Mutation of HERC2 causes developmental delay with Angelman-like features

@article{Harlalka2012MutationOH,
  title={Mutation of HERC2 causes developmental delay with Angelman-like features},
  author={G. Harlalka and E. Baple and H. Cross and S. K{\"u}hnle and M. Cubillos-Rojas and K. Matentzoglu and M. Patton and K. Wagner and R. Coblentz and D. L. Ford and D. Mackay and B. Chioza and M. Scheffner and J. L. Rosa and A. Crosby},
  journal={Journal of Medical Genetics},
  year={2012},
  volume={50},
  pages={65 - 73}
}
Background Deregulation of the activity of the ubiquitin ligase E6AP (UBE3A) is well recognised to contribute to the development of Angelman syndrome (AS). The ubiquitin ligase HERC2, encoded by the HERC2 gene is thought to be a key regulator of E6AP. Methods and results Using a combination of autozygosity mapping and linkage analysis, we studied an autosomal-recessive neurodevelopmental disorder with some phenotypic similarities to AS, found among the Old Order Amish. Our molecular… Expand
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Novel loss-of-function mutation in HERC2 is associated with severe developmental delay and paediatric lethality
TLDR
This study ascertained a consanguineous family with a presumed autosomal recessive severe neurodevelopmental disorder that leads to paediatric lethality and identified a homozygous HERC2 frameshift variant that results in a premature stop codon and complete loss of HerC2 protein. Expand
Complete loss of function of the ubiquitin ligase HERC2 causes a severe neurodevelopmental phenotype
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TLDR
Overall, the analysis of the HERC2-associated proteome revealed striking differential protein expression between cases and controls, and the canonical pathway and protein interaction network findings suggest derangements of multiple pathways in HERC 2-associated disease. Expand
From UBE3A to Angelman syndrome: a substrate perspective
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Interestingly, proteins altered in AS are linked to additional ASDs that are not previously associated with changes in UBE3A, indicating a possible molecular overlap underlying the broad-spectrum phenotypes of these neurogenetic disorders. Expand
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TLDR
Expectations are very high for approaches that aim to restore UBE3A protein levels, which potentially offer a disease‐modifying therapy for Angelman syndrome and several other neurodevelopmental disorders. Expand
Angelman syndrome–associated point mutations in the Zn2+-binding N-terminal (AZUL) domain of UBE3A ubiquitin ligase inhibit binding to the proteasome
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Analysis of the interaction of UBE3A and the proteasomal subunit PSMD4 indicates that impaired binding to the 26S proteasome and consequential deregulation of Wnt/β-catenin signaling might contribute to the functional defect of these mutants in Angelman syndrome. Expand
Blended phenotype of combination of HERC2 and AP3B2 deficiency and Angelman syndrome caused by paternal isodisomy of chromosome 15
TLDR
The first reported case of a 3-year-old boy with an atypical phenotype of Angelman syndrome due to uniparental isodisomy with two recessive homozygous pathogenic variants: in HERC2 and AP3B2 is presented. Expand
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It is proposed that the siblings' phenotype results from the combined effects of mutations in both AP4M1 and AZGP1 that account for the neurological signs and the morbid obesity of early onset, respectively. Expand
Gene discovery and cellular modelling of rare autosomal recessive neurodevelopmental conditions
TLDR
This project aimed to delineate novel genetic causes of neurodevelopmental conditions using next generation sequencing (NGS) technologies in a family-based approach and established new genotype-phenotype correlations that will be beneficial for future clinical diagnosis and patient care. Expand
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TLDR
Clinically, the data indicate that the five molecular classes can be divided into four phenotypic groups: deletions, UPD and ID patients,UBE3A mutation patients, and subjects with unknown aetiology. Expand
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