Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Mar 15;26(6):1031-1040.
doi: 10.1093/hmg/ddw391.

Novel UCHL1 mutations reveal new insights into ubiquitin processing

Siri L Rydning  1   2 , Paul H Backe  3   4 , Mirta M L Sousa  5 , Zafar Iqbal  1 , Ane-Marte Øye  6 , Ying Sheng  6 , Mingyi Yang  3   4 , Xiaolin Lin  3   4 , Geir Slupphaug  5   7 , Tonje H Nordenmark  8 , Magnus D Vigeland  6 , Magnar Bjørås  2   3   5 , Chantal M Tallaksen  1   2 , Kaja K Selmer  6
Affiliations

Novel UCHL1 mutations reveal new insights into ubiquitin processing

Siri L Rydning et al. Hum Mol Genet. .

Erratum in

  • Novel UCHL1 mutations reveal new insights into ubiquitin processing.
    Rydning SL, Backe PH, Sousa MML, Iqbal Z, Øye AM, Sheng Y, Yang M, Lin X, Slupphaug G, Nordenmark TH, Vigeland MD, Bjørås M, Tallaksen CM, Selmer KK. Rydning SL, et al. Hum Mol Genet. 2017 Mar 15;26(6):1217-1218. doi: 10.1093/hmg/ddx072. Hum Mol Genet. 2017. PMID: 28334853 No abstract available.

Abstract

Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 has been implicated in early-onset progressive neurodegeneration (MIM no. 615491), so far only in one family. In this study a second family is characterized, and the functional consequences of the identified mutations in UCHL1 are explored. Three siblings developed childhood-onset optic atrophy, followed by spasticity and ataxia. Whole exome sequencing identified compound heterozygous variants in UCHL1, c.533G > A (p.Arg178Gln) and c.647C > A (p.Ala216Asp), cosegregating with the phenotype. Enzymatic activity of purified recombinant proteins analysed by ubiquitin hydrolase assays showed a 4-fold increased hydrolytic activity of the recombinant UCHL1 mutant Arg178Gln compared to wild type, whereas the Ala216Asp protein was insoluble. Structural 3D analysis of UCHL1 by computer modelling suggests that Arg178 is a rate-controlling residue in catalysis which is partly abolished in the Arg178Gln mutant and, consequently, the Arg178Gln mutant increases the enzymatic turnover. UCHL1 protein levels in fibroblasts measured by targeted mass spectrometry showed a total amount of UCHL1 in control fibroblasts about 4-fold higher than in the patients. Hence, studies of the identified missense variants reveal surprisingly different functional consequences as the insoluble Ala216Asp variant leads to loss of function, whereas the Arg178Gln leads to increased enzyme activity. The reported patients have remarkably preserved cognition, and we propose that the increased enzyme activity of the Arg178Gln variant offers a protective effect on cognitive function. This study establishes the importance of UCHL1 in neurodegeneration, provides new mechanistic insight about ubiquitin processing, and underlines the complexity of the different roles of UCHL1.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

MeSH terms

LinkOut - more resources