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 Habibzadeh; Majid 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 A Faghihi

doi:10.1016/j.ajhg.2019.03.001

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 A Faghihi

Hussman Institute for Human Genomics

Research output: Contribution to journal › Article › peer-review

19 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 language	English (US)
Pages (from-to)	767-773
Number of pages	7
Journal	American journal of human genetics
Volume	104
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2019.03.001
State	Published - 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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10.1016/j.ajhg.2019.03.001

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Farazi Fard, M. A., Rebelo, A. P., Buglo, E., Nemati, H., Dastsooz, H., Gehweiler, I., Reich, S., Reichbauer, J., Quintáns, B., Ordóñez-Ugalde, A., Cortese, A., Courel, S., Abreu, L., Powell, E., Danzi, M., Martuscelli, N. B., Bis-Brewer, D. M., Tao, F., Zarei, F., ... Faghihi, M. A. (2019). Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia. American journal of human genetics, 104(4), 767-773. https://doi.org/10.1016/j.ajhg.2019.03.001

Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia. / Farazi Fard, Mohammad Ali; Rebelo, Adriana P.; Buglo, Elena; Nemati, Hamid; Dastsooz, Hassan; Gehweiler, Ina; Reich, Selina; Reichbauer, Jennifer; Quintáns, Beatriz; Ordóñez-Ugalde, Andrés; Cortese, Andrea; Courel, Steve; Abreu, Lisa; Powell, Eric; Danzi, Matt; Martuscelli, Nicole B.; Bis-Brewer, Dana M.; Tao, Feifei; Zarei, Fariba; Habibzadeh, Parham; Yavarian, Majid; Modarresi, Farzaneh; Silawi, Mohammad; Tabatabaei, Zahra; Yousefi, Masoume; Farpour, Hamid Reza; Kessler, Christoph; Mangold, Elisabeth; Kobeleva, Xenia; Mueller, Amelie J.; Haack, Tobias B.; Tarnopolsky, Mark; Gan-Or, Ziv; Rouleau, Guy A.; Synofzik, Matthis; Sobrido, María Jesús; Jordanova, Albena; Schüle, Rebecca; Zuchner, Stephan; Faghihi, Mohammad A.

In: American journal of human genetics, Vol. 104, No. 4, 04.04.2019, p. 767-773.

Research output: Contribution to journal › Article › peer-review

Farazi Fard, MA, Rebelo, AP, Buglo, E, Nemati, H, Dastsooz, H, Gehweiler, I, Reich, S, Reichbauer, J, Quintáns, B, Ordóñez-Ugalde, A, Cortese, A, Courel, S, Abreu, L, Powell, E, Danzi, M, Martuscelli, NB, Bis-Brewer, DM, Tao, F, Zarei, F, Habibzadeh, P, Yavarian, M, Modarresi, F, Silawi, M, Tabatabaei, Z, Yousefi, M, Farpour, HR, Kessler, C, Mangold, E, Kobeleva, X, Mueller, AJ, Haack, TB, Tarnopolsky, M, Gan-Or, Z, Rouleau, GA, Synofzik, M, Sobrido, MJ, Jordanova, A, Schüle, R, Zuchner, S & Faghihi, MA 2019, 'Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia', American journal of human genetics, vol. 104, no. 4, pp. 767-773. https://doi.org/10.1016/j.ajhg.2019.03.001

Farazi Fard, Mohammad Ali ; Rebelo, Adriana P. ; Buglo, Elena ; Nemati, Hamid ; Dastsooz, Hassan ; Gehweiler, Ina ; Reich, Selina ; Reichbauer, Jennifer ; Quintáns, Beatriz ; Ordóñez-Ugalde, Andrés ; Cortese, Andrea ; Courel, Steve ; Abreu, Lisa ; Powell, Eric ; Danzi, Matt ; Martuscelli, Nicole B. ; Bis-Brewer, Dana M. ; Tao, Feifei ; Zarei, Fariba ; Habibzadeh, Parham ; Yavarian, Majid ; Modarresi, Farzaneh ; Silawi, Mohammad ; Tabatabaei, Zahra ; Yousefi, Masoume ; Farpour, Hamid Reza ; Kessler, Christoph ; Mangold, Elisabeth ; Kobeleva, Xenia ; Mueller, Amelie J. ; Haack, Tobias B. ; Tarnopolsky, Mark ; Gan-Or, Ziv ; Rouleau, Guy A. ; Synofzik, Matthis ; Sobrido, María Jesús ; Jordanova, Albena ; Schüle, Rebecca ; Zuchner, Stephan ; Faghihi, Mohammad A. / Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia. In: American journal of human genetics. 2019 ; Vol. 104, No. 4. pp. 767-773.

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title = "Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia",

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",

author = "{Farazi Fard}, {Mohammad Ali} and Rebelo, {Adriana P.} and Elena Buglo and Hamid Nemati and Hassan Dastsooz and Ina Gehweiler and Selina Reich and Jennifer Reichbauer and Beatriz Quint{\'a}ns and Andr{\'e}s Ord{\'o}{\~n}ez-Ugalde and Andrea Cortese and Steve Courel and Lisa Abreu and Eric Powell and Matt Danzi and Martuscelli, {Nicole B.} and Bis-Brewer, {Dana M.} and Feifei Tao and Fariba Zarei and Parham Habibzadeh and Majid Yavarian and Farzaneh Modarresi and Mohammad Silawi and Zahra Tabatabaei and Masoume Yousefi and Farpour, {Hamid Reza} and Christoph Kessler and Elisabeth Mangold and Xenia Kobeleva and Mueller, {Amelie J.} and Haack, {Tobias B.} and Mark Tarnopolsky and Ziv Gan-Or and Rouleau, {Guy A.} and Matthis Synofzik and Sobrido, {Mar{\'i}a Jes{\'u}s} and Albena Jordanova and Rebecca Sch{\"u}le and Stephan Zuchner and Faghihi, {Mohammad A}",

note = "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 f{\"u}r 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 Europ{\'e}en de D{\'e}veloppement {\'E}conomique et R{\'e}gional). 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{\textquoteright}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 f{\"u}r 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 Europ{\'e}en de D{\'e}veloppement {\'E}conomique et R{\'e}gional ). 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: {\textcopyright} 2019",

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doi = "10.1016/j.ajhg.2019.03.001",

language = "English (US)",

volume = "104",

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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

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Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia

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