HUWE1 mutation explains phenotypic severity in a case of familial idiopathic intellectual disability

Isrie, Mala; Kalscheuer, Vera M.; Holvoet, Maureen; Fieremans, Nathalie; Esch, Hilde Van; Devriendt, Koenraad

doi:10.1016/j.ejmg.2013.05.005

Cited by 16 publications

(12 citation statements)

References 18 publications

(19 reference statements)

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“…Its dysregulation leads to various movement disturbances, dementia and hypogonadotropic hypogonadism [44,45]. Thus, it is not surprising that a growing group of ID proteins are directly involved in UPS-mediated protein degradation, such as UBE3A [46] [47], UBE2A [48,49,50,51], UBE3B [52,47], HUWE1 [53,54,55], MID1 [56][57][58][59], CUL4B [60,[61][62][63], UBR1 [64,65,66], TRIP12 [67][68][69], and RNF216 [45,[70][71][72].…”

Section: Discussionmentioning

confidence: 99%

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

et al. 2018

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RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes cosegregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.

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Section: Discussionmentioning

confidence: 99%

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

et al. 2018

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“…Several studies have revealed a crucial role of the UPS in the spatial and temporal control of protein turnover in the nervous system, which regulates the development and maintenance of specialized neuronal structures, and consequently , neuronal transmission. Thus, it is not surprising that a growing group of ID linked proteins are directly involved in UPS-mediated protein degradation such as UBE3A, UBE2A, UBE3B, HUWE1, MID1, CUL4B, and UBR1 (Badura-Stronka et al, 2010; Basel-Vanagaite et al, 2012; Budny et al, 2010; Flex et al, 2013; Froyen et al, 2008; Hwang et al, 2011; Isrie et al, 2013; Kishino et al, 1997; Matsuura et al, 1997; Nascimento et al, 2006; Tarpey et al, 2007; Zenker et al, 2005; Zou et al, 2007). …”

Section: Genes Linked To Id and Asdmentioning

confidence: 99%

Intellectual disability and autism spectrum disorders: Causal genes and molecular mechanisms

Srivastava

Schwartz

2014

Neuroscience & Biobehavioral Reviews

182

153

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Intellectual disability (ID) and Autism Spectrum disorder (ASD) are the most common developmental disorders present in humans. Combined, they affect between 3-5% of the population. Additionally, they can be found together in the same individual thereby complicating treatment. The causative factors (genes, epigenetic and environmental) are quite varied and likely interact so as to further complicate the assessment of an individual patient. Nonetheless, much valuable information has been gained by identifying candidate genes for ID or ASD. Understanding the etiology of either ID or ASD is of utmost importance for families. It allows a determination of the risk of recurrence, the possibility of other comorbidity medical problems, the molecular and cellular nature of the pathobiology and hopefully potential therapeutic approaches.

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“…Increased copies of HUWE1 are associated with non-syndromic intellectual disability (Friez et al, 2016 #922; Froyen et al, 2012; Froyen et al, 2008; Madrigal et al, 2007). Missense mutations in HUWE1 occur in multiple families with intellectual disability, including families with Juberg-Marsidi-Brooks syndrome (Friez et al, 2016; Froyen et al, 2008; Isrie et al, 2013). This suggests both increased and decreased HUWE1 function could be associated with intellectual disability, but evidence from an in vivo model system supporting or refuting this possibility remains absent.…”

Section: Introductionmentioning

confidence: 99%

The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development

et al. 2017

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Summary Genetic changes in the HECT ubiquitin ligase HUWE1 are associated with intellectual disability, but it remains unknown whether HUWE1 functions in post-mitotic neurons to affect circuit function. Using genetics, pharmacology and electrophysiology, we show that EEL-1, the HUWE1 ortholog in C. elegans, preferentially regulates GABAergic presynaptic transmission. Decreasing or increasing EEL-1 function alters GABAergic transmission and excitatory/inhibitory (E/I) balance in the worm motor circuit, which leads to impaired locomotion and increased sensitivity to electroshock. Furthermore, multiple mutations associated with intellectual disability impair EEL-1 function. While synaptic transmission defects did not result from abnormal synapse formation, sensitizing genetic backgrounds revealed that EEL-1 functions in the same pathway as the RING family ubiquitin ligase RPM-1 to regulate synapse formation and axon termination. These findings from a simple model circuit provide insight into the molecular mechanisms required to obtain E/I balance, and could have implications for the link between HUWE1 and intellectual disability.

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HUWE1 mutation explains phenotypic severity in a case of familial idiopathic intellectual disability

Cited by 16 publications

References 18 publications

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Intellectual disability and autism spectrum disorders: Causal genes and molecular mechanisms

The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development

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