Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064165%3A_____%2F25%3A10485727" target="_blank" >RIV/00064165:_____/25:10485727 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11110/25:10485727
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=iCysuGHZoF" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=iCysuGHZoF</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/ana.27077" target="_blank" >10.1002/ana.27077</a>
Alternative languages
Result language
angličtina
Original language name
Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder
Original language description
Objective: De novo variants in cullin-3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype–phenotype correlation, and investigate the underlying pathogenic mechanism. Methods: Genetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells. Results: We assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss-of-function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro. Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells. Interpretation: Our study further refines the clinical and mutational spectrum of CUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30103 - Neurosciences (including psychophysiology)
Result continuities
Project
—
Continuities
V - Vyzkumna aktivita podporovana z jinych verejnych zdroju
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Annals of Neurology
ISSN
0364-5134
e-ISSN
1531-8249
Volume of the periodical
97
Issue of the periodical within the volume
1
Country of publishing house
US - UNITED STATES
Number of pages
14
Pages from-to
76-89
UT code for WoS article
001317007900001
EID of the result in the Scopus database
2-s2.0-85204741826