Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

Leslie E. Sanderson; Kristina Lanko; Maysoon Alsagob; Rawan Almass; Nada Al-Ahmadi; Maryam Najafi; Mohammad A. Al-Muhaizea; Hamad Alzaidan; Hesham Aldhalaan; Elena Perenthaler; Herma C. Van Der Linde; Anita Nikoncuk; Nikolas A. Kühn; Dinu Antony; Tarek Mustafa Owaidah; Salmo Raskin; Luana Gabriela Dalla Rosa Vieira; Romulo Mombach; Najmeh Ahangari; Tainá Regina Damaceno Silveira; Najim Ameziane; Arndt Rolfs; Aljohara Alharbi; Raghda M. Sabbagh; Khalid Alahmadi; Bashayer Alawam; Hazem Ghebeh; Aljouhra Alhargan; Anoud A. Albader; Faisal S. Binhumaid; Ewa Goljan; Dorota Monies; Osama M. Mustafa; Mazhor Aldosary; Albandary Albakheet; Banan Alyounes; Faten Almutairi; Ali Al-Odaib; Durdane Bekar Aksoy; A. Nazli Basak; Robin Palvadeau; Daniah Trabzuni; Jill A. Rosenfeld; Ehsan Ghayoor Karimiani; Brian F. Meyer; Bedri Karakas; Futwan Al-Mohanna; Stefan T. Arold; Dilek Colak; Reza Maroofian; Henry Houlden; Aida M. Bertoli-Avella; Miriam Schmidts; Tahsin Stefan Barakat; Tjakko J. Van Ham; Namik Kaya

doi:10.1093/brain/awaa459

Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

Leslie E. Sanderson, Kristina Lanko, Maysoon Alsagob, Rawan Almass, Nada Al-Ahmadi, Maryam Najafi, Mohammad A. Al-Muhaizea, Hamad Alzaidan, Hesham Aldhalaan, Elena Perenthaler, Herma C. Van Der Linde, Anita Nikoncuk, Nikolas A. Kühn, Dinu Antony, Tarek Mustafa Owaidah, Salmo Raskin, Luana Gabriela Dalla Rosa Vieira, Romulo Mombach, Najmeh Ahangari, Tainá Regina Damaceno SilveiraNajim Ameziane, Arndt Rolfs, Aljohara Alharbi, Raghda M. Sabbagh, Khalid Alahmadi, Bashayer Alawam, Hazem Ghebeh, Aljouhra Alhargan, Anoud A. Albader, Faisal S. Binhumaid, Ewa Goljan, Dorota Monies, Osama M. Mustafa, Mazhor Aldosary, Albandary Albakheet, Banan Alyounes, Faten Almutairi, Ali Al-Odaib, Durdane Bekar Aksoy, A. Nazli Basak, Robin Palvadeau, Daniah Trabzuni, Jill A. Rosenfeld, Ehsan Ghayoor Karimiani, Brian F. Meyer, Bedri Karakas, Futwan Al-Mohanna, Stefan T. Arold, Dilek Colak, Reza Maroofian, Henry Houlden, Aida M. Bertoli-Avella, Miriam Schmidts, Tahsin Stefan Barakat, Tjakko J. Van Ham^*, Namik Kaya

^*Corresponding author for this work

Clinical Genetics

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Abstract

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.

Original language	English
Pages (from-to)	769-780
Number of pages	12
Journal	Brain
Volume	144
Issue number	3
DOIs	https://doi.org/10.1093/brain/awaa459
Publication status	Published - 1 Mar 2021

Bibliographical note

Funding:
N.K. is supported through intramural funds from King Faisal Specialist Hospital and Research Centre, and grants from King Salman Center for Disability Research and NSTIP/King Abdulaziz City for Science and Technology (2180004, 2180022, 2120022, 14-MED2007-20). S.T.A. was supported by King Abdullah University of Science and Technology, Office of Sponsored Research, award number FCC/1/1976-25. D.C. is supported by KFSHRC Research grant (RAC#2110006). D.C. has received funds from NSTIP/KACST (11-BIO2072-20). T.S.B. is supported by the Netherlands Organisation for Scientific Research (ZonMW Veni, grant 91617021), a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. T.V.H. is supported by an Erasmus University Rotterdam (EUR) fellowship. L.S. is supported by a LEaDing fellowship from the European Union’s Horizon 2020 research and innovation programme, under the Marie Skłodowska-Curie grant agreement No 707404. M.S. acknowledges funding from the “Deutsche Forschungsgemeinschaft” (DFG CRC1140 KIDGEM and SFB1453 NEPHGEN) and the European Research Council (ERC StG TREATCilia, grant No 716344). A.N.B. is supported by the Suna and Inan Kirac Foundation and Koc University- KUTTAM. The views expressed are those of the author(s) and not necessarily those of the funding agencies. B.F.M. acknowledges fund from NTSIP/ King Abdulaziz City for Science and Technology (08-MED499-20).

Publisher Copyright: © 2021 The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.

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Sanderson, L. E., Lanko, K., Alsagob, M., Almass, R., Al-Ahmadi, N., Najafi, M., Al-Muhaizea, M. A., Alzaidan, H., Aldhalaan, H., Perenthaler, E., Van Der Linde, H. C., Nikoncuk, A., Kühn, N. A., Antony, D., Owaidah, T. M., Raskin, S., Vieira, L. G. D. R., Mombach, R., Ahangari, N., ... Kaya, N. (2021). Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking. Brain, 144(3), 769-780. https://doi.org/10.1093/brain/awaa459

@article{e4916caa59094a698c0c11eb8621c0a0,

title = "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking",

abstract = "Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.",

author = "Sanderson, {Leslie E.} and Kristina Lanko and Maysoon Alsagob and Rawan Almass and Nada Al-Ahmadi and Maryam Najafi and Al-Muhaizea, {Mohammad A.} and Hamad Alzaidan and Hesham Aldhalaan and Elena Perenthaler and {Van Der Linde}, {Herma C.} and Anita Nikoncuk and K{\"u}hn, {Nikolas A.} and Dinu Antony and Owaidah, {Tarek Mustafa} and Salmo Raskin and Vieira, {Luana Gabriela Dalla Rosa} and Romulo Mombach and Najmeh Ahangari and Silveira, {Tain{\'a} Regina Damaceno} and Najim Ameziane and Arndt Rolfs and Aljohara Alharbi and Sabbagh, {Raghda M.} and Khalid Alahmadi and Bashayer Alawam and Hazem Ghebeh and Aljouhra Alhargan and Albader, {Anoud A.} and Binhumaid, {Faisal S.} and Ewa Goljan and Dorota Monies and Mustafa, {Osama M.} and Mazhor Aldosary and Albandary Albakheet and Banan Alyounes and Faten Almutairi and Ali Al-Odaib and Aksoy, {Durdane Bekar} and Basak, {A. Nazli} and Robin Palvadeau and Daniah Trabzuni and Rosenfeld, {Jill A.} and Karimiani, {Ehsan Ghayoor} and Meyer, {Brian F.} and Bedri Karakas and Futwan Al-Mohanna and Arold, {Stefan T.} and Dilek Colak and Reza Maroofian and Henry Houlden and Bertoli-Avella, {Aida M.} and Miriam Schmidts and Barakat, {Tahsin Stefan} and {Van Ham}, {Tjakko J.} and Namik Kaya",

note = "Funding: N.K. is supported through intramural funds from King Faisal Specialist Hospital and Research Centre, and grants from King Salman Center for Disability Research and NSTIP/King Abdulaziz City for Science and Technology (2180004, 2180022, 2120022, 14-MED2007-20). S.T.A. was supported by King Abdullah University of Science and Technology, Office of Sponsored Research, award number FCC/1/1976-25. D.C. is supported by KFSHRC Research grant (RAC#2110006). D.C. has received funds from NSTIP/KACST (11-BIO2072-20). T.S.B. is supported by the Netherlands Organisation for Scientific Research (ZonMW Veni, grant 91617021), a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. T.V.H. is supported by an Erasmus University Rotterdam (EUR) fellowship. L.S. is supported by a LEaDing fellowship from the European Union{\textquoteright}s Horizon 2020 research and innovation programme, under the Marie Sk{\l}odowska-Curie grant agreement No 707404. M.S. acknowledges funding from the “Deutsche Forschungsgemeinschaft” (DFG CRC1140 KIDGEM and SFB1453 NEPHGEN) and the European Research Council (ERC StG TREATCilia, grant No 716344). A.N.B. is supported by the Suna and Inan Kirac Foundation and Koc University- KUTTAM. The views expressed are those of the author(s) and not necessarily those of the funding agencies. B.F.M. acknowledges fund from NTSIP/ King Abdulaziz City for Science and Technology (08-MED499-20). Publisher Copyright: {\textcopyright} 2021 The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.",

year = "2021",

month = mar,

day = "1",

doi = "10.1093/brain/awaa459",

language = "English",

volume = "144",

pages = "769--780",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

number = "3",

}

Sanderson, LE , Lanko, K, Alsagob, M, Almass, R, Al-Ahmadi, N, Najafi, M, Al-Muhaizea, MA, Alzaidan, H, Aldhalaan, H, Perenthaler, E, Van Der Linde, HC, Nikoncuk, A, Kühn, NA, Antony, D, Owaidah, TM, Raskin, S, Vieira, LGDR, Mombach, R, Ahangari, N, Silveira, TRD, Ameziane, N, Rolfs, A, Alharbi, A, Sabbagh, RM, Alahmadi, K, Alawam, B, Ghebeh, H, Alhargan, A, Albader, AA, Binhumaid, FS, Goljan, E, Monies, D, Mustafa, OM, Aldosary, M, Albakheet, A, Alyounes, B, Almutairi, F, Al-Odaib, A, Aksoy, DB, Basak, AN, Palvadeau, R, Trabzuni, D, Rosenfeld, JA, Karimiani, EG, Meyer, BF, Karakas, B, Al-Mohanna, F, Arold, ST, Colak, D, Maroofian, R, Houlden, H, Bertoli-Avella, AM, Schmidts, M, Barakat, TS , Van Ham, TJ & Kaya, N 2021, 'Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking', Brain, vol. 144, no. 3, pp. 769-780. https://doi.org/10.1093/brain/awaa459

TY - JOUR

T1 - Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

AU - Sanderson, Leslie E.

AU - Lanko, Kristina

AU - Alsagob, Maysoon

AU - Almass, Rawan

AU - Al-Ahmadi, Nada

AU - Najafi, Maryam

AU - Al-Muhaizea, Mohammad A.

AU - Alzaidan, Hamad

AU - Aldhalaan, Hesham

AU - Perenthaler, Elena

AU - Van Der Linde, Herma C.

AU - Nikoncuk, Anita

AU - Kühn, Nikolas A.

AU - Antony, Dinu

AU - Owaidah, Tarek Mustafa

AU - Raskin, Salmo

AU - Vieira, Luana Gabriela Dalla Rosa

AU - Mombach, Romulo

AU - Ahangari, Najmeh

AU - Silveira, Tainá Regina Damaceno

AU - Ameziane, Najim

AU - Rolfs, Arndt

AU - Alharbi, Aljohara

AU - Sabbagh, Raghda M.

AU - Alahmadi, Khalid

AU - Alawam, Bashayer

AU - Ghebeh, Hazem

AU - Alhargan, Aljouhra

AU - Albader, Anoud A.

AU - Binhumaid, Faisal S.

AU - Goljan, Ewa

AU - Monies, Dorota

AU - Mustafa, Osama M.

AU - Aldosary, Mazhor

AU - Albakheet, Albandary

AU - Alyounes, Banan

AU - Almutairi, Faten

AU - Al-Odaib, Ali

AU - Aksoy, Durdane Bekar

AU - Basak, A. Nazli

AU - Palvadeau, Robin

AU - Trabzuni, Daniah

AU - Rosenfeld, Jill A.

AU - Karimiani, Ehsan Ghayoor

AU - Meyer, Brian F.

AU - Karakas, Bedri

AU - Al-Mohanna, Futwan

AU - Arold, Stefan T.

AU - Colak, Dilek

AU - Maroofian, Reza

AU - Houlden, Henry

AU - Bertoli-Avella, Aida M.

AU - Schmidts, Miriam

AU - Barakat, Tahsin Stefan

AU - Van Ham, Tjakko J.

AU - Kaya, Namik

N1 - Funding: N.K. is supported through intramural funds from King Faisal Specialist Hospital and Research Centre, and grants from King Salman Center for Disability Research and NSTIP/King Abdulaziz City for Science and Technology (2180004, 2180022, 2120022, 14-MED2007-20). S.T.A. was supported by King Abdullah University of Science and Technology, Office of Sponsored Research, award number FCC/1/1976-25. D.C. is supported by KFSHRC Research grant (RAC#2110006). D.C. has received funds from NSTIP/KACST (11-BIO2072-20). T.S.B. is supported by the Netherlands Organisation for Scientific Research (ZonMW Veni, grant 91617021), a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. T.V.H. is supported by an Erasmus University Rotterdam (EUR) fellowship. L.S. is supported by a LEaDing fellowship from the European Union’s Horizon 2020 research and innovation programme, under the Marie Skłodowska-Curie grant agreement No 707404. M.S. acknowledges funding from the “Deutsche Forschungsgemeinschaft” (DFG CRC1140 KIDGEM and SFB1453 NEPHGEN) and the European Research Council (ERC StG TREATCilia, grant No 716344). A.N.B. is supported by the Suna and Inan Kirac Foundation and Koc University- KUTTAM. The views expressed are those of the author(s) and not necessarily those of the funding agencies. B.F.M. acknowledges fund from NTSIP/ King Abdulaziz City for Science and Technology (08-MED499-20). Publisher Copyright: © 2021 The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.

PY - 2021/3/1

Y1 - 2021/3/1

N2 - Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.

AB - Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.

UR - http://www.scopus.com/inward/record.url?scp=85104275765&partnerID=8YFLogxK

U2 - 10.1093/brain/awaa459

DO - 10.1093/brain/awaa459

M3 - Article

C2 - 33764426

AN - SCOPUS:85104275765

SN - 0006-8950

VL - 144

SP - 769

EP - 780

JO - Brain

JF - Brain

IS - 3

ER -

Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

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