TY - JOUR
T1 - Characterizing the molecular phenotype of an Atp7a(T985I) conditional knock in mouse model for X-linked distal hereditary motor neuropathy (dHMNX)
AU - Perez-Siles, Gonzalo
AU - Grant, Adrienne
AU - Ellis, Melina
AU - Ly, Carolyn
AU - Kidambi, Aditi
AU - Khalil, Mamdouh
AU - Llanos, Roxana M.
AU - Fontaine, Sharon La
AU - Strickland, Alleene V.
AU - Züchner, Stephan
AU - Bermeo, Sandra
AU - Neist, Elysia
AU - Brennan-Speranza, Tara C.
AU - Takata, Reinaldo I.
AU - Speck-Martins, Carlos E.
AU - Mercer, Julian F B
AU - Nicholson, Garth A.
AU - Kennerson, Marina L.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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 Atp7aT985I, the orthologue of the human ATP7AT994I identified in dHMNX patients. Although a degenerative motor phenotype is not observed, the knock in Atp7aT985I/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. Atp7aT985I/Y mice have reduced Atp7a protein levels and recapitulate the defective trafficking and altered post-translational regulatory mechanisms observed in the human ATP7AT994I 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.
AB - 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 Atp7aT985I, the orthologue of the human ATP7AT994I identified in dHMNX patients. Although a degenerative motor phenotype is not observed, the knock in Atp7aT985I/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. Atp7aT985I/Y mice have reduced Atp7a protein levels and recapitulate the defective trafficking and altered post-translational regulatory mechanisms observed in the human ATP7AT994I 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.
UR - http://www.scopus.com/inward/record.url?scp=84988360214&partnerID=8YFLogxK
U2 - 10.1039/c6mt00082g
DO - 10.1039/c6mt00082g
M3 - Article
C2 - 27293072
AN - SCOPUS:84988360214
SN - 1756-5901
VL - 8
SP - 981
EP - 992
JO - Metallomics
JF - Metallomics
IS - 9
ER -