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).
