Hereditary ataxia

Gene: UCHL1

Green List (high evidence)

UCHL1 (ubiquitin C-terminal hydrolase L1)
EnsemblGeneIds (GRCh38): ENSG00000154277
EnsemblGeneIds (GRCh37): ENSG00000154277
OMIM: 191342, Gene2Phenotype
UCHL1 is in 10 panels

2 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

Comment on list classification: Upgraded from Red to Green - ataxia and other cerebellar signs are a feature of this UCHL1-related neurodegenerative disorder. At least 4 unrelated families reported (PMIDs: 23359680; 28007905; 29735986; 32656641) with different biallelic variants, supported by functional and animal model data.
Created: 11 May 2021, 10:12 a.m. | Last Modified: 11 May 2021, 10:12 a.m.
Panel Version: 1.219
Associated with relevant phenotype in OMIM (MIM# 615491) but is currently not listed in Gene2Phenotype.

- PMID: 23359680 (2013) - Three sibs born to consanguineous parents with an early-onset progressive neurodegenerative syndrome characterised by childhood-onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfuction, and spasticity with upper motor neuron dysfunction. Homozygosity mapping followed by WES revealed a homozygous missense variant, (c.20A>C; p.Glu7Ala) in UCHL1 which segregated with the disorder. Some in vitro functional analysis of the variant showing near complete loss of UCHL1 hydrolase activity.

- PMID: 28007905 (2017) - Three sibs, born of unrelated Norwegian parents, with childhood-onset optic atrophy, followed by spasticity and ataxia due to comp het variants in UCHL1, c.533G>A (p.Arg178Gln) and c.647C>A (p.Ala216Asp), cosegregating with the phenotype. Functional evaluation of the variants indicates different functional consequences as the insoluble Ala216Asp variant led to LoF, whereas the Arg178Gln led to increased enzyme activity.

- PMID: 29735986 (2018) - Two sibs harbouring a homozygous splice-site variant (c.459+2T>C) in the UCHL1 gene who presented an early-onset neurodegenerative disorder characterised by SPG, optic atrophy, seizures, and facial dysmorphism. Clinical description does not include ataxia however both sibs displayed cerebellar signs such as dysarthria, nystagmus, tremors and gait impairment.

- PMID: 32656641 (2020) - Two sibs with a childhood-onset neurodegenerative disorder starting with motor DD and optic atrophy leading to progressive visual loss, cerebellar ataxia, spastic paraparesis, and motor neuropathy. Both sibs developed hypertrophic cardiomyopathy in their 30s and died of sudden cardiac death at age 43 and 40, respectively. WES identified a novel homozygous (c.627_629del; p.Gly210del) deletion in UCHL1. Their unaffected mother was heterozygous for the variant but the father was unavailable for genetic testing.

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UCHL1-deficient mice display axonal degeneration, progressive sensory motor ataxia, and premature death. UCHL1 is thought to have important roles in axonal repair after injury, axonal transport, and synaptic function (PMID: 11555633; 33159930)
Created: 11 May 2021, 10:09 a.m. | Last Modified: 11 May 2021, 10:09 a.m.
Panel Version: 1.216

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 79, autosomal recessive, OMIM:615491

Publications

Jonathan Williams (Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust)

Red List (low evidence)

Evidence (including functional) for a single variant
Created: 24 Nov 2015, 4:57 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Early onset ataxia and optic neuropathy

Publications

Variants in this GENE are reported as part of current diagnostic practice

History Filter Activity

11 May 2021, Gel status: 3

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: uchl1 has been classified as Green List (High Evidence).

11 May 2021, Gel status: 1

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: UCHL1 were changed from Early onset ataxia and optic neuropathy to Spastic paraplegia 79, autosomal recessive, OMIM:615491

11 May 2021, Gel status: 1

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: UCHL1 were set to PMID: 23359680

11 Jul 2016, Gel status: 1

Gene classified by Genomics England curator

emma baple (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

11 Jul 2016, Gel status: 1

Gene classified by Genomics England curator

emma baple (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

24 Nov 2015, Gel status: 0

Created

Jonathan Williams (Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust)

UCHL1 was created by jonathan.williams

24 Nov 2015, Gel status: 0

Added New Source

Jonathan Williams (Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust)

UCHL1 was added to Hereditary ataxiapanel. Sources: Expert Review