Multiple sclerosis severity variant in DYSF-ZNF638 locus associates with neuronal loss and inflammation

Hendrik J. Engelenburg; Aletta M.R. van den Bosch; J. Q.Alida Chen; Cheng Chih Hsiao; Marie José Melief; Adil Harroud; Inge Huitinga; Jörg Hamann; Joost Smolders

doi:10.1016/j.isci.2025.112430

Multiple sclerosis severity variant in DYSF-ZNF638 locus associates with neuronal loss and inflammation

Hendrik J. Engelenburg^*, Aletta M.R. van den Bosch, J. Q.Alida Chen, Cheng Chih Hsiao, Marie José Melief, Adil Harroud, Inge Huitinga, Jörg Hamann, Joost Smolders^*

^*Corresponding author for this work

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Abstract

The genetic variant rs10191329^AA has been identified to associate with faster disability accrual in multiple sclerosis (MS). We investigated the impact of rs10191329^AA carriership on MS pathology and flanking genes dysferlin (DYSF) and zinc finger protein 638 (ZNF638) in the Netherlands Brain Bank cohort (n = 290) by comparing rs10191329^AA (n = 6) to matched rs10191329^CC carriers (n = 12). rs10191329^AA carriership associated with more acute axonal stress, reduced layer 2 neuronal density, and a higher proportion of lesions with foamy microglia. In rs10191329^AA donors, normal appearing white matter was characterized by a higher proportion of ZNF638⁺ oligodendrocytes, and normal appearing gray matter showed more DYSF⁺ cells. Nuclear RNA sequencing showed an upregulation of mitochondrial genes in rs10191329^AA carriers. These data suggest that MS severity associates with an increased susceptibility to neurodegeneration and chronic inflammation. Understanding the role of DYSF, ZNF638, and mitochondrial pathways may reveal new therapeutic targets to attenuate MS progression.

Original language	English
Article number	112430
Journal	iScience
Volume	28
Issue number	5
DOIs	https://doi.org/10.1016/j.isci.2025.112430
Publication status	Published - 16 May 2025

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Multiple sclerosis severity variant in DYSF-ZNF638 locus associates with neuronal loss and inflammationFinal published version, 13.7 MBLicence: CC BY

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title = "Multiple sclerosis severity variant in DYSF-ZNF638 locus associates with neuronal loss and inflammation",

abstract = "The genetic variant rs10191329AA has been identified to associate with faster disability accrual in multiple sclerosis (MS). We investigated the impact of rs10191329AA carriership on MS pathology and flanking genes dysferlin (DYSF) and zinc finger protein 638 (ZNF638) in the Netherlands Brain Bank cohort (n = 290) by comparing rs10191329AA (n = 6) to matched rs10191329CC carriers (n = 12). rs10191329AA carriership associated with more acute axonal stress, reduced layer 2 neuronal density, and a higher proportion of lesions with foamy microglia. In rs10191329AA donors, normal appearing white matter was characterized by a higher proportion of ZNF638+ oligodendrocytes, and normal appearing gray matter showed more DYSF+ cells. Nuclear RNA sequencing showed an upregulation of mitochondrial genes in rs10191329AA carriers. These data suggest that MS severity associates with an increased susceptibility to neurodegeneration and chronic inflammation. Understanding the role of DYSF, ZNF638, and mitochondrial pathways may reveal new therapeutic targets to attenuate MS progression.",

author = "Engelenburg, {Hendrik J.} and {van den Bosch}, {Aletta M.R.} and Chen, {J. Q.Alida} and Hsiao, {Cheng Chih} and Melief, {Marie Jos{\'e}} and Adil Harroud and Inge Huitinga and J{\"o}rg Hamann and Joost Smolders",

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year = "2025",

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doi = "10.1016/j.isci.2025.112430",

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T1 - Multiple sclerosis severity variant in DYSF-ZNF638 locus associates with neuronal loss and inflammation

AU - Engelenburg, Hendrik J.

AU - van den Bosch, Aletta M.R.

AU - Chen, J. Q.Alida

AU - Hsiao, Cheng Chih

AU - Melief, Marie José

AU - Harroud, Adil

AU - Huitinga, Inge

AU - Hamann, Jörg

AU - Smolders, Joost

PY - 2025/5/16

Y1 - 2025/5/16

N2 - The genetic variant rs10191329AA has been identified to associate with faster disability accrual in multiple sclerosis (MS). We investigated the impact of rs10191329AA carriership on MS pathology and flanking genes dysferlin (DYSF) and zinc finger protein 638 (ZNF638) in the Netherlands Brain Bank cohort (n = 290) by comparing rs10191329AA (n = 6) to matched rs10191329CC carriers (n = 12). rs10191329AA carriership associated with more acute axonal stress, reduced layer 2 neuronal density, and a higher proportion of lesions with foamy microglia. In rs10191329AA donors, normal appearing white matter was characterized by a higher proportion of ZNF638+ oligodendrocytes, and normal appearing gray matter showed more DYSF+ cells. Nuclear RNA sequencing showed an upregulation of mitochondrial genes in rs10191329AA carriers. These data suggest that MS severity associates with an increased susceptibility to neurodegeneration and chronic inflammation. Understanding the role of DYSF, ZNF638, and mitochondrial pathways may reveal new therapeutic targets to attenuate MS progression.

AB - The genetic variant rs10191329AA has been identified to associate with faster disability accrual in multiple sclerosis (MS). We investigated the impact of rs10191329AA carriership on MS pathology and flanking genes dysferlin (DYSF) and zinc finger protein 638 (ZNF638) in the Netherlands Brain Bank cohort (n = 290) by comparing rs10191329AA (n = 6) to matched rs10191329CC carriers (n = 12). rs10191329AA carriership associated with more acute axonal stress, reduced layer 2 neuronal density, and a higher proportion of lesions with foamy microglia. In rs10191329AA donors, normal appearing white matter was characterized by a higher proportion of ZNF638+ oligodendrocytes, and normal appearing gray matter showed more DYSF+ cells. Nuclear RNA sequencing showed an upregulation of mitochondrial genes in rs10191329AA carriers. These data suggest that MS severity associates with an increased susceptibility to neurodegeneration and chronic inflammation. Understanding the role of DYSF, ZNF638, and mitochondrial pathways may reveal new therapeutic targets to attenuate MS progression.

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DO - 10.1016/j.isci.2025.112430

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JO - iScience

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Multiple sclerosis severity variant in DYSF-ZNF638 locus associates with neuronal loss and inflammation

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