Medical Genetics, , 02-106 Warsaw , Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Kmie\u0107","sequence":"additional","affiliation":[{"name":"The Children's Memorial Health Institute Department of Neurology and Epileptology, , 04-730 Warsaw , Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Mazurkiewicz-Be\u0142dzi\u0144ska","sequence":"additional","affiliation":[{"name":"Medical University of Gda\u0144sk Department of Developmental Neurology, , 80-952 Gda\u0144sk , Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5110-4462","authenticated-orcid":false,"given":"Wojciech","family":"Pokrzywa","sequence":"additional","affiliation":[{"name":"International Institute of Molecular and Cell Biology in Warsaw Laboratory of Protein Metabolism, , 02-109 Warsaw , Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6286-5526","authenticated-orcid":false,"given":"Rafa\u0142","family":"P\u0142oski","sequence":"additional","affiliation":[{"name":"Medical University of Warsaw Department of Medical Genetics, , 02-106 Warsaw , Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,11,7]]},"reference":[{"issue":"4","key":"2023112014581974200_ref1","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/S2215-0366(16)30376-5","article-title":"Neurodevelopmental disorders","volume":"4","author":"Thapar","year":"2017","journal-title":"Lancet Psychiat"},{"issue":"7642","key":"2023112014581974200_ref2","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/nature21062","article-title":"Prevalence and architecture of de novo mutations in developmental disorders","volume":"542","author":"Deciphering Developmental Disorders Study","year":"2017","journal-title":"Nature"},{"key":"2023112014581974200_ref3","doi-asserted-by":"crossref","first-page":"733012","DOI":"10.3389\/fnmol.2021.733012","article-title":"Neurodevelopmental Disorders (NDD) caused by genomic alterations of the Ubiquitin-Proteasome System (UPS): the possible contribution of immune dysregulation to disease pathogenesis","volume":"14","author":"Ebstein","year":"2021","journal-title":"Front. 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