Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia

Am J Hum Genet. 2019 Apr 4;104(4):767-773. doi: 10.1016/j.ajhg.2019.03.001.

Mohammad Ali Farazi Fard ¹, Adriana P Rebelo ², Elena Buglo ², Hamid Nemati ³, Hassan Dastsooz ⁴, Ina Gehweiler ⁵, Selina Reich ⁵, Jennifer Reichbauer ⁵, Beatriz Quintáns ⁶, Andrés Ordóñez-Ugalde ⁶, Andrea Cortese ², Steve Courel ², Lisa Abreu ², Eric Powell ⁷, Matt C Danzi ², Nicole B Martuscelli ⁸, Dana M Bis-Brewer ², Feifei Tao ², Fariba Zarei ³, Parham Habibzadeh ⁹, Majid Yavarian ¹, Farzaneh Modarresi ¹⁰, Mohammad Silawi ¹, Zahra Tabatabaei ¹, Masoume Yousefi ¹, Hamid Reza Farpour ³, Christoph Kessler ⁵, Elisabeth Mangold ¹¹, Xenia Kobeleva ¹², Ivailo Tournev ¹³, Teodora Chamova ¹⁴, Amelie J Mueller ¹⁵, Tobias B Haack ¹⁵, Mark Tarnopolsky ¹⁶, Ziv Gan-Or ¹⁷, Guy A Rouleau ¹⁷, Matthis Synofzik ⁵, María-Jesús Sobrido ⁶, Albena Jordanova ¹⁸, Rebecca Schüle ⁵, Stephan Zuchner ², Mohammad Ali Faghihi ¹⁹

Affiliations

1 Persian BayanGene Research and Training Center, Shiraz, Iran.
2 John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL 33136, USA.
3 Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
4 Persian BayanGene Research and Training Center, Shiraz, Iran; Italian Institute for Genomic Medicine, University of Turin, Turin 10126 Italy.
5 Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen 72076, Germany; German Center for Neurodegenerative Diseases, Tübingen 72706, Germany.
6 Neurogenetics Group Instituto de Investigación Sanitaria, Hospital Clínico de Santiago, Santiago de Compostela 15706, Spain.
7 The Genesis Project foundation Miami, FL 33136, USA.
8 Department of Biology University of Miami, Miami, FL 33136, USA.
9 Persian BayanGene Research and Training Center, Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.
10 Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136 USA.
11 Institute of Human Genetics University of Bonn, Bonn 53113, Germany.
12 Department of Neurology, University of Bonn, Bonn 53113, Germany.
13 Department of Neurology, Medical University-Sofia, Sofia 1431, Bulgaria; Department of Cognitive Science and Psychology, New Bulgarian University, Sofia 1618, Bulgaria.
14 Department of Neurology, Medical University-Sofia, Sofia 1431, Bulgaria.
15 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen 72706, Germany; Centre for Rare Diseases, University of Tübingen, Tübingen 72706, Germany.
16 Department of Pediatrics, McMaster University, Hamilton, Ontario L8S 4L8, Canada.
17 Department of Human Genetics, McGill University, Montréal, Quebec H3A 0G4, Canada; Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
18 Molecular Neurogenomics Group, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerpen 2610, Belgium; Molecular Medicine Center Department of Medical Chemistry and Biochemistry, Medical University-Sofia, Sofia 1431, Bulgaria.
19 Persian BayanGene Research and Training Center, Shiraz, Iran; Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136 USA. Electronic address: mfaghihi@med.miami.edu.

PMID: 30929741 DOI: 10.1016/j.ajhg.2019.03.001

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.

Keywords

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

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