Novel loss-of-function variants in WDR26 cause Skraban-Deardorff syndrome in two Chinese patients DOI Creative Commons
Qi Yang,

Xunzhao Zhou,

Sheng Yi

et al.

Frontiers in Pediatrics, Journal Year: 2024, Volume and Issue: 12

Published: Sept. 18, 2024

Introduction Mutations in the protein WD repeat structural domain 26 ( WDR26 , MIM 617424) have been identified as cause of autosomal dominant Skraban-Deardorff syndrome, a rare genetic disorder characterized by intellectual disability (ID), developmental delay (DD), hypotonia, epilepsy, infant feeding difficulties, gait abnormalities and distinctive facial features. The objective this study is to investigate factors that may contribute development syndrome affected individuals. Methods In study, we used whole-exome sequencing (WES) analyze pathogenic likely variants two unrelated Chinese patients with DD ID. We confirmed origin conducting Sanger classified them according ACMG/AMP guidelines. Results Here, novel de novo (c.1797delC(p.His599fs*11) c.1414C>T(p.Gln472*)) gene syndrome. These exhibit range symptoms, including varying degrees ID, DD, speech delay, an abnormal wide-foot and/or stiff-legged gait, dysmorphism, behavioural abnormalities, or without seizures. Conclusions report caused gene. showed clinical phenotype similar variant. Compared reported cases variants, patient 2 presented complication severe problems, hyperactivity, social anxiety, self-mutilation, impulsivity violent behaviour. This research broadens features addition, symptoms become more pronounced ages. Furthermore, our highlights diversity findings assist healthcare professionals providing accurate testing counselling families improving overall management condition.

Language: Английский

Non-canonical substrate recognition by the human WDR26-CTLH E3 ligase regulates prodrug metabolism DOI Creative Commons

Karthik V Gottemukkala,

Jakub Chrustowicz, Dawafuti Sherpa

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(10), P. 1948 - 1963.e11

Published: May 1, 2024

The yeast glucose-induced degradation-deficient (GID) E3 ubiquitin ligase forms a suite of complexes with interchangeable receptors that selectively recruit N-terminal degron motifs metabolic enzyme substrates. orthologous higher eukaryotic C-terminal to LisH (CTLH) complex has been proposed also recognize substrates through an alternative subunit, WDR26, which promotes the formation supramolecular CTLH assemblies. Here, we discover human WDR26 binds nicotinamide/nicotinic-acid-mononucleotide-adenylyltransferase 1 (NMNAT1) and mediates its E3-dependent ubiquitylation independently canonical GID/CTLH E3-family substrate receptors. subunit YPEL5 inhibits NMNAT1 cellular turnover by WDR26-CTLH E3, thereby affecting NMNAT1-mediated activation cytotoxicity prodrug tiazofurin. Cryoelectron microscopy (cryo-EM) structures NMNAT1- YPEL5-bound reveal internal basic motif essential for targeting mimicry YPEL5's N terminus antagonizing binding. Thus, our data provide mechanistic understanding how YPEL5-WDR26-CTLH acts as modulator NMNAT1-dependent metabolism.

Language: Английский

Citations

10
mTORC1 regulates the pyrimidine salvage pathway by controlling UCK2 turnover via the CTLH-WDR26 E3 ligase DOI Creative Commons
Brittany Q Pham, Sang Ah Yi, Alban Ordureau

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(1), P. 115179 - 115179

Published: Jan. 1, 2025

Language: Английский

Citations

1
Muskelin is a substrate adaptor of the highly regulated Drosophila embryonic CTLH E3 ligase DOI Creative Commons
Chloe A. Briney, Jesslyn C. Henriksen,

Chien-Chen Lin

et al.

EMBO Reports, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Abstract The maternal-to-zygotic transition (MZT) is a conserved developmental process where the maternally-derived protein and mRNA cache replaced with newly made zygotic gene products. We have previously shown that in Drosophila deposited RNA-binding proteins ME31B, Cup, Trailer Hitch are ubiquitylated by CTLH E3 ligase cleared. However, organization regulation of complex remain poorly understood flies because lacks an identifiable substrate adaptor, mechanisms restricting degradation ME31B its cofactors to MZT unknown. Here, we show multi-pronged, including transcriptional control OVO autoinhibition ligase. One major regulatory target subunit Muskelin, which demonstrate adaptor for complex. Finally, find Muskelin has few targets beyond three known proteins, showing exquisite specificity. Thus, multiple levels integrated restrict activity embryonic early embryogenesis, during time it regulates important proteins.

Language: Английский

Citations

0
The interactome of tau phosphorylated at T217 in Alzheimer’s disease human brain tissue DOI Creative Commons
Tomas Kavanagh,

Manon Thierry,

Kaleah Balcomb

et al.

Acta Neuropathologica, Journal Year: 2025, Volume and Issue: 149(1)

Published: May 3, 2025

Abstract Hyperphosphorylated tau (pTau) in Alzheimer’s disease (AD) brain tissue is a complex mix of multiple species that are variably phosphorylated. The emerging studies suggest phosphorylation specific residues may alter the role tau. pTau can be explored through protein interactome studies. aim this study was to analyse phosphorylated at T217 (pT217), which biomarker one earliest accumulating AD. pT217 interactors were identified fresh-frozen human from 10 cases advanced AD using affinity purification-mass spectrometry. included balanced cohort APOE ε3/ε3 and ε4/ε4 genotypes ( n = 5 each) explore how apolipoprotein E altered interactions. results compared our previous dataset profiled PHF1-enriched determine if individual have different interactomes. 23 proteins as bona fide interactors, including known interactor SQSTM1. enriched fewer tau, suggesting an earlier stage pathology development. Notable five subunits CTLH E3 ubiquitin ligase (WDR26, ARMC8, GID8, RANBP9, MAEA), has not previously been linked In significantly interacted with 46 28 cases, but these overlapped. both genotypes. interactions SQSTM1, WDR26 RANBP9 validated co-immunoprecipitation immunofluorescent microscopy post-mortem tissue, showed colocalisation pathology. Our report for first time highlight significant novel

Language: Английский

Citations

0
Muskelin acts as a substrate receptor of the highly regulated Drosophila CTLH E3 ligase during the maternal-to-zygotic transition DOI
Chloe A. Briney, Jesslyn C. Henriksen, Chenwei Lin

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 1, 2024

The maternal-to-zygotic transition (MZT) is a conserved developmental process where the maternally-derived protein and mRNA cache replaced with newly made zygotic gene products. We have previously shown that in

Language: Английский

Citations

0
Novel loss-of-function variants in WDR26 cause Skraban-Deardorff syndrome in two Chinese patients DOI Creative Commons
Qi Yang,

Xunzhao Zhou,

Sheng Yi

et al.

Frontiers in Pediatrics, Journal Year: 2024, Volume and Issue: 12

Published: Sept. 18, 2024

Introduction Mutations in the protein WD repeat structural domain 26 ( WDR26 , MIM 617424) have been identified as cause of autosomal dominant Skraban-Deardorff syndrome, a rare genetic disorder characterized by intellectual disability (ID), developmental delay (DD), hypotonia, epilepsy, infant feeding difficulties, gait abnormalities and distinctive facial features. The objective this study is to investigate factors that may contribute development syndrome affected individuals. Methods In study, we used whole-exome sequencing (WES) analyze pathogenic likely variants two unrelated Chinese patients with DD ID. We confirmed origin conducting Sanger classified them according ACMG/AMP guidelines. Results Here, novel de novo (c.1797delC(p.His599fs*11) c.1414C>T(p.Gln472*)) gene syndrome. These exhibit range symptoms, including varying degrees ID, DD, speech delay, an abnormal wide-foot and/or stiff-legged gait, dysmorphism, behavioural abnormalities, or without seizures. Conclusions report caused gene. showed clinical phenotype similar variant. Compared reported cases variants, patient 2 presented complication severe problems, hyperactivity, social anxiety, self-mutilation, impulsivity violent behaviour. This research broadens features addition, symptoms become more pronounced ages. Furthermore, our highlights diversity findings assist healthcare professionals providing accurate testing counselling families improving overall management condition.

Language: Английский

Citations

0