Mutation of HERC2 causes developmental delay with Angelman-like features

@article{Harlalka2012MutationOH,
  title={Mutation of HERC2 causes developmental delay with Angelman-like features},
  author={Gaurav V Harlalka and Emma L. Baple and Harold E Cross and Simone Kühnle and Monica Cubillos-Rojas and Konstantin Matentzoglu and Michael A. Patton and Karin Wagner and Roselyn Coblentz and Debra L Ford and Deborah J G Mackay and Barry A. Chioza and Martin Scheffner and Jose Luis Rosa and Andrew H. 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… 
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Novel loss-of-function mutation in HERC2 is associated with severe developmental delay and paediatric lethality

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.

Complete loss of function of the ubiquitin ligase HERC2 causes a severe neurodevelopmental phenotype

It is shown that loss of HERC2 function leads to the accumulation of XPA and BRCA1 in the patient’s fibroblasts and generates decreased sensitivity to apoptosis and increased level of DNA repair.

The HERC2 ubiquitin ligase is essential for embryonic development and regulates motor coordination

A mouse with targeted inactivation of the Herc2 gene is described, establishing a crucial role of HERC2 in embryonic development and motor coordination and identifying an impaired motor synchronization with normal neuromuscular function.

From UBE3A to Angelman syndrome: a substrate perspective

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.

UBE3A reinstatement as a disease‐modifying therapy for Angelman syndrome

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.

The HERC proteins and the nervous system.

New genes involved in Angelman syndrome-like: Expanding the genetic spectrum

WES identified 10 de novo and 1 X-linked pathogenic/likely pathogenic variants in 10 neurodevelopmental genes (SYNGAP1, VAMP2, TBL1XR1, ASXL3, SATB2, SMARCE1, SPTAN1, KCNQ3, SLC6A1 and LAS1L), highlighting the wide genetic heterogeneity in AS-like patients and expands the differential diagnosis.

Angelman syndrome–associated point mutations in the Zn2+-binding N-terminal (AZUL) domain of UBE3A ubiquitin ligase inhibit binding to the proteasome

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.

Blended phenotype of combination of HERC2 and AP3B2 deficiency and Angelman syndrome caused by paternal isodisomy of chromosome 15

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.

Contiguous mutation syndrome in the era of high-throughput sequencing

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.
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