TY - JOUR
T1 - Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia
AU - Farazi Fard, Mohammad Ali
AU - Rebelo, Adriana P.
AU - Buglo, Elena
AU - Nemati, Hamid
AU - Dastsooz, Hassan
AU - Gehweiler, Ina
AU - Reich, Selina
AU - Reichbauer, Jennifer
AU - Quintáns, Beatriz
AU - Ordóñez-Ugalde, Andrés
AU - Cortese, Andrea
AU - Courel, Steve
AU - Abreu, Lisa
AU - Powell, Eric
AU - Danzi, Matt
AU - Martuscelli, Nicole B.
AU - Bis-Brewer, Dana M.
AU - Tao, Feifei
AU - Zarei, Fariba
AU - Habibzadeh, Parham
AU - Yavarian, Majid
AU - Modarresi, Farzaneh
AU - Silawi, Mohammad
AU - Tabatabaei, Zahra
AU - Yousefi, Masoume
AU - Farpour, Hamid Reza
AU - Kessler, Christoph
AU - Mangold, Elisabeth
AU - Kobeleva, Xenia
AU - Mueller, Amelie J.
AU - Haack, Tobias B.
AU - Tarnopolsky, Mark
AU - Gan-Or, Ziv
AU - Rouleau, Guy A.
AU - Synofzik, Matthis
AU - Sobrido, María Jesús
AU - Jordanova, Albena
AU - Schüle, Rebecca
AU - Zuchner, Stephan
AU - Faghihi, Mohammad A
N1 - Funding Information:
We are thankful to the families who participated in this research. We thank Els De Vriendt for the excellent technical assistance. S.Z. and R.S. are supported by National Institutes of Health grant R01NS072248. The project was further supported by the European Union's Horizon 2020 research and innovation program under grant 779257 (Solve-RD; R.S.) and in the context of the ERA-NET Cofund action N° 643578 by the German Bundesministerium für Bildung und Forschung (BMBF) (01GM1607) for the E-Rare-3 network PREPARE (M.S. S.R. and associated partner S.Z.). M.J.S. was supported by Instituto de Salud Carlos III grant PS09/01830 and FEDER (Fonds Européen de Développement Économique et Régional). A.J. is supported by an Excellence (TOP) grant of the University of Antwerp. The study was partly supported by NIMAD research grant (940714) awarded to MAF. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health. T.B.H. was supported by the BMBF through the “Juniorverbund in der Systemmedizin” “mitOmics” (FKZ 01ZX1405C to T.B.H.).
Funding Information:
We are thankful to the families who participated in this research. We thank Els De Vriendt for the excellent technical assistance. S.Z. and R.S. are supported by National Institutes of Health grant R01NS072248 . The project was further supported by the European Union’s Horizon 2020 research and innovation program under grant 779257 (Solve-RD; R.S.) and in the context of the ERA-NET Cofund action N° 643578 by the German Bundesministerium für Bildung und Forschung ( BMBF ) ( 01GM1607 ) for the E-Rare-3 network PREPARE (M.S., S.R., and associated partner S.Z.). M.J.S. was supported by Instituto de Salud Carlos III grant PS09/01830 and FEDER ( Fonds Européen de Développement Économique et Régional ). A.J. is supported by an Excellence (TOP) grant of the University of Antwerp . The study was partly supported by NIMAD research grant ( 940714 ) awarded to MAF . The views expressed are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health. T.B.H. was supported by the BMBF through the “Juniorverbund in der Systemmedizin” “mitOmics” ( FKZ 01ZX1405C to T.B.H.).
Publisher Copyright:
© 2019
PY - 2019/4/4
Y1 - 2019/4/4
N2 - 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.
AB - 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.
KW - animal model
KW - endosomal trafficking
KW - genetic diseases
KW - hereditary spastic paraplegia
KW - neurodegenerative diseases
KW - spasticity
KW - ubiquitination
KW - zebrafish
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UR - http://www.scopus.com/inward/citedby.url?scp=85063658693&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2019.03.001
DO - 10.1016/j.ajhg.2019.03.001
M3 - Article
C2 - 30929741
AN - SCOPUS:85063658693
VL - 104
SP - 767
EP - 773
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 4
ER -