Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 605109

HECT DOMAIN AND RCC1-LIKE DOMAIN 1; HERC1

Alternative titles; symbols

P532

HGNC Approved Gene Symbol: HERC1

Cytogenetic location: 15q22.31 Genomic coordinates (GRCh38) : 15:63,608,618-63,833,948 (from NCBI)

Gene-Phenotype Relationships

TEXT

Description

The HERC1 gene encodes a large protein with a HECT domain and 2 RCC1-like domains (RLD) that acts as an E3-ubiquitin ligase targeting proteins for degradation and plays a putative role in intracellular membrane trafficking. The HECT domain interacts with the TSC1 (605284)-TSC2 (191092) complex and likely contributes to a regulatory role for HERC1 in the mTOR (601231) pathway by acting as a ubiquitin ligase for TSC2 and decreasing its stability. The RLD domains act as guanine nucleotide exchange factors (GEF) for small proteins, such as ARF (103180) and Rab family GTPases, involved in intracellular membrane trafficking (Rosa et al., 1996 and Aggarwal et al., 2016).

Cloning and Expression

Using a cDNA fragment showing significant homology to RCC1 to screen a human fetal brain cDNA library, Rosa et al. (1996) isolated a full-length cDNA for HERC1 encoding a deduced 4,861-amino acid protein. The authors originally designated the protein p619 based on its calculated molecular mass, but noted in an erratum that the correct M(r) of the protein is approximately 532 kD (p532). The HERC1 protein contains both an N-terminal and a C-terminal RLD domain, 7 WD domains characteristic of the beta subunit of heterotrimeric G proteins thought to be involved in protein-protein interactions, 3 putative SH3 binding sites, 7 polar amino acid regions, a putative leucine zipper, and a C-terminal HECT domain. Northern blot analysis detected a 15-kb HERC1 transcript expressed ubiquitously in all human and mouse tissues examined, with the highest levels in testis and brain and the lowest in liver. HERC1 was overexpressed in all human tumor cell lines tested, independent of their developmental origin. Subcellular localization studies indicated that HERC1 is located in the cytosol and the Golgi apparatus.

Gene Function

Rosa et al. (1996) found that the C-terminal RLD of HERC1 interacts specifically with myristoylated ARF (103180), a small GTP-binding protein that is also located in the Golgi. The N-terminal RLD stimulated guanine nucleotide exchange on ARF1 and on certain members of the RAB family of proteins, including RAB3A (179490) and RAB5 (179512). Using the yeast 2-hybrid system, Rosa and Barbacid (1997) found that the C-terminal RLD of HERC1 interacts with the clathrin heavy chain (118955). This interaction occurs only in the cytosol and is mediated by the formation of an ATP-dependent ternary complex with the heat shock protein HSP70 (see 140550). Rosa and Barbacid (1997) suggested that HERC1 is involved in membrane transport processes.

By immunocomplex analysis of mouse brain lysates, Chong-Kopera et al. (2006) identified Herc1 as a Tsc2 (191092)-interacting protein via the C-terminal region of Herc1, which contains the E3 ubiquitin ligase domain. Herc1 interacts with Tsc2 and negatively regulates the mTorc1 (see MTOR, 601231) pathway. Herc1 did not associate with Tsc1 (605284), but Tsc1 efficiently competes with Herc1 for Tsc2 binding. The findings provided a potential biochemical mechanism of TSC1 in TSC2 stabilization by inhibiting the interaction between TSC2 and the E3 ubiquitin ligase HERC1.

Mapping

By FISH, Cruz et al. (1999) mapped the HERC1 gene to chromosome 15q22.

Molecular Genetics

In 2 sibs, born of unrelated Colombian parents, with macrocephaly, dysmorphic facies, and psychomotor retardation (MDFPMR; 617011), Ortega-Recalde et al. (2015) identified compound heterozygous mutations in the HERC1 gene (W875X, 605109.0001 and G4520E, 605109.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.

In an 18-year-old man, born of consanguineous Moroccan parents, with MDFPMR, Nguyen et al. (2016) identified a homozygous truncating mutation in the HERC1 gene (R3250X; 605109.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient fibroblasts showed decreased mutant transcripts and complete absence of the protein, suggesting that the mutation results in nonsense-mediated mRNA decay. Patient fibroblasts did not show changes in either TSC2 (191092) or mTORC1 (see MTOR, 601231) compared to controls; HERC2 (605837) levels were also unchanged. Nguyen et al. (2016) postulated that alterations in the mTOR pathway resulting from loss of HERC1 could be tissue-specific.

In 2 sibs, born of consanguineous Indian parents, with MDFPMR, Aggarwal et al. (2016) identified a homozygous splice site mutation in the HECT1 gene (605109.0004). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Aggarwal et al. (2016) suggested that loss of the HECT domain, which would occur in these patients, is likely of pathogenic significance because that domain interacts with TSC2 (191092) and decreases its stability by ubiquitinization and targeted degradation, which could disrupt regulation of the mTOR pathway. The mutation could also disrupt intracellular trafficking.

In 2 sisters, born of consanguineous Azerbaijani parents, with MDFPMR, Schwarz et al. (2020) identified a homozygous missense mutation in the HERC1 gene (R4691P; 605109.0005). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was located in the C-terminal HECT domain, leading Schwarz et al. (2020) to hypothesize that it affects protein folding and interaction with binding partners. Testing in fibroblasts from one of the sibs showed increased expression of the HERC1 protein compared to controls. Schwarz et al. (2020) observed enhanced S6K1 (608938) phosphorylation and a decreased LC3B-II:LCB-I ratio, indicating decreased autophagy, under nutrient starvation in patient fibroblasts, compared to controls. Schwarz et al. (2020) concluded that the R4691P mutation has a gain-of-function effect, leading to increased activity of mTORC1.

Animal Model

Mashimo et al. (2009) described a mouse mutant, 'tambaleante' (tbl, meaning 'staggering' in Spanish), characterized by severe ataxia, abnormal hindlimb posture, and tremor associated with progressive degeneration of Purkinje cells in the cerebellum beginning at 2 months of age. Mutant mice also had reduced growth and lifespan compared to wildtype. Positional cloning identified a homozygous missense mutation (G483E) in the Herc1 domain as responsible for the phenotype. The mutation occurred at a highly conserved residue in the N-terminal RLD1 domain. Mutant tissue showed an increase of the mutant protein, a decrease in mTOR activity, and an increase in autophagy in the cerebellum.

By electrophysiologic analysis of motor function of tbl mice, Bachiller et al. (2015) found that Herc1 malfunction produces motor defects at about 30 days of age prior to the onset of ataxia and cerebellar cell loss. Examination of the skeletal muscle showed that mutant mice had morphologic and functional defects at the neuromuscular junction, including smaller postsynaptic regions and impaired synaptic vesicle release, compared to controls. These changes were evident as early as 2 weeks of age. Overall, the findings suggested that HERC1 is essential for proper development, maintenance, and function of the neuromuscular junction.

Ruiz et al. (2016) performed electron microscopic analysis of various regions of the central nervous system in homozygous tbl mutant mice. Features of autophagy, including autophagosomes, lysosomes, altered mitochondria, and some chromatin alteration, were present in Purkinje cells in the cerebellum, as well as in neocortical and hippocampal pyramidal cells and spinal cord motor neurons. The neuronal loss was more dramatic in the cerebellum. Autophagy signs were not found in interneurons or neuroglia cells. These findings suggested that affected neurons are projection neurons that have a high degree of neuronal activity, and that regions other than the cerebellum may be affected. Ruiz et al. (2016) suggested that deregulation of the ubiquitin-proteasome system resulting from an Herc1 mutation may have resulted in increased autophagic activity.

ALLELIC VARIANTS 5 Selected Examples):

.0001 MACROCEPHALY, DYSMORPHIC FACIES, AND PSYCHOMOTOR RETARDATION

HERC1, TRP875TER
SNP: rs879253786, ClinVar: RCV000235009

In 2 sibs, born of unrelated Colombian parents, with macrocephaly, dysmorphic facies, and psychomotor retardation (MDFPMR; 617011), Ortega-Recalde et al. (2015) identified compound heterozygous mutations in the HERC1 gene: a c.2625G-A transition (c.2625G-A, NM_003922.3), resulting in a trp875-to-ter (W875X) substitution, and a c.13559G-A transition, resulting in a gly4520-to-glu (G4520E; 605109.0002) substitution at a highly conserved residue. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against public SNP databases, including dbSNP (builds 129-137). The mutations segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.

.0002 MACROCEPHALY, DYSMORPHIC FACIES, AND PSYCHOMOTOR RETARDATION

HERC1, GLY4520GLU
SNP: rs769677823, gnomAD: rs769677823, ClinVar: RCV000235003

For discussion of the c.13559G-A transition (c.13559G-A, NM_003922.3) in the HERC1 gene, resulting in a gly4520-to-glu (G4520E) substitution, that was found in compound heterozygous state in 2 sibs with macrocephaly, dysmorphic facies, and psychomotor retardation (MDFPMR; 617011), by Ortega-Recalde et al. (2015), see 617011.0001.

.0003 MACROCEPHALY, DYSMORPHIC FACIES, AND PSYCHOMOTOR RETARDATION

HERC1, ARG3250TER ({dbSNP SCV000212106})
SNP: rs753780877, gnomAD: rs753780877, ClinVar: RCV000186608, RCV000235006

In an 18-year-old man, born of consanguineous Moroccan parents, with macrocephaly, dysmorphic facies, and psychomotor retardation (MDFPMR; 617011), Nguyen et al. (2016) identified a homozygous c.9748C-T transition (SCV000212106) in exon 49 of the HERC1 gene, resulting in an arg3250-to-ter (R3250X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in any publicly available databases. Patient fibroblasts showed decreased mutant transcripts and complete absence of the protein, suggesting that the mutation results in nonsense-mediated mRNA decay. Patient fibroblasts did not show changes in either TSC2 (191092) or mTORC1 (see MTOR, 601231) compared to controls; HERC2 (605837) levels were also unchanged. Nguyen et al. (2016) postulated that alterations in the mTOR pathway resulting from loss of HERC1 could be tissue-specific.

.0004 MACROCEPHALY, DYSMORPHIC FACIES, AND PSYCHOMOTOR RETARDATION

HERC1, IVS26, A-C, -2
SNP: rs797045141, ClinVar: RCV000190895, RCV000235008

In 2 sibs, born of consanguineous Indian parents, with macrocephaly, dysmorphic facies, and psychomotor retardation (MDFPMR; 617011) Aggarwal et al. (2016) identified a homozygous A-to-C transversion (c.4906-2A-C) in the HERC1 gene, resulting in a splice site mutation, the deletion of 10 bp in exon 27, causing a frameshift and premature termination. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP, 1000 Genomes Project, Exome Variant Server, and ExAC databases; it segregated with the disorder in the family. Patient cells showed significantly decreased levels of mutant mRNA, suggesting that the mutation results in nonsense-mediated mRNA decay. Aggarwal et al. (2016) suggested that loss of the HECT domain, which would occur in these patients, is likely of pathogenic significance because that domain interacts with TSC2 (191092) and decreases its stability by ubiquitinization and targeted degradation, which could putatively activate the mTOR pathway, resulting in overgrowth.

.0005 MACROCEPHALY, DYSMORPHIC FACIES, AND PSYCHOMOTOR RETARDATION

HERC1, ARG4691PRO
SNP: rs757446033, gnomAD: rs757446033, ClinVar: RCV001265603

In 2 sisters, born of consanguineous Azerbaijani parents, with macrocephaly, dysmorphic facies, and psychomotor retardation (MDFPMR; 617011), Schwarz et al. (2020) identified homozygosity for a c.14072G-C transversion (c.14072G-C, NM_003922) in the HERC1 gene, resulting in an arg4691-to-pro (R4601P) substitution at a highly conserved residue in the C-terminal HECT domain. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in homozygous state in the gnomAD or 1000 Genomes Project databases. Fibroblasts from one of the patients showed increased expression of the HERC1 protein, enhanced S6K1 (608938) phosphorylation under nutrient starvation, and decreased LC3B-II:LCB-I ratio, indicating decreased autophagy, under nutrient starvation compared to controls. Schwarz et al. (2020) concluded that the R4691P mutation leads to a gain of function and increased activity of mTORC1.

REFERENCES

1. Aggarwal, S., Bhowmik, A. D., Ramprasad, V. L., 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. 170A: 1868-1873, 2016. [PubMed: 27108999] [Full Text: https://doi.org/10.1002/ajmg.a.37654\]
2. Bachiller, S., Rybkina, T., Porras-Garcia, E., Perez-Villegas, E., Tabares, L., Armengol, J. A., Carrion, A. M., Ruiz, R.The HERC1 E3 ubiquitin ligase is essential for normal development and for neurotransmission at the mouse neuromuscular junction. Cell. Molec. Life Sci. 72: 2961-2971, 2015. [PubMed: 25746226] [Full Text: https://doi.org/10.1007/s00018-015-1878-2\]
3. Chong-Kopera, H., Inoki, K., Li, Y., Zhu, T., Garcia-Gonzalo, F. R., Rosa, J. L., Guan, K.-L.TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase. J. Biol. Chem. 281: 8313-8316, 2006. [PubMed: 16464865] [Full Text: https://doi.org/10.1074/jbc.C500451200\]
4. Cruz, C., Paladugu, A., Ventura, F., Bartrons, R., Aldaz, M., Rosa, J. L.Assignment of the human P532 gene (HERC1) to chromosome 15q22 by fluorescence in situ hybridization. Cytogenet. Cell Genet. 86: 68-69, 1999. [PubMed: 10516438] [Full Text: https://doi.org/10.1159/000015414\]
5. Mashimo, T., Hadjebi, O., Amair-Pinedo, F., Tsurumi, T., Langa, F., Serikawa, T., Sotelo, C., Guenet, J.-L., Rosa, J. L.Progressive Purkinje cell degeneration in tambaleante mutant mice is a consequence of a missense mutation in HERC1 E3 ubiquitin ligase. PLoS Genet. 5: e1000784, 2009. Note: Electronic Article. [PubMed: 20041218] [Full Text: https://doi.org/10.1371/journal.pgen.1000784\]
6. Nguyen, L. S., Schneider, T., Rio, M., Moutton, S., Siquier-Pernet, K., Verny, F., Boddaert, N., Desguerre, I., Munich, A., Rosa, J. L., Cormier-Daire, V., Colleaux, L.A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy. Europ. J. Hum. Genet. 24: 455-458, 2016. [PubMed: 26153217] [Full Text: https://doi.org/10.1038/ejhg.2015.140\]
7. Ortega-Recalde, O., Beltran, O. I., Galvez, J. M., Palma-Montero, A., Restrepo, C. M., Mateus, H. E., Laissue, P.Biallelic HERC1 mutations in a syndromic form of overgrowth and intellectual disability. Clin. Genet. 88: e1-e3, 2015. Note: Electronic Article. [PubMed: 26138117] [Full Text: https://doi.org/10.1111/cge.12634\]
8. Rosa, J. L., 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: 1-6, 1997. [PubMed: 9233772] [Full Text: https://doi.org/10.1038/sj.onc.1201170\]
9. Rosa, J. L., Casaroli-Marano, R. P., Buckler, A. J., 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: 4262-4273, 1996. Note: Erratum. EMBO J. 15: 4262-4273, 1996. [PubMed: 8861955]
10. Ruiz, R., Perez-Villegas, E. M., Bachiller, S., Rosa, J. L., Armengol, J. A.HERC1 ubiquitin ligase mutation affects neocortical, CA3 hippocampal and spinal cord projection neurons: an ultrastructural study. Front. Neuroanat. 10: 42, 2016. [PubMed: 27147983] [Full Text: https://doi.org/10.3389/fnana.2016.00042\]
11. Schwarz, J. M., Pedrazza, L., Stenzel, W., Rosa, J. L., Schuelke, M., Strussberg, R.A new homozygous HERC1 gain-of-function variant in MDFPMR syndrome leads to mTORC1 hyperactivation and reduced autophagy during cell catabolism. Molec. Genet. Metab. 131: 126-134, 2020. [PubMed: 32921582] [Full Text: https://doi.org/10.1016/j.ymgme.2020.08.008\]

Contributors:

Hilary J. Vernon - updated : 04/13/2021
Cassandra L. Kniffin - updated : 6/29/2016

Creation Date:

Catherine Nocente : 7/5/2000

Edit History:

carol : 04/14/2021
carol : 04/13/2021
carol : 08/04/2016
carol : 07/15/2016
carol : 7/13/2016
ckniffin : 6/29/2016
alopez : 7/21/2009
joanna : 9/14/2000
carol : 7/10/2000