Truncating variants in UBAP1 associated with childhood-onset nonsyndromic hereditary spastic paraplegia

Hum Mutat. 2020 Mar;41(3):632-640. doi: 10.1002/humu.23950. Epub 2019 Nov 25.

Abstract

Hereditary spastic paraplegia (HSP) is a group of disorders with predominant symptoms of lower-extremity weakness and spasticity. Despite the delineation of numerous genetic causes of HSP, a significant portion of individuals with HSP remain molecularly undiagnosed. Through exome sequencing, we identified five unrelated families with childhood-onset nonsyndromic HSP, all presenting with progressive spastic gait, leg clonus, and toe walking starting from 7 to 8 years old. A recurrent two-base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense-mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified in this study are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant-negative effect on the normal function of the endosome-specific endosomal sorting complexes required for the transport-I complex.

Keywords: UBAP1; autosomal dominant; escape of nonsense-mediated decay; hereditary spastic paraplegia.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Carrier Proteins / genetics*
  • Child
  • Female
  • Genetic Association Studies* / methods
  • Genetic Loci
  • Genetic Predisposition to Disease*
  • Humans
  • Lymphocytes / immunology
  • Lymphocytes / metabolism
  • Male
  • Mutation*
  • Pedigree
  • Phenotype
  • Spastic Paraplegia, Hereditary / diagnosis*
  • Spastic Paraplegia, Hereditary / genetics*
  • Whole Exome Sequencing

Substances

  • Carrier Proteins
  • UBAP1 protein, human