Mutation of HERC2 causes developmental delay with Angelman-like features

  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},
  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… 

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.

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.



Distinct phenotypes distinguish the molecular classes of Angelman syndrome

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.

Molecular and Clinical Aspects of Angelman Syndrome

Analysis of parent-specific DNA methylation imprints in the critical 15q11.2–q13 genomic region identifies 75–80% of all individuals with the Angelman syndrome, including those with cytogenetic deletions, imprinting center defects and paternal uniparental disomy.

Structure of the highly conserved HERC2 gene and of multiple partially duplicated paralogs in human.

The results establish that some genes not only have a protein coding function but can also play a structural role in the genome and provide significant insights into the structure of complex duplicons and into the evolutionary pathways of formation, dispersal, and genomic instability of duplicons.

NEK8 mutations affect ciliary and centrosomal localization and may cause nephronophthisis.

The genetic and functional data support the assumption that mutations in NEK8 cause nephronophthisis (NPHP9), adding another link between proteins mutated in cystic kidney disease and their localization to cilia and centrosomes.

Physical and Functional Interaction of the HECT Ubiquitin-protein Ligases E6AP and HERC2*

It is reported that the giant protein HERC2, which is like E6AP a member of the HECT family of ubiquitin-protein ligases, binds to E 6AP and the data obtained indicate that HerC2 acts as a regulator of E6 AP.

Angelman syndrome (AS, MIM 105830)

The main clinical characteristics include severe mental retardation, epileptic seizures and EEG abnormalilties, neurological problems and distinct facial dysmorphic features, although these patients present mostly a happy personality with periods of inappropriate laughter.

The ancestral gene for transcribed, low-copy repeats in the Prader-Willi/Angelman region encodes a large protein implicated in protein trafficking, which is deficient in mice with neuromuscular and spermiogenic abnormalities.

The identification of the ancestral gene ( HERC2) and a family of duplicated, truncated copies that comprise these low-copy repeats suggest that Herc2 is an important gene encoding a GEF involved in protein trafficking and degradation pathways in the cell.

HERC2 is an E3 ligase that targets BRCA1 for degradation.

It is shown that HERC2, a protein recently implicated in DNA damage repair, targets BARD1-uncoupled BRCA1 for degradation, and that herC2 depletion antagonizes the effects of Bard1 depletion by restoring BRCa1 expression and G(2)-M checkpoint activity.

A very large protein with diverse functional motifs is deficient in rjs (runty, jerky, sterile) mice.

On the basis of sequence homology and conserved synteny, the rjs gene is the single mouse homolog of a previously described five- or six-member human gene family, represented by at least two genes from human chromosome 15q11-q13.

Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints.

It is postulate that the END repeats flanking 15q11-q13 mediate homologous recombination resulting in deletion and proposed that active transcription of these repeats in male and female germ cells may facilitate the homologously recombination process.