Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia

Mohammad Ali Farazi Fard, Adriana P. Rebelo, Elena Buglo, Hamid Nemati, Hassan Dastsooz, Ina Gehweiler, Selina Reich, Jennifer Reichbauer, Beatriz Quintáns, Andrés Ordóñez-Ugalde, Andrea Cortese, Steve Courel, Lisa Abreu, Eric Powell, Matt Danzi, Nicole B. Martuscelli, Dana M. Bis-Brewer, Feifei Tao, Fariba Zarei, Parham HabibzadehMajid Yavarian, Farzaneh Modarresi, Mohammad Silawi, Zahra Tabatabaei, Masoume Yousefi, Hamid Reza Farpour, Christoph Kessler, Elisabeth Mangold, Xenia Kobeleva, Amelie J. Mueller, Tobias B. Haack, Mark Tarnopolsky, Ziv Gan-Or, Guy A. Rouleau, Matthis Synofzik, María Jesús Sobrido, Albena Jordanova, Rebecca Schüle, Stephan Zuchner, Mohammad Ali Faghihi

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

The diagnostic gap for rare neurodegenerative diseases is still considerable, despite continuous advances in gene identification. Many novel Mendelian genes have only been identified in a few families worldwide. Here we report the identification of an autosomal-dominant gene for hereditary spastic paraplegia (HSP) in 10 families that are of diverse geographic origin and whose affected members all carry unique truncating changes in a circumscript region of UBAP1 (ubiquitin-associated protein 1). HSP is a neurodegenerative disease characterized by progressive lower-limb spasticity and weakness, as well as frequent bladder dysfunction. At least 40% of affected persons are currently undiagnosed after exome sequencing. We identified pathological truncating variants in UBAP1 in affected persons from Iran, USA, Germany, Canada, Spain, and Bulgarian Roma. The genetic support ranges from linkage in the largest family (LOD = 8.3) to three confirmed de novo mutations. We show that mRNA in the fibroblasts of affected individuals escapes nonsense-mediated decay and thus leads to the expression of truncated proteins; in addition, concentrations of the full-length protein are reduced in comparison to those in controls. This suggests either a dominant-negative effect or haploinsufficiency. UBAP1 links endosomal trafficking to the ubiquitination machinery pathways that have been previously implicated in HSPs, and UBAP1 provides a bridge toward a more unified pathophysiology.

Original languageEnglish (US)
Pages (from-to)767-773
Number of pages7
JournalAmerican journal of human genetics
Volume104
Issue number4
DOIs
StatePublished - Apr 4 2019

Keywords

  • animal model
  • endosomal trafficking
  • genetic diseases
  • hereditary spastic paraplegia
  • neurodegenerative diseases
  • spasticity
  • ubiquitination
  • zebrafish

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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