HERC1

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]