HERC1 explained

Probable E3 ubiquitin-protein ligase HERC1 is an enzyme that in humans is encoded by the HERC1 gene.^{[1] [2]}

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^[3]

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,^[4] a recessive mutation of the Herc1 gene located on mouse chromosome 9 that increases Herc1 protein levels.^[5] 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.^[6] In addition to the cerebellum, Herc1tbl mutants had lower dendritic spine widths in CA1 pyramidal neurons.^[7] Herc1-tbl mutant mice are also characterized by cerebellar ataxia, an unstable gait, and a limb-flexion reflex triggered by tail lifting^[8] seen in other cerebellar mutants, the reverse of the normal limb extensor reflex.^[9]

Relative to wild-type mice, Herc1-tbl mutant mice fell sooner and more often from a rotarod,^{[10] [11]} fell sooner from a vertical pole,^{[12] [13]} slipped more often and took more time to reach the end of a stationary beam,^[14] and had weaker forelimb grip strength measured by a grip strength meter.^[15] The rotarod deficit was rescued when Herc1tbl mutants were bred with transgenic mice expressing normal human HERC1.^[16] Herc1tbl mutants were also less adept at landing correctly on all four legs when released in the air.^[17]

Biallelic HERC1 mutations were reported in two siblings with facial dysmorphism, macrocephaly, motor development delay, ataxic gait, hypotonia, and intellectual disability.^[18] 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.^[19] Facial dysmorphism, macrocephaly, and intellectual disability but without cerebellar ataxia were also reported in two siblings with a HERC1 splice variant mutation.^[20] 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.^[21]

Further reading

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

Notes and References

1. Rosa JL, Casaroli-Marano RP, Buckler AJ, Vilaro S, Barbacid M . 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 . Dec 1996 . 8861955 . 452152 . 10.1002/j.1460-2075.1996.tb00801.x.
2. Rosa JL, Barbacid M . 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 . Aug 1997 . 9233772 . 10.1038/sj.onc.1201170 . free .
3. Web site: Entrez Gene: HERC1 hect (homologous to the E6-AP (UBE3A) carboxyl terminus) domain and RCC1 (CHC1)-like domain (RLD) 1.
4. Wassef M, Sotelo C, Cholley B, Brehier A, Thomasset M . 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 . Dec 1996 . 3678603 . 10.1016/0012-1606(87)90490-8.
5. Mashimo T, Hadjebi O, Amair-Pinedo F, Tsurumi T, Langa F, Serikawa T, Sotelo C, Guénet JL, Rosa JL . 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 . 2009 . 20041218 . 2791161 . 10.1371/journal.pgen.1000784 . free .
6. Wassef M, Sotelo C, Cholley B, Brehier A, Thomasset M . 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 . Dec 1996 . 3678603 . 10.1016/0012-1606(87)90490-8.
7. Pérez-Villegas EM, Pérez-Rodríguez M, Negrete-Díaz JV, Ruiz R, Rosa JL, de Toledo GA, Rodríguez-Moreno A, Armengol JA . HERC1 Ubiquitin ligase is required for hippocampal learning and memory . Front Neuroanat . 14 . 592797. 2020 . 33328904 . 7710975 . 10.3389/fnana.2020.592797. free .
8. Mashimo T, Hadjebi O, Amair-Pinedo F, Tsurumi T, Langa F, Serikawa T, Sotelo C, Guénet JL, Rosa JL . 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 . 2009 . 20041218 . 2791161 . 10.1371/journal.pgen.1000784 . free .
9. Lalonde R, Strazielle C . Brain regions and genes affecting limb-clasping responses . Brain Res Rev . 67 . 1–2 . 252–9 . 2011 . 21356243 . 10.1016/j.brainresrev.2011.02.005. 206345554 .
10. Bachiller S, Rybkina T, Porras-García E, Pérez-Villegas E, Tabares L, Armengol JA, Carrión AM, Ruiz R . The HERC1 E3 Ubiquitin Ligase is essential for normal development and for neurotransmission at the mouse neuromuscular junction . Life Sci . 72 . 15 . 2961–71 . 2015 . 25746226 . 10.1007/s00018-015-1878-2. 1976227 . 11113414 .
11. Fuca E, Guglielmotto M, Boda E, Rossi F, Leto K, Buffo A . Preventive motor training but not progenitor grafting ameliorates cerebellar ataxia and deregulated autophagy in tambaleante mice . Neurobiol Dis . 102 . 49–59 . 2017 . 28237314 . 452152 . 10.1016/j.nbd.2017.02.005.
12. Porras-Garcia ME, Ruiz R, Pérez-Villegas EM, Armengol JÁ . Motor learning of mice lacking cerebellar Purkinje cells . Front Neuroanat . 7 . 4 . 2013 . 23630472 . 452152 . 10.3389/fnana.2013.00004. free .
13. Mashimo T, Hadjebi O, Amair-Pinedo F, Tsurumi T, Langa F, Serikawa T, Sotelo C, Guénet JL, Rosa JL . 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 . 2009 . 20041218 . 2791161 . 10.1371/journal.pgen.1000784 . free .
14. Fuca E, Guglielmotto M, Boda E, Rossi F, Leto K, Buffo A . Preventive motor training but not progenitor grafting ameliorates cerebellar ataxia and deregulated autophagy in tambaleante mice . Neurobiol Dis . 102 . 49–59 . 2017 . 28237314 . 452152 . 10.1016/j.nbd.2017.02.005.
15. Bachiller S, Rybkina T, Porras-García E, Pérez-Villegas E, Tabares L, Armengol JA, Carrión AM, Ruiz R . The HERC1 E3 Ubiquitin Ligase is essential for normal development and for neurotransmission at the mouse neuromuscular junction . Life Sci . 72 . 15 . 2961–71 . 2015 . 25746226 . 10.1007/s00018-015-1878-2. 1976227 . 11113414 .
16. Mashimo T, Hadjebi O, Amair-Pinedo F, Tsurumi T, Langa F, Serikawa T, Sotelo C, Guénet JL, Rosa JL . 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 . 2009 . 20041218 . 2791161 . 10.1371/journal.pgen.1000784 . free .
17. Porras-Garcia ME, Ruiz R, Pérez-Villegas EM, Armengol JÁ . Motor learning of mice lacking cerebellar Purkinje cells . Front Neuroanat . 7 . 4 . 2013 . 23630472 . 452152 . 10.3389/fnana.2013.00004. free .
18. Ortega-Recalde O, Beltrán OI, Gálvez JM, Palma-Montero A, Restrepo CM, Mateus HE, Laissue P . Biallelic HERC1 mutations in a syndromic form of overgrowth and intellectual disability. . Clin Genet . 88 . 4 . e1-3. 2015 . 26138117 . 10.1111/cge.12634. 5725254 .
19. 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 . 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 . 2016 . 26153217 . 10.1038/ejhg.2015.140. 4755376 .
20. Aggarwal S, Bhowmik AD, Ramprasad, VL, Murugan S, Dalal A . 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 . 2016 . 27108999 . 10.1002/ajmg.a.37654 . 44849688 .
21. Utine GE, Taşkıran EZ, Koşukcu C, Karaosmanoğlu B, Güleray N, Doğan ÖA, Kiper PÖ, Boduroğlu K, Alikaşifoğlu M . HERC1 mutations in idiopathic intellectual disability. . Eur J Med Genet . 60 . 5 . 279–83 . 2017 . 28323226 . 10.1016/j.ejmg.2017.03.007.