Abstract:
:Ubiquitin C-terminal hydrolase-L1 (UCHL1), a neuron-specific de-ubiquitinating enzyme, is one of the most abundant proteins in the brain. We describe three siblings from a consanguineous union with a previously unreported early-onset progressive neurodegenerative syndrome featuring childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfuction, and spasticity with upper motor neuron dysfunction. Through homozygosity mapping of the affected individuals followed by whole-exome sequencing of the index case, we identified a previously undescribed homozygous missense mutation within the ubiquitin binding domain of UCHL1 (UCHL1(GLU7ALA)), shared by all affected subjects. As demonstrated by isothermal titration calorimetry, purified UCHL1(GLU7ALA), compared with WT, exhibited at least sevenfold reduced affinity for ubiquitin. In vitro, the mutation led to a near complete loss of UCHL1 hydrolase activity. The GLU7ALA variant is predicted to interfere with the substrate binding by restricting the proper positioning of the substrate for tunneling underneath the cross-over loop spanning the catalytic cleft of UCHL1. This interference with substrate binding, combined with near complete loss of hydrolase activity, resulted in a >100-fold reduction in the efficiency of UCHL1(GLU7ALA) relative to WT. These findings demonstrate a broad requirement of UCHL1 in the maintenance of the nervous system.
journal_name
Proc Natl Acad Sci U S Aauthors
Bilguvar K,Tyagi NK,Ozkara C,Tuysuz B,Bakircioglu M,Choi M,Delil S,Caglayan AO,Baranoski JF,Erturk O,Yalcinkaya C,Karacorlu M,Dincer A,Johnson MH,Mane S,Chandra SS,Louvi A,Boggon TJ,Lifton RP,Horwich AL,Gunel Mdoi
10.1073/pnas.1222732110subject
Has Abstractpub_date
2013-02-26 00:00:00pages
3489-94issue
9eissn
0027-8424issn
1091-6490pii
1222732110journal_volume
110pub_type
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