HERC1
Available structures
PDBHuman UniProt search: PDBe RCSB
Identifiers
AliasesHERC1, p532, p619, HECT and RLD domain containing E3 ubiquitin protein ligase family member 1, MDFPMR
External IDsOMIM: 605109 MGI: 2384589 HomoloGene: 31207 GeneCards: HERC1
Orthologs
SpeciesHumanMouse
Entrez

8925

235439

Ensembl

ENSG00000103657

ENSMUSG00000038664

UniProt

Q15751

n/a

RefSeq (mRNA)

NM_003922

NM_145617

RefSeq (protein)

NP_003913

n/a

Location (UCSC)Chr 15: 63.61 – 63.83 MbChr 9: 66.26 – 66.42 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Probable E3 ubiquitin-protein ligase HERC1 is an enzyme that in humans is encoded by the HERC1 gene.[5][6][7]

The protein encoded by this gene stimulates guanine nucleotide exchange on ARF1 and Rab proteins. This protein is thought to be involved in membrane transport processes[7]

Knowledge of the gene is facilitated by the discovery of a mouse mutation. The tambaleante (tbl) mutation arose spontaneously on the DW/J-Pas genetic background,[8] a recessive mutation of the Herc1 gene located on mouse chromosome 9 that increases Herc1 protein levels.[9] This protein is largely expressed in many tissues (Sanchez-Tena et al., 2016; https://www.proteinatlas.org/ENSG00000103657-HERC1/tissue) and multiple brain regions including the cerebellum (https://www.proteinatlas.org/ENSG00000103657-HERC1/brain).

Herc1-tbl (tambaleante) mutant mice are characterized by Purkinje cell loss.[8] In addition to the cerebellum, Herc1tbl mutants had lower dendritic spine widths in CA1 pyramidal neurons.[10] Herc1-tbl mutant mice are also characterized by cerebellar ataxia, an unstable gait, and a limb-flexion reflex triggered by tail lifting[9] seen in other cerebellar mutants, the reverse of the normal limb extensor reflex.[11]

Relative to wild-type mice, Herc1-tbl mutant mice fell sooner and more often from a rotarod,[12][13] fell sooner from a vertical pole,[14][9] slipped more often and took more time to reach the end of a stationary beam,[13] and had weaker forelimb grip strength measured by a grip strength meter.[12] The rotarod deficit was rescued when Herc1tbl mutants were bred with transgenic mice expressing normal human HERC1.[9] Herc1tbl mutants were also less adept at landing correctly on all four legs when released in the air.[14]

Biallelic HERC1 mutations were reported in two siblings with facial dysmorphism, macrocephaly, motor development delay, ataxic gait, hypotonia, and intellectual disability.[15] Likewise, a nonsense HERC1 variant was reported in one subject with an autosomal recessive condition consisting of facial dysmorphism, macrocephaly, epilepsy, motor development delay, cerebellar atrophy, and intellectual disability.[16] Facial dysmorphism, macrocephaly, and intellectual disability but without cerebellar ataxia were also reported in two siblings with a HERC1 splice variant mutation.[17] The lack of cerebellar involvement was ascribed either to the nature of the mutation or the influence of modifier genes. Another patient with a frameshift HERC1 mutation predicted to truncate the protein displayed facial dysmorphism, macrocephaly, epileptiform discharges, hypotonia, intellectual disability, and autistic features.[18]

Notes

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000103657 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000038664 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Rosa JL, Casaroli-Marano RP, Buckler AJ, Vilaro S, Barbacid M (Dec 1996). "p619, a giant protein related to the chromosome condensation regulator RCC1, stimulates guanine nucleotide exchange on ARF1 and Rab proteins". EMBO J. 15 (16): 4262–73. doi:10.1002/j.1460-2075.1996.tb00801.x. PMC 452152. PMID 8861955.
  6. ↑ Rosa JL, Barbacid M (Aug 1997). "A giant protein that stimulates guanine nucleotide exchange on ARF1 and Rab proteins forms a cytosolic ternary complex with clathrin and Hsp70". Oncogene. 15 (1): 1–6. doi:10.1038/sj.onc.1201170. PMID 9233772.
  7. 1 2 "Entrez Gene: HERC1 hect (homologous to the E6-AP (UBE3A) carboxyl terminus) domain and RCC1 (CHC1)-like domain (RLD) 1".
  8. 1 2 Wassef M, Sotelo C, Cholley B, Brehier A, Thomasset M (Dec 1996). "Cerebellar mutations affecting the postnatal survival of Purkinje cells in the mouse disclose a longitudinal pattern of differentially sensitive cells". Dev Biol. 124 (2): 379–89. doi:10.1016/0012-1606(87)90490-8. PMID 3678603.
  9. 1 2 3 4 Mashimo T, Hadjebi O, Amair-Pinedo F, Tsurumi T, Langa F, Serikawa T, Sotelo C, Guénet JL, Rosa JL (2009). "Progressive Purkinje cell degeneration in tambaleante mutant mice is a consequence of a missense mutation in HERC1 E3 ubiquitin ligase". PLOS Genet. 5 (2): e1000784. doi:10.1371/journal.pgen.1000784. PMC 2791161. PMID 20041218.
  10. ↑ Pérez-Villegas EM, Pérez-Rodríguez M, Negrete-Díaz JV, Ruiz R, Rosa JL, de Toledo GA, Rodríguez-Moreno A, Armengol JA (2020). "HERC1 Ubiquitin ligase is required for hippocampal learning and memory". Front Neuroanat. 14: 592797. doi:10.3389/fnana.2020.592797. PMC 7710975. PMID 33328904.
  11. ↑ Lalonde R, Strazielle C (2011). "Brain regions and genes affecting limb-clasping responses". Brain Res Rev. 67 (1–2): 252–9. doi:10.1016/j.brainresrev.2011.02.005. PMID 21356243. S2CID 206345554.
  12. 1 2 Bachiller S, Rybkina T, Porras-García E, Pérez-Villegas E, Tabares L, Armengol JA, Carrión AM, Ruiz R (2015). "The HERC1 E3 Ubiquitin Ligase is essential for normal development and for neurotransmission at the mouse neuromuscular junction". Life Sci. 72 (15): 2961–71. doi:10.1007/s00018-015-1878-2. PMID 25746226. S2CID 1976227.
  13. 1 2 Fuca E, Guglielmotto M, Boda E, Rossi F, Leto K, Buffo A (2017). "Preventive motor training but not progenitor grafting ameliorates cerebellar ataxia and deregulated autophagy in tambaleante mice". Neurobiol Dis. 102: 49–59. doi:10.1016/j.nbd.2017.02.005. PMC 452152. PMID 28237314.
  14. 1 2 Porras-Garcia ME, Ruiz R, Pérez-Villegas EM, Armengol JÁ (2013). "Motor learning of mice lacking cerebellar Purkinje cells". Front Neuroanat. 7: 4. doi:10.3389/fnana.2013.00004. PMC 452152. PMID 23630472.
  15. ↑ Ortega-Recalde O, Beltrán OI, Gálvez JM, Palma-Montero A, Restrepo CM, Mateus HE, Laissue P (2015). "Biallelic HERC1 mutations in a syndromic form of overgrowth and intellectual disability". Clin Genet. 88 (4): e1-3. doi:10.1111/cge.12634. PMID 26138117. S2CID 5725254.
  16. ↑ Nguyen LS, Schneider T, Rio M, Moutton S, Siquier-Pernet K, Verny F, Boddaert N, Desguerre I, Munich A, Rosa JL, Cormier-Daire V, Colleaux L (2016). "A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy". Eur J Hum Genet. 24 (3): 455–8. doi:10.1038/ejhg.2015.140. PMC 4755376. PMID 26153217.
  17. ↑ Aggarwal S, Bhowmik AD, Ramprasad, VL, Murugan S, Dalal A (2016). "A splice site mutation in HERC1 leads to syndromic intellectual disability with macrocephaly and facial dysmorphism: Further delineation of the phenotypic spectrum". Am J Med Genet A. 15 (16): 4262–73. doi:10.1002/ajmg.a.37654. PMID 27108999. S2CID 44849688.
  18. ↑ Utine GE, Taşkıran EZ, Koşukcu C, Karaosmanoğlu B, Güleray N, Doğan ÖA, Kiper PÖ, Boduroğlu K, Alikaşifoğlu M (2017). "HERC1 mutations in idiopathic intellectual disability". Eur J Med Genet. 60 (5): 279–83. doi:10.1016/j.ejmg.2017.03.007. PMID 28323226.

Further reading


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