Alternative titles; symbols
HGNC Approved Gene Symbol: UCHL1
Cytogenetic location: 4p13 Genomic coordinates (GRCh38): 4:41,256,928-41,268,455 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p13 | {?Parkinson disease 5, susceptibility to} | 613643 | Autosomal dominant | 3 |
| Spastic paraplegia 79A, autosomal dominant | 620221 | Autosomal dominant | 3 | |
| Spastic paraplegia 79B, autosomal recessive | 615491 | Autosomal recessive | 3 |
UCHL1 is a member of a gene family whose products hydrolyze small C-terminal adducts of ubiquitin to generate the ubiquitin monomer. Expression of UCHL1 is highly specific to neurons and to cells of the diffuse neuroendocrine system and their tumors. It is present in all neurons (Doran et al., 1983).
Day and Thompson (1987) cloned UCHL1 cDNA. The deduced protein, which they called PGP9.5, contains 212 amino acids.
Doran et al. (1983) purified the PGP9.5 protein reported by Jackson and Thompson (1981) and found that it has a molecular mass of 27 kD. They showed that the protein is present in brain at concentrations at least 50 times greater than in other organs and is a major protein component of neuronal cytoplasm.
By Northern blot analysis, Leroy et al. (1998) detected a 1.3-kb transcript expressed only in brain. Examination of specific brain regions revealed expression in all areas tested, particularly in the substantia nigra.
Day et al. (1990) determined that the UCHL1 gene contains 9 exons and spans 10 kb. The 5-prime region contains elements common to many genes and other elements that are shared with the 5-prime regions of the genes encoding neurofilament neuron-specific enolase (ENO2; 131360) and THY1 antigen (188230). Leroy et al. (1998) confirmed that UCHL1 has 9 coding exons, and they identified a high GC content between exons 1 and 3.
By PCR analysis of DNA from a panel of human/rodent somatic cell hybrids, Edwards et al. (1991) mapped UCHL1 to chromosome 4. By in situ hybridization, they regionalized the assignment to 4p14.
Stumpf (2023) mapped the UCHL1 gene to chromosome 4p13 based on an alignment of the UCHL1 sequence (GenBank AK315368) with the genomic sequence (GRCh38).
Liu et al. (2002) found that UCHL1, especially variants linked to higher susceptibility to Parkinson disease-5 (PARK5; 613643), caused the accumulation of alpha-synuclein (163890) in cultured cells, an effect that could not be explained by its recognized hydrolase activity. UCHL1 exhibited a second, dimerization-dependent ubiquityl ligase activity. A polymorphic variant of UCHL1, ser18 to tyr (S18Y; 191342.0002), associated in some studies with decreased risk for Parkinson disease, had reduced ligase activity compared with the wildtype enzyme, but it had comparable hydrolase activity. The authors concluded that the ligase and hydrolase activities of UCHL1 may play roles in proteasomal protein degradation, a process critical for neuronal health.
In contrast to the UCHL3 (603090) isozyme, which is expressed in all tissues, UCHL1 is expressed exclusively in neurons and testis/ovary. Osaka et al. (2003) observed that UCHL1 associated and colocalized with monoubiquitin and elongated ubiquitin half-life. In the gracile axonal dystrophy (gad) mouse, in which the function of UCHL1 is lost, the authors demonstrated a reduced level of monoubiquitin in neurons. In contrast, overexpression of UCHL1 caused an increase in the level of ubiquitin in both cultured cells and mice. The authors suggested that UCHL1, with avidity and affinity for ubiquitin, may insure ubiquitin stability within neurons.
Using coimmunoprecipitation analysis in transfected mammalian cells, Kabuta et al. (2008) showed that human UCHL1 interacted with LAMP2A (309060), a lysosomal receptor for chaperone-mediated autophagy (CMA), and the CMA pathway components HSC70 (HSPA8; 600816) and HSP90 (HSP90AA1; 140571). Analysis with recombinant proteins revealed that UCHL1 interacted directly with the cytoplasmic region of LAMP2A. UCHL1 was not degraded by CMA pathway, but instead was degraded by macroautophagy. Analysis with UCHL1 mutants showed that interaction of UBCHL1 with the CMA machinery was independent of UCHL1 enzymatic activity and interaction of UCHL1 with monoubiquitin.
Using Western blot analysis, Reinicke et al. (2019) demonstrated that mouse Uchl1 was expressed in dendritic cells (DCs) and that its expression and enzymatic activity were regulated by immune stimuli. Cross-priming of the Cd8 (see 186910) T-cell response required Uchl1, and as a result, deletion of Uchl1 in mice impaired the Cd8 T-cell response and affected early innate neutrophil influx upon Listeria infection. Loss of Uchl1 did not interfere with phagocytosis and phagosome maturation in DCs. However, Uchl1 deletion reduced trafficking of recycling major histocompatibility complex class I molecules through cross-presentation.
Spastic Paraplegia 79B, Autosomal Recessive
In 3 sibs, born of consanguineous Turkish parents, with autosomal recessive spastic paraplegia-79B (SPG79B; 615491), Bilguvar et al. (2013) identified a homozygous missense mutation in the UCHL1 gene (E7A; 191342.0003). The mutation, which was found by homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in E. coli showed that the E7A mutant protein had decreased binding to ubiquitin and significantly decreased (less than 10%) hydrolase activity compared to wildtype. The patients had onset of progressive visual loss due to optic atrophy at around age 5 years, followed by spasticity, cerebellar ataxia, peripheral neuropathy, and myokymia, consistent with systemic neurodegeneration and deficits at the neuromuscular junction. The clinical features resembled those of the Uchl1-null mouse (Yamazaki et al., 1988). Bilguvar et al. (2013) noted that neither parent, each of whom was heterozygous for the mutation, had evidence of Parkinson disease. The findings indicated the importance of UCHL1 in the maintenance of nervous system integrity.
In 3 sibs with SPG79B, including a pair of monozygotic twin brothers, born of unrelated Norwegian parents, Rydning et al. (2017) identified compound heterozygous missense mutations in the UCHL1 gene: R178Q (191342.0004) and A216D (191342.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in E. coli showed that the R178Q mutation resulted in a 4-fold increase in enzyme activity compared to controls. Because expression of the A216D mutation resulted in inclusion bodies, containing presumably misfolded, aggregated proteins, activity assays of this mutant were not possible.
Spastic Paraplegia 79A with Ataxia, Autosomal Dominant
In 34 patients from 18 unrelated families with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; 620221), Park et al. (2022) identified heterozygous putative loss-of-function mutations in the UCHL1 gene (see, e.g., 191342.0006-191342.0010). The mutations, which were found by diagnostic exome and genome sequencing, segregated with the disorder in the families from whom information was available. None were present in the gnomAD database. Functional studies of the variants were not performed, but mass spectrometry analysis of fibroblasts derived from affected members of 3 different families showed a significant decrease in UCHL1 protein levels, suggesting that haploinsufficiency for this gene is the pathogenetic mechanism for this phenotype.
Possible Role in Parkinson Disease
Ubiquitin C-terminal hydrolase L1 represents 1 to 2% of total soluble brain protein (Wilkinson et al., 1989). Its occurrence in Lewy bodies and its function in the proteasome pathway make it a compelling candidate gene in Parkinson disease. In a German family with typical Parkinson disease (PARK5; 613643), Leroy et al. (1998) identified a missense mutation in the UCHL1 gene, ile93 to met (I93M; 191342.0001), which caused a partial loss of the catalytic activity of this thiol protease. They suggested that this could lead to aberrations in the proteolytic pathway and aggregation of proteins. Healy et al. (2006) noted that the findings of Leroy et al. (1998) had never been replicated and thus the association was uncertain.
Lincoln et al. (1999) sequenced the entire coding region of the UCHL1 gene in 11 families with a pattern of Parkinson disease consistent with autosomal dominant inheritance. Although they found polymorphisms in noncoding regions, the only amino acid change was S18Y (191342.0002). The S18Y allele was found in approximately 20% of chromosomes in a Caucasian population, suggesting that it is unlikely to be pathogenic. Lincoln et al. (1999) concluded that the I93M variant must be a rare cause of Parkinson disease or a harmless substitution whose occurrence in the family reflected chance.
Among 3,023 white individuals, Healy et al. (2006) found that the S18Y variant was not protective against PD under any genetic mode of inheritance. A haplotype-tagging approach also did not detect other associated variants in the UCHL1 gene. Furthermore, no association was observed in an updated metaanalysis including 6,594 individuals. A cumulative metaanalysis showed a trend toward a null effect.
The gracile axonal dystrophy (gad) mouse is an autosomal recessive mutant that shows sensory ataxia at an early age, followed by motor ataxia later (Yamazaki et al., 1988). Pathologically, the mutant is characterized by 'dying-back' type axonal degeneration and formation of spheroid bodies in nerve terminals. Pathologic observations in the human have associated brain aging and neurodegenerative diseases with progressive accumulation of ubiquitinated protein conjugates. In gad mice, accumulation of amyloid beta-protein and ubiquitin-positive deposits occur retrogradely along the sensory and motor nervous systems. Suh et al. (1995) showed that the gad mutation is located on mouse chromosome 5. Saigoh et al. (1999) found that the gad mutation is caused by an in-frame deletion including exons 7 and 8 of the Uchl1 gene, encoding the ubiquitin carboxy-terminal hydrolase selectively expressed in the nervous system and testis. The gad allele encodes a truncated Uchl1 protein lacking a segment of 42 amino acids containing a catalytic residue. Since this protein is thought to stimulate protein degradation by generating free monomeric ubiquitin, the gad mutation appears to affect protein turnover. The findings suggested that altered function of the ubiquitin system directly causes neurodegeneration. The gad mouse provides a useful model for investigating human neurodegenerative disorders.
Kurihara et al. (2000) showed that mice homozygous for a targeted deletion of the related Uchl3 gene (603090) are indistinguishable from wildtype. To assess whether the 2 hydrolases have redundant function, Kurihara et al. (2001) generated mice homozygous for both Uchl1(gad) and Uchl3(delta3-7). The double homozygotes weighed 30% less than single homozygotes and displayed an earlier onset of lethality, possibly due to dysphagia. Axonal degeneration of the nucleus tractus solitarius and area postrema of the medulla was noted in these mice. The double homozygotes also displayed a more severe axonal degeneration of the gracile tract of the medulla and spinal cord than had been observed in Uchl1(gad) single homozygotes. In addition, degeneration of dorsal root ganglia cell bodies was detected in both the double homozygotes and Uchl3(delta3-7) single homozygotes. Given that both Uchl1(gad) and Uchl3(delta3-7) single homozygotes displayed distinct degenerative defects that were exacerbated in the double homozygotes, the authors concluded that Uchl1 and Uchl3 may have both separate and overlapping functions in the maintenance of neurons of the gracile tract, nucleus tractus solitarius, and area postrema.
Gong et al. (2006) found that inhibition of Uchl1 in mouse hippocampal slices reduced normal synaptic function and long-term potentiation. Levels of soluble Uchl1 were reduced in hippocampi of App (104760)/Ps1 (PSEN1; 104311) mice, which start depositing amyloid-beta (A-beta) at age 8 to 10 weeks and reproduce some cognitive deficits seen in Alzheimer disease (see 104300) patients. Restoration of Uchl1 levels in mouse hippocampal slices treated with oligomeric amyloid-beta and in slices from App/Ps1 mice restored enzymatic activity and synaptic function. Injection of Uchl1 improved contextual fear learning in App/Ps1 mice. Treatment of hippocampal slices with Uchl1 before applying A-beta blocked the reduction of protein kinase A (PKA; see 188830) activity observed in the absence of pretreatment. Uchl1 also reversed the inhibition of Creb (CREB1; 123810) phosphorylation induced by A-beta. Gong et al. (2006) concluded that the PKA-CREB pathway mediates the effects of UCHL1 on A-beta-induced synaptic dysfunction.
MacDonald (1999) discussed the significance of the ubiquitin-proteasome system and degenerative disease in general, and the significance of the findings in the gad mouse specifically.
In neurons derived from gad mice, Kyratzi et al. (2008) found that lack of Uchl1 led to a decrease of free ubiquitin, but no overall decrease in proteasome function or enhanced sensitivity to oxidative stress. The findings suggested that wildtype UCHL1 acts as a stabilizer of monomeric ubiquitin in neuronal cells.
Reinicke et al. (2019) found that heterozygous or homozygous Uchl1 deficiency resulted in accelerated postnatal sensorimotor reflexes with decreased levels of polyubiquitinated proteins in juvenile mice, followed by motor degeneration in old adult mice. Absence of Uchl1 promoted mTorc1 (601231) activity and increased protein synthesis in mouse neurons. Proteasomal degradation was enhanced in Uchl1-deficient juvenile mice and declined in aged mice. As a result, Uchl1-deficient mice exhibited age- and brain area-dependent reduction in monoubiquitin and accumulation of polyubiquitinated proteins when neurodegeneration was already advanced. Furthermore, abnormal protein synthesis and degradation was associated with endoplasmic reticulum stress and ATP depletion, leading to alteration of protein homeostasis strains in Uchl1-deficient neurons. Rapamycin treatment reduced protein synthesis and ubiquitin accumulation in vitro and ameliorated the neurologic phenotype of Uchl1 deficiency in vivo.
In a brother and sister with typical Parkinson disease (PARK5; 613643), Leroy et al. (1998) identified a heterozygous 277C-G transversion in exon 2 of the UCHL1 gene, resulting in an ile93-to-met (I93M) substitution in a highly conserved region. A paternal uncle and the paternal grandfather were also affected, but the father was not affected, indicating incomplete penetrance. The mutation was not found in 500 control chromosomes. In vitro functional expression studies in E. coli showed that the mutant protein had about a 50% reduction in catalytic activity compared to wildtype. Leroy et al. (1998) noted that UCHL1 had been identified as a component of Lewy bodies.
Healy et al. (2006) noted that the findings of Leroy et al. (1998) had never been replicated and thus the association was uncertain.
Kabuta et al. (2008) showed that human UCHL1 with the I93M mutation exhibited enhanced interaction with the CMA pathway components LAMP2A (309060), HSC70 (HSPA8; 600816), and HSP90 (HSP90AA1; 140571) compared with wildtype UCHL1 and caused accumulation of alpha-synuclein (SNCA; 163890) due to inhibition of CMA-dependent degradation of alpha-synuclein. The aberrant interaction of UCHL1 I93M with the CMA machinery was independent of UCHL1 interaction with monoubiquitin and did not affect degradation of proteins by macroautophagy. Furthermore, the I93M mutation did not cause loss of UCHL1 function, and the aberrant interaction was independent of UCHL1 enzymatic activity.
This variant, formerly titled PARKINSON DISEASE 5, RESISTANCE TO, has been reclassified based on the following conflicting evidence.
Lincoln et al. (1999) identified a ser18-to-tyr (S18Y) polymorphism in exon 3 of the UCHL1 gene. The S18Y allele was found in approximately 20% of chromosomes in a Caucasian population, and the authors suggested that it is unlikely to be pathogenic.
Liu et al. (2002) found that the S18Y variant had reduced ubiquityl ligase activity compared with the wildtype enzyme, but it had comparable hydrolase activity.
Maraganore et al. (2004) performed a collaborative pooled analysis of data from 11 published studies of the UCHL1 S18Y variant and Parkinson disease (613643): 3 studies had reported no association for the variant and PD, 4 reported associations in PD subgroups only, and 4 reported an inverse association of S18Y and PD. From a total of 1,970 cases and 2,224 controls, Maraganore et al. (2004) found an overall inverse association of S18Y with PD. Carriers of the variant allele (Y/Y plus Y/S compared to S/S) had an odds ratio (OR) of 0.84, and homozygotes for the variant allele (Y/Y compared to S/S plus Y/S) had an OR of 0.71. There was a linear trend in the log OR consistent with a gene dosage effect. The inverse association was most apparent for young cases compared with young controls.
Among 3,023 white individuals, Healy et al. (2006) found that the S18Y variant was not protective against PD under any genetic mode of inheritance. Furthermore, no association was observed in an updated metaanalysis including 6,594 individuals. A cumulative metaanalysis showed a trend toward a null effect.
Kyratzi et al. (2008) found that the S18Y variant of the UCHL1 gene, but not wildtype, conferred a specific antioxidant protective function when expressed at physiologic levels in human neuroblastoma cells and primary cortical neurons. The effect appeared to result from a decrease in reactive oxygen species in response to insult. The results provided indirect evidence for the importance of oxidative stress as a pathogenetic factor in certain forms of sporadic PD. Overexpression of wildtype or the S18Y variant did not appear to directly impact the proteasome, although they both led to stabilization of free ubiquitin.
Rudolph et al. (2011) examined the possible effects of the S18Y polymorphism on cataract formation. Using dynamic allele-specific hybridization, they analyzed 493 patients with cataract and 142 controls for the S18Y polymorphism. Significant differences were observed in allele and genotype frequencies between controls and cataract patients with a positive UCHL1 allele A carrier status associated with the cataract diagnosis. Rudolph et al. (2011) concluded that their study did not support a protective role for the S18Y polymorphism in cataract development. Instead, their findings suggested that this polymorphism might have a disease-promoting effect.
In 3 sibs, born of consanguineous Turkish parents, with autosomal recessive spastic paraplegia-79B (SPG79B; 615491), Bilguvar et al. (2013) identified a homozygous A-to-C transversion in the UCHL1 gene, resulting in a glu7-to-ala (E7A) substitution at a highly conserved residue in the ubiquitin-binding domain. The mutation, which was found by homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the dbSNP or 1000 Genomes Project databases, in 2,400 control exomes of European individuals, or in 948 Turkish control chromosomes. Molecular modeling predicted that the E7A substitution may interfere with substrate binding by restricting the proper positioning of the substrate for tunneling underneath the crossover L8 loop spanning the catalytic cleft. In vitro functional expression studies in E. coli showed that the E7A mutant protein had decreased binding to ubiquitin and significantly decreased (less than 10%) hydrolase activity compared to wildtype. The patients had onset of progressive visual loss due to optic atrophy at around age 5 years, followed by spasticity, cerebellar ataxia, peripheral neuropathy, and myokymia, consistent with systemic neurodegeneration and deficits at the neuromuscular junction. The clinical features resembled those of the Uchl1-null mouse (Yamazaki et al., 1988). Bilguvar et al. (2013) noted that neither parent, each of whom was heterozygous for the mutation, had evidence of Parkinson disease.
In 3 sibs, including a pair of monozygotic twin brothers, born of unrelated Norwegian parents, with autosomal recessive spastic paraplegia-79B (SPG79B; 615491), Rydning et al. (2017) identified compound heterozygous missense mutations in the UCHL1 gene: a c.533G-A transition (c.533G-A, NM_004181.4), resulting in an arg178-to-gln (R178Q) substitution at a highly conserved residue in the active site, and a c.647C-A transversion, resulting in an ala216-to-asp (A216D; 191342.0005) substitution in a beta-sheet that constitutes a hydrophobic core. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases, or in 961 controls. In the ExAC database, the c.647C-A variant was absent, whereas the c.533G-A variant was reported in heterozygous state in 10 individuals. In vitro functional expression studies in E. coli showed that the R178Q mutation resulted in a 4-fold increase in enzyme activity compared to controls. Because expression of the A216D mutation resulted in inclusion bodies, containing presumably misfolded, aggregated proteins, no activity assays of this mutant were possible. Patient fibroblasts showed decreased levels of the UCHL1 protein, at about 25 to 35% of controls, and consisted only of the R178Q mutant; the A216D mutant protein was not detected in patient cells, suggesting that it is degraded. Rydning et al. (2017) noted that the patients did not have cognitive dysfunction, and speculated that the nonsoluble A216D protein results in reduction of UCHL1 function and contributes to neurodegeneration, whereas the increased enzymatic activity of R178Q many compensate and even protect cognitive function. This family had previously been reported by Nyberg-Hansen and Refsum (1972).
For discussion of the c.647C-A transversion (c.647C-A, NM_004181.4) in the UCHL1 gene, resulting in an ala216-to-asp (A216D) substitution, that was found in compound heterozygous state in 3 sibs with autosomal recessive spastic paraplegia-79B (SPG79B; 615491) by Rydning et al. (2017), see 191342.0004.
In 6 affected members of a multigenerational family (family 1) with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; 620221), Park et al. (2022) identified a heterozygous 1-bp duplication (c.64_dup, NM_004181.4) in the UCHL1 gene, resulting in a frameshift and premature termination (Val22GlyfsTer39). The mutation, which was found by diagnostic exome and genome sequencing, segregated with the disorder in the family and was not present in the gnomAD database. Functional studies of the variant were not performed, but mass spectrometry analysis of patient fibroblasts showed a significant decrease in UCHL1 protein levels, suggesting that haploinsufficiency for this gene is the pathogenetic mechanism for this phenotype.
In 4 affected members of a multigenerational family (family 2) with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; 620221), Park et al. (2022) identified a heterozygous 16-bp deletion (c.349_364del, NM_004181.4) in the UCHL1 gene, resulting in a frameshift and premature termination (Phe117ArgfsTer33). The mutation, which was found by diagnostic exome and genome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed, but mass spectrometry analysis of patient fibroblasts showed a significant decrease in UCHL1 protein levels, suggesting that haploinsufficiency for this gene is the pathogenetic mechanism for this phenotype. One of the patients in this family had an additional diagnosis of ALS (105400) and carried a heterozygous pathogenic missense mutation (D91A) in the SOD1 gene (147450).
In 4 affected members of 2 unrelated families (families 6 and 7) with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; 620221), Park et al. (2022) identified a heterozygous c.73C-T transition (c.73C-T, NM_004181.4) in the UCHL1 gene, resulting in a gln25-to-ter (Q25X) substitution. The mutation, which was found by diagnostic exome and genome sequencing, segregated with the disorder in family 6 (information from members of family 7 was not available), and was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function and cause haploinsufficiency.
In a mother and daughter (family 12) with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; 620221), Park et al. (2022) identified a heterozygous 4-bp duplication (c.95_98dup, NM_004181.4) in the UCHL1 gene, resulting in a frameshift and premature termination (Leu34GlyfsTer28). The mutation, which was found by diagnostic exome and genome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function and cause haploinsufficiency.
In 5 members of 3 unrelated families (families 15-17) with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; 620221), Park et al. (2022) identified a heterozygous 3-bp in-frame duplication (c.154_156dup, NM_004181.4) in the UCHL1 gene, resulting in the duplication of residue leu52 (Leu52dup). The mutation, which was found by extended screening for UCHL1 variants, segregated with the disorder in family 17 and was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to be pathogenic.
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