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Loss-of-function variants in CUL3 cause a syndromic neurodevelopmental disorder


Abstract

Purpose De novovariants inCUL3(Cullin-3 ubiquitin ligase) 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 inCUL3,describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism.MethodsGenetic data and detailed clinical records were collected via multi-center collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells.ResultsWe assembled a cohort of 35 individuals with heterozygousCUL3variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 33 have loss-of-function (LoF) and two have missense variants.CUL3LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugatesin vitro. Specifically, we show that cyclin E1 (CCNE1) and 4E-BP1 (EIF4EBP1), two prominent substrates of CUL3, fail to be targeted for proteasomal degradation in patient-derived cells.ConclusionOur study further refines the clinical and mutational spectrum ofCUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism.

Abstract

Purpose De novovariants inCUL3(Cullin-3 ubiquitin ligase) 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 inCUL3,describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism.MethodsGenetic data and detailed clinical records were collected via multi-center collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells.ResultsWe assembled a cohort of 35 individuals with heterozygousCUL3variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 33 have loss-of-function (LoF) and two have missense variants.CUL3LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugatesin vitro. Specifically, we show that cyclin E1 (CCNE1) and 4E-BP1 (EIF4EBP1), two prominent substrates of CUL3, fail to be targeted for proteasomal degradation in patient-derived cells.ConclusionOur study further refines the clinical and mutational spectrum ofCUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism.

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Additional indexing

Item Type:Working Paper
Communities & Collections:04 Faculty of Medicine > Institute of Medical Genetics
07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Genetic Medicine, Genomic Medicine
Language:English
Date:16 June 2023
Deposited On:29 Jun 2023 07:53
Last Modified:22 Sep 2023 12:29
Series Name:medRxiv
Number of Pages:37
ISSN:0959-535X
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1101/2023.06.13.23290941
Other Identification Number:PMID: 37398376 / PMCID: PMC10312857
  • Content: Published Version
  • Language: English