Probable E3 ubiquitin-protein ligase HERC1 is an enzyme that in humans is encoded by the HERC1gene.[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
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. ISSN0378-1119. PMID34990797. WikidataQ110874820.
^ abWassef 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. PMID3678603.
^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. PMID26138117. S2CID5725254.
^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. PMID27108999. S2CID44849688.
^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. PMID28323226.
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. PMID10516438. S2CID46241923.
