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Modelling the pathogenesis of X-linked distal hereditary motor neuropathy using patient-derived iPSCs.

ABSTRACT: ATP7A encodes a copper-transporting P-type ATPase and is one of 23 genes in which mutations produce distal hereditary motor neuropathy (dHMN), a group of diseases characterized by length-dependent axonal degeneration of motor neurons. We have generated induced pluripotent stem cell (iPSC)-derived motor neurons from a patient with the p.T994I ATP7A gene mutation as an in vitro model for X-linked dHMN (dHMNX). Patient motor neurons show a marked reduction of ATP7A protein levels in the soma when compared to control motor neurons and failed to upregulate expression of ATP7A under copper-loading conditions. These results recapitulate previous findings obtained in dHMNX patient fibroblasts and in primary cells from a rodent model of dHMNX, indicating that patient iPSC-derived motor neurons will be an important resource for studying the role of copper in the pathogenic processes that lead to axonal degeneration in dHMNX.

SUBMITTER: Perez-Siles G 

PROVIDER: S-EPMC6994953 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Modelling the pathogenesis of X-linked distal hereditary motor neuropathy using patient-derived iPSCs.

Perez-Siles Gonzalo G   Cutrupi Anthony A   Ellis Melina M   Kuriakose Jakob J   La Fontaine Sharon S   Mao Di D   Uesugi Motonari M   Takata Reinaldo I RI   Speck-Martins Carlos E CE   Nicholson Garth G   Kennerson Marina L ML  

Disease models & mechanisms 20200113 2

<i>ATP7A</i> encodes a copper-transporting P-type ATPase and is one of 23 genes in which mutations produce distal hereditary motor neuropathy (dHMN), a group of diseases characterized by length-dependent axonal degeneration of motor neurons. We have generated induced pluripotent stem cell (iPSC)-derived motor neurons from a patient with the p.T994I <i>ATP7A</i> gene mutation as an <i>in vitro</i> model for X-linked dHMN (dHMNX). Patient motor neurons show a marked reduction of ATP7A protein leve  ...[more]

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