Characterizing the molecular phenotype of an Atp7a(T985I) conditional knock in mouse model for X-linked distal hereditary motor neuropathy (dHMNX)

Perez-Siles, Gonzalo, Grant, Adrienne, Ellis, Melina, Ly, Carolyn, Kidambi, Aditi, Khalil, Mamdouh, Llanos, Roxana M., La Fontaine, Sharon, Strickland, Alleene V., Züchner, Stephan, Bermeo, Sandra, Neist, Elysia, Brennan-Speranza, Tara C., Takata, Reinaldo I., Speck-Martins, Carlos E., Mercer, Julian F., Nicholson, Garth A. and Kennerson, Marina L. 2016, Characterizing the molecular phenotype of an Atp7a(T985I) conditional knock in mouse model for X-linked distal hereditary motor neuropathy (dHMNX), Metallomics: integrated biometal science, no. 9, pp. 981-992, doi: 10.1039/c6mt00082g.

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Title Characterizing the molecular phenotype of an Atp7a(T985I) conditional knock in mouse model for X-linked distal hereditary motor neuropathy (dHMNX)
Author(s) Perez-Siles, Gonzalo
Grant, Adrienne
Ellis, Melina
Ly, Carolyn
Kidambi, Aditi
Khalil, Mamdouh
Llanos, Roxana M.
La Fontaine, SharonORCID iD for La Fontaine, Sharon orcid.org/0000-0002-9948-074X
Strickland, Alleene V.
Züchner, Stephan
Bermeo, Sandra
Neist, Elysia
Brennan-Speranza, Tara C.
Takata, Reinaldo I.
Speck-Martins, Carlos E.
Mercer, Julian F.
Nicholson, Garth A.
Kennerson, Marina L.
Journal name Metallomics: integrated biometal science
Issue number 9
Start page 981
End page 992
Total pages 12
Publisher Royal Society of Chemistry
Place of publication Cambridge, Eng.
Publication date 2016-09-01
ISSN 1756-591X
Summary ATP7A is a P-type ATPase essential for cellular copper (Cu) transport and homeostasis. Loss-of-function ATP7A mutations causing systemic Cu deficiency are associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome. We previously identified two rare ATP7A missense mutations (P1386S and T994I) leading to a non-fatal form of motor neuron disorder, X-linked distal hereditary motor neuropathy (dHMNX), without overt signs of systemic Cu deficiency. Recent investigations using a tissue specific Atp7a knock out model have demonstrated that Cu plays an essential role in motor neuron maintenance and function, however the underlying pathogenic mechanisms of ATP7A mutations causing axonal degeneration remain unknown. We have generated an Atp7a conditional knock in mouse model of dHMNX expressing Atp7a(T985I), the orthologue of the human ATP7A(T994I) identified in dHMNX patients. Although a degenerative motor phenotype is not observed, the knock in Atp7a(T985I/Y) mice show altered Cu levels within the peripheral and central nervous systems, an increased diameter of the muscle fibres and altered myogenin and myostatin gene expression. Atp7a(T985I/Y) mice have reduced Atp7a protein levels and recapitulate the defective trafficking and altered post-translational regulatory mechanisms observed in the human ATP7A(T994I) patient fibroblasts. Our model provides a unique opportunity to characterise the molecular phenotype of dHMNX and the time course of cellular events leading to the process of axonal degeneration in this disease.
Language eng
DOI 10.1039/c6mt00082g
Field of Research 060802 Animal Cell and Molecular Biology
111699 Medical Physiology not elsewhere classified
Socio Economic Objective 970106 Expanding Knowledge in the Biological Sciences
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2016, Royal Society of Chemistry
Persistent URL http://hdl.handle.net/10536/DRO/DU:30084776

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