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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References

SHOWING 1-10 OF 22 REFERENCES
Distinct phenotypes distinguish the molecular classes of Angelman syndrome
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
Molecular and Clinical Aspects of Angelman Syndrome
TLDR
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. Expand
Structure of the highly conserved HERC2 gene and of multiple partially duplicated paralogs in human.
TLDR
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. Expand
NEK8 mutations affect ciliary and centrosomal localization and may cause nephronophthisis.
TLDR
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. Expand
Physical and Functional Interaction of the HECT Ubiquitin-protein Ligases E6AP and HERC2*
TLDR
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. Expand
Angelman syndrome (AS, MIM 105830)
TLDR
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. Expand
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.
TLDR
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. Expand
HERC2 is an E3 ligase that targets BRCA1 for degradation.
TLDR
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. Expand
A very large protein with diverse functional motifs is deficient in rjs (runty, jerky, sterile) mice.
TLDR
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. Expand
Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints.
TLDR
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. Expand
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