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HERC1
Available structures PDB Human UniProt search: PDBe RCSB List of PDB id codes 4O2W, 4QT6
Identifiers
Aliases	HERC1, p532, p619, HECT and RLD domain containing E3 ubiquitin protein ligase family member 1, MDFPMR
External IDs	OMIM: 605109; MGI: 2384589; HomoloGene: 31207; GeneCards: HERC1; OMA:HERC1 - orthologs
Gene location (Human) Chr. Chromosome 15 (human) Band 15q22.31 Start 63,608,618 bp End 63,833,948 bp
Gene location (Mouse) Chr. Chromosome 9 (mouse) Band 9|9 C Start 66,257,732 bp End 66,416,057 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in middle temporal gyrus Brodmann area 23 ganglionic eminence right hemisphere of cerebellum primary visual cortex prefrontal cortex Achilles tendon Skeletal muscle tissue of biceps brachii muscle of thigh right frontal lobe Top expressed in perirhinal cortex CA3 field cingulate gyrus entorhinal cortex medial dorsal nucleus primary motor cortex cerebellar vermis medullary collecting duct lobe of cerebellum habenula More reference expression data BioGPS More reference expression data
Gene ontology Molecular function ubiquitin-protein transferase activity guanyl-nucleotide exchange factor activity transferase activity Cellular component cytoplasm cytosol Golgi apparatus membrane Biological process cerebellar Purkinje cell differentiation negative regulation of autophagy neuron projection development protein ubiquitination neuromuscular process controlling balance Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 9: 66.26 – 66.42 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Probable E3 ubiquitin-protein ligase HERC1 is an enzyme that in humans is encoded by the HERC1 gene.

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

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, a recessive mutation of the Herc1 gene located on mouse chromosome 9 that increases Herc1 protein levels. 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. In addition to the cerebellum, Herc1tbl mutants had lower dendritic spine widths in CA1 pyramidal neurons. Herc1-tbl mutant mice are also characterized by cerebellar ataxia, an unstable gait, and a limb-flexion reflex triggered by tail lifting seen in other cerebellar mutants, the reverse of the normal limb extensor reflex.

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

Biallelic HERC1 mutations were reported in two siblings with facial dysmorphism, macrocephaly, motor development delay, ataxic gait, hypotonia, and intellectual disability. 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. Facial dysmorphism, macrocephaly, and intellectual disability but without cerebellar ataxia were also reported in two siblings with a HERC1 splice variant mutation. 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.

Notes

The 2022 version of this article was updated by an external expert under a dual publication model. The corresponding academic peer reviewed article was published in Gene and can be cited as: Robert Lalonde; Catherine Strazielle (10 March 2022). "The Herc1 gene in neurobiology". Gene. Gene Wiki Review Series. 814. doi:10.1016/J.GENE.2021.146144. ISSN 0378-1119. PMID 34990797. Wikidata Q110874820.

References

1. ^ GRCh38: Ensembl release 89: ENSG00000103657 – Ensembl, May 2017
2. ^ 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. ^ "Entrez Gene: HERC1 hect (homologous to the E6-AP (UBE3A) carboxyl terminus) domain and RCC1 (CHC1)-like domain (RLD) 1".
8. ^ 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. ^ 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. ^ 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. PMC 11113414. PMID 25746226. S2CID 1976227.
13. ^ 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. ^ 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

• Ewing RM, Chu P, Elisma F, et al. (2007). "Large-scale mapping of human protein–protein interactions by mass spectrometry". Mol. Syst. Biol. 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.
• Kimura K, Wakamatsu A, Suzuki Y, et al. (2006). "Diversification of transcriptional modulation: Large-scale identification and characterization of putative alternative promoters of human genes". Genome Res. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
• Garcia-Gonzalo FR, Bartrons R, Ventura F, Rosa JL (2005). "Requirement of phosphatidylinositol-4,5-bisphosphate for HERC1-mediated guanine nucleotide release from ARF proteins". FEBS Lett. 579 (2): 343–8. doi:10.1016/j.febslet.2004.11.095. PMID 15642342.
• Garcia-Gonzalo FR, Muñoz P, González E, et al. (2004). "The giant protein HERC1 is recruited to aluminum fluoride-induced actin-rich surface protrusions in HeLa cells". FEBS Lett. 559 (1–3): 77–83. doi:10.1016/S0014-5793(04)00030-4. PMID 14960311.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Garcia-Gonzalo FR, Cruz C, Muñoz P, et al. (2003). "Interaction between HERC1 and M2-type pyruvate kinase". FEBS Lett. 539 (1–3): 78–84. doi:10.1016/S0014-5793(03)00205-9. PMID 12650930. S2CID 32809019.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Cruz C, Paladugu A, Ventura F, et al. (1999). "Assignment of the human P532 gene (HERC1) to chromosome 15q22 by fluorescence in situ hybridization". Cytogenet. Cell Genet. 86 (1): 68–9. doi:10.1159/000015414. PMID 10516438. S2CID 46241923.
• Ji Y, Walkowicz MJ, Buiting K, et al. (1999). "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". Hum. Mol. Genet. 8 (3): 533–42. doi:10.1093/hmg/8.3.533. PMID 9949213.
• Yu W, Andersson B, Worley KC, et al. (1997). "Large-Scale Concatenation cDNA Sequencing". Genome Res. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174.
• Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Andersson B, Wentland MA, Ricafrente JY, et al. (1996). "A "double adaptor" method for improved shotgun library construction". Anal. Biochem. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474.

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