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

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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 (US)
Journal	Brain : a journal of neurology
DOIs	https://doi.org/10.1093/brain/awaa459
State	Published - Mar 25 2021

ASJC Scopus subject areas

Clinical Neurology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/brain/awaa459

https://repository.kaust.edu.sa/bitstream/10754/668296/1/awaa459.pdf

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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 : a journal of neurology. https://doi.org/10.1093/brain/awaa459

@article{eb6905b5cfed4f8a9cceeeb6b01ce443,

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 = "KAUST Repository Item: Exported on 2021-03-29 Acknowledgements: We are grateful to the families for their participation. We thank the Saudi Human Genome Program, Core Facilities, and Purchasing Departments at King Faisal Specialist Hospital and Research Center (KFSHRC) and special thanks to Mr Faisal Al-Otaibi for quickly handling our orders and requests. Wim Quint and Kirke Tadema (Erasmus MC) are acknowledged for their expertise in OKR analysis.",

year = "2021",

month = mar,

day = "25",

doi = "10.1093/brain/awaa459",

language = "English (US)",

journal = "Brain : a journal of neurology",

issn = "0006-8950",

publisher = "Oxford University Press",

}

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 : a journal of neurology. 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 - KAUST Repository Item: Exported on 2021-03-29 Acknowledgements: We are grateful to the families for their participation. We thank the Saudi Human Genome Program, Core Facilities, and Purchasing Departments at King Faisal Specialist Hospital and Research Center (KFSHRC) and special thanks to Mr Faisal Al-Otaibi for quickly handling our orders and requests. Wim Quint and Kirke Tadema (Erasmus MC) are acknowledged for their expertise in OKR analysis.

PY - 2021/3/25

Y1 - 2021/3/25

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://hdl.handle.net/10754/668296

UR - https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaa459/6187999

U2 - 10.1093/brain/awaa459

DO - 10.1093/brain/awaa459

M3 - Article

C2 - 33764426

SN - 0006-8950

JO - Brain : a journal of neurology

JF - Brain : a journal of neurology

ER -

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

Abstract

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