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 C Danzi; Nicole B Martuscelli; Dana M Bis-Brewer; Feifei Tao; Fariba Zarei; Parham Habibzadeh; Majid Yavarian; Farzaneh Modarresi; Mohammad Silawi; Zahra Tabatabaei; Masoume Yousefi; Hamid Reza Farpour; Christoph Kessler; Elisabeth Mangold; Xenia Kobeleva; Ivailo Tournev; Teodora Chamova; 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

doi:10.1016/j.ajhg.2019.03.001

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Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia

Journal article

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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, …

American journal of human genetics, Vol.104(4), pp.767-773

2019-04-04

DOI: https://doi.org/10.1016/j.ajhg.2019.03.001

PMID: 30929741

Abstract

genetic diseases

neurodegenerative diseases

hereditary spastic paraplegia

ubiquitination

endosomal trafficking

spasticity

zebrafish

animal model

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.951 Huntington's Disease
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia
Creators: Mohammad Ali Farazi Fard - Persian BayanGene Research and Training Center, Shiraz, Iran
Adriana P Rebelo - John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL 33136, USA
Elena Buglo - John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL 33136, USA
Hamid Nemati - Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Hassan Dastsooz - Persian BayanGene Research and Training Center, Shiraz, Iran
Ina Gehweiler - Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen 72076, Germany
Selina Reich - Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen 72076, Germany
Jennifer Reichbauer - Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen 72076, Germany
Beatriz Quintáns - Neurogenetics Group Instituto de Investigación Sanitaria, Hospital Clínico de Santiago, Santiago de Compostela 15706, Spain
Andrés Ordóñez-Ugalde - Neurogenetics Group Instituto de Investigación Sanitaria, Hospital Clínico de Santiago, Santiago de Compostela 15706, Spain
Andrea Cortese - John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL 33136, USA
Steve Courel - John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL 33136, USA
Lisa Abreu - John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL 33136, USA
Eric Powell - The Genesis Project foundation Miami, FL 33136, USA
Matt C Danzi - John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL 33136, USA
Nicole B Martuscelli - Department of Biology University of Miami, Miami, FL 33136, USA
Dana M Bis-Brewer - John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL 33136, USA
Feifei Tao - John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL 33136, USA
Fariba Zarei - Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Parham Habibzadeh - Persian BayanGene Research and Training Center, Shiraz, Iran
Majid Yavarian - Persian BayanGene Research and Training Center, Shiraz, Iran
Farzaneh Modarresi - Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136 USA
Mohammad Silawi - Persian BayanGene Research and Training Center, Shiraz, Iran
Zahra Tabatabaei - Persian BayanGene Research and Training Center, Shiraz, Iran
Masoume Yousefi - Persian BayanGene Research and Training Center, Shiraz, Iran
Hamid Reza Farpour - Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Christoph Kessler - Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen 72076, Germany
Elisabeth Mangold - Institute of Human Genetics University of Bonn, Bonn 53113, Germany
Xenia Kobeleva - Department of Neurology, University of Bonn, Bonn 53113, Germany
Ivailo Tournev - Department of Neurology, Medical University-Sofia, Sofia 1431, Bulgaria
Teodora Chamova - Department of Neurology, Medical University-Sofia, Sofia 1431, Bulgaria
Amelie J Mueller - Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen 72706, Germany
Tobias B Haack - Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen 72706, Germany
Mark Tarnopolsky - Department of Pediatrics, McMaster University, Hamilton, Ontario L8S 4L8, Canada
Ziv Gan-Or - Department of Human Genetics, McGill University, Montréal, Quebec H3A 0G4, Canada
Guy A Rouleau - Department of Human Genetics, McGill University, Montréal, Quebec H3A 0G4, Canada
Matthis Synofzik - Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen 72076, Germany
María-Jesús Sobrido - Neurogenetics Group Instituto de Investigación Sanitaria, Hospital Clínico de Santiago, Santiago de Compostela 15706, Spain
Albena Jordanova - Molecular Neurogenomics Group, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerpen 2610, Belgium
Rebecca Schüle - Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen 72076, Germany
Stephan Zuchner - John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL 33136, USA
Mohammad Ali Faghihi - Persian BayanGene Research and Training Center, Shiraz, Iran
Publication Details: American journal of human genetics, Vol.104(4), pp.767-773
Publisher: Elsevier Inc
Academic Unit: Leadership Department; Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Dept of Psychiatry & Behavioral Sciences
Language: English
Resource Type: Journal article
PMID: 30929741
Record Identifier: 991031576653002976