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Relevance to Autism

A de novo missense variant in HUWE1 was identified in a male ASD proband, but not in the proband's less severely affected brother (Nava et al., 2012).

Molecular Function

E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins. Regulates neural differentiation and proliferation by catalyzing the polyubiquitination and degradation of MYCN. Defects in HUWE1 are the cause of mental retardation syndromic X-linked Turner type (MRXST) [MIM:300706], also known as mental retardation and macrocephaly syndrome. MRXST shows clinical variability, and associated phenotypes include macrocephaly and variable contractures. A chromosomal microduplication involving HUWE1 and HSD17B10 is the cause of mental retardation X-linked type 17 (MRX17) [MIM:300705]; also known as mental retardation X-linked type 31 (MRX31).

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE.
ASD
ID
Support
Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes
ASD
Support
Diagnostic yield of whole-exome sequencing in non-syndromic intellectual disability
DD, ID
Epilepsy/seizures, autistic features
Support
Large-scale discovery of novel genetic causes of developmental disorders.
DD
Support
Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.
ASD
Support
Case Report: Whole Exome Sequencing Revealed Disease-Causing Variants in Two Genes in a Patient With Autism Spectrum Disorder, Intellectual Disability, Hyperactivity, Sleep and Gastrointestinal Distur
ASD
DD, ID
Support
Copy-number gains of HUWE1 due to replication- and recombination-based rearrangements.
ID
Support
Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.
ASD
Support
Exploring the biological role of postzygotic and germinal de novo mutations in ASD
ASD
Support
Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.
ASD
ID
Support
Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy
ASD
Support
Exome sequencing reveals a novel splice site variant in HUWE1 gene in patients with suspected Say-Meyer syndrome.
Say-Meyer syndrome
ASD, ID
Support
Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability.
ID
Support
High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.
ID
Autistic behavior
Support
Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.
ASD
Microcephaly
Support
Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability
ID
Highly Cited
Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation.
ID
Recent Recommendation
HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients.
ID
Autistic features, hand stereotypies
Recent Recommendation
The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development.
Recent Recommendation
Ubiquitin ligase HUWE1 regulates axon branching through the Wnt/-catenin pathway in a Drosophila model for intellectual disability.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN432R001 
 missense_variant 
 c.2849T>A 
 p.Val950Asp 
 De novo 
 NA 
 Multiplex 
 GEN432R002 
 missense_variant 
 c.12037C>T 
 p.Arg4013Trp 
 Familial 
 Maternal 
 Multi-generational 
 GEN432R003 
 missense_variant 
 c.8942G>A 
 p.Arg2981His 
 Familial 
 Maternal 
 Multi-generational 
 GEN432R004 
 missense_variant 
 c.12559C>T 
 p.Arg4187Cys 
 Familial 
 Maternal 
 Multi-generational 
 GEN432R005 
 copy_number_gain 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN432R006 
 copy_number_gain 
  
  
 Familial 
 Maternal (3/4), paternal (1/4) 
 1 simplex, 3 multiplex 
 GEN432R007 
 missense_variant 
 c.2007T>G 
 p.His669Gln 
 De novo 
 NA 
 Simplex 
 GEN432R008 
 missense_variant 
 c.2429A>C 
 p.Asn810Thr 
 Familial 
 Maternal 
 Multi-generational 
 GEN432R009 
 missense_variant 
 c.11911C>T 
 p.Arg3971Trp 
 De novo 
 NA 
  
 GEN432R010 
 missense_variant 
 c.3431A>T 
 p.Asp1144Val 
 De novo 
 NA 
  
 GEN432R011 
 missense_variant 
 c.344C>T 
 p.Ser115Phe 
 De novo 
 NA 
  
 GEN432R012 
 missense_variant 
 c.329G>A 
 p.Arg110Gln 
 De novo 
 NA 
 Simplex 
 GEN432R013 
 missense_variant 
 c.329G>A 
 p.Arg110Gln 
 De novo 
 NA 
 Simplex 
 GEN432R014 
 missense_variant 
 c.329G>A 
 p.Arg110Gln 
 De novo 
 NA 
 Simplex 
 GEN432R015 
 missense_variant 
 c.344C>T 
 p.Ser115Phe 
 De novo 
 NA 
 Simplex 
 GEN432R016 
 splice_site_variant 
 c.567+1G>C 
  
 De novo 
 NA 
 Simplex 
 GEN432R017 
 missense_variant 
 c.1978G>A 
 p.Gly660Arg 
 De novo 
 NA 
 Simplex 
 GEN432R018 
 missense_variant 
 c.2007T>G 
 p.His669Gln 
 De novo 
 NA 
 Simplex 
 GEN432R019 
 missense_variant 
 c.3982A>G 
 p.Met1328Val 
 De novo 
 NA 
 Simplex 
 GEN432R020 
 missense_variant 
 c.6267T>G 
 p.Ile2089Met 
 De novo 
 NA 
 Simplex 
 GEN432R021 
 missense_variant 
 c.9208C>T 
 p.Arg3070Cys 
 De novo 
 NA 
 Simplex 
 GEN432R022 
 missense_variant 
 c.9208C>T 
 p.Arg3070Cys 
 De novo 
 NA 
 Simplex 
 GEN432R023 
 missense_variant 
 c.9581T>C 
 p.Phe3194Ser 
 De novo 
 NA 
 Simplex 
 GEN432R024 
 missense_variant 
 c.12067C>T 
 p.Arg4023Cys 
 Familial 
 Maternal 
 Multiplex 
 GEN432R025 
 missense_variant 
 c.12205A>T 
 p.Ile4069Phe 
 De novo 
 NA 
 Simplex 
 GEN432R026 
 missense_variant 
 c.12225C>G 
 p.Asn4075Lys 
 De novo 
 NA 
 Simplex 
 GEN432R027 
 missense_variant 
 c.12317A>G 
 p.Tyr4106Cys 
 De novo 
 NA 
 Simplex 
 GEN432R028 
 missense_variant 
 c.12469C>G 
 p.Leu4157Val 
 De novo 
 NA 
 Simplex 
 GEN432R029 
 missense_variant 
 c.12732G>C 
 p.Glu4244Asp 
 De novo 
 NA 
 Simplex 
 GEN432R030 
 missense_variant 
 c.12885G>C 
 p.Lys4295Asn 
 Familial 
 Maternal 
 Multi-generational 
 GEN432R031 
 splice_site_variant 
 c.693+1G>T 
  
 De novo 
 NA 
  
 GEN432R032 
 missense_variant 
 c.1736A>C 
 p.Asn579Thr 
 Familial 
 Maternal 
  
 GEN432R033 
 frameshift_variant 
 c.8932del 
 p.Asp2978MetfsTer12 
 Unknown 
  
 Multiplex 
 GEN432R034 
 missense_variant 
 c.10384A>G 
 p.Ile3462Val 
 De novo 
 NA 
  
 GEN432R035 
 missense_variant 
 c.12344C>T 
 p.Ala4115Val 
 De novo 
 NA 
 Simplex 
 GEN432R036 
 splice_site_variant 
 c.145-2A>G 
  
 Familial 
 Maternal 
 Multiplex 
 GEN432R037 
 missense_variant 
 c.1125G>T 
 p.Met375Ile 
 Familial 
 Maternal 
 Multiplex (monozygotic twins) 
 GEN432R038 
 missense_variant 
 c.12209C>G 
 p.Ser4070Cys 
 Familial 
 Maternal 
 Unknown 
 GEN432R039 
 splice_site_variant 
 c.693+1G>A 
  
 Unknown 
  
  
 GEN432R040 
 missense_variant 
 c.9212G>A 
 p.Arg3071His 
 De novo 
 NA 
 Simplex 
 GEN432R041 
 missense_variant 
 c.1708C>T 
 p.Pro570Ser 
 De novo 
 NA 
 Simplex 
 GEN432R042 
 missense_variant 
 c.12365G>A 
 p.Arg4122His 
 Familial 
 Maternal 
 Simplex 
 GEN432R043 
 splice_site_variant 
 c.4095+1G>A 
  
 Familial 
 Maternal 
 Simplex 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
X
Deletion-Duplication
 24
 
X
Duplication
 1
 
X
Duplication
 1
 
X
Duplication
 1
 
X
Deletion
 1
 
X
Deletion
 4
 
X
Deletion-Duplication
 1
 
X
Deletion
 1
 
X
Deletion-Duplication
 18
 

No Animal Model Data Available


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
CUL3 cullin 3 8452 B7Z600 IP; MS; COMPASS
Bennett EJ , et al. 2010
NCKAP1 NCK-associated protein 1 NM_205842 Q9Y2A7 LC/MS
Thompson JW , et al. 2014
SHOC2 soc-2 suppressor of clear homolog 103216511 A0A0D9QYN1 IP/WB
Jang ER , et al. 2015
TBL1X transducin (beta)-like 1X-linked 6907 O60907 LC-MS/MS
Havugimana PC , et al. 2012
TOP3B topoisomerase (DNA) III beta 8940 O95985 HITS-CLIP
Xu D , et al. 2013

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