CMT 1B: Early Onset: CHOP deletion does not mitigate the phenotype of the PO R98

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(Oral presentation at Antwerp Consortium July 2009)

CHOP deletion does not mitigate the phenotype of the PO R98C knockin mouse model

of early-onset CMT lB.

M.A. Saporta1, B.R. Shy1, M. Pennuto2

, C. Southwood3

, A. Gow3

, C. Ferri2

, M.L. Feltri2

M.N. Crowther4

, D.A. Kirschner4

, L. Wrabetz2 and M.E. Shy

'Department of Neurology, Wayne State University, Detroit, MI, USA; 'San

Raffaele Scientific Institute, DlBIT, Milano, Italy; 'Department of Pediatrics,

Wayne State University, Detroit, MI, USA; 'Biology Department, Boston College,

Chestnut Hill, MA, USA

Background: R98C knockin mice are an authentic model of early onset CMT IB, an

inhehited neuropathy associated with mutations in the myelin protein zero (mpz)

gene. Previous studies have demonstrated that the mutated protein is retained in

the endoplasmatic

reticulum of Schwann cells, raising the possibility that UPR activation may play

an important role in the toxic gain of function associated with this condition.

MethodslMaterials: To study the influence of the transcription factor CHOP, an

UPRmediator, in the phenotype of the R98C mice, we cross bred this colony with

Chop null mice. The phenotype of the resulting strain was characterized by nerve

conduction studies and

morphometric and ultrastctural analysis. Further characterization, including

molecular and X-ray diffraction analysis, is underway

Results: The clinical phenotype of PO R98C heterozygous and homozygous animals

was not modified by ablation of CHOP and nerve conduction velocities were

similar to what was previously described in the original R98C model (wild type:

274 mis, heterozygous: 15 mis,

homozygous: 4.7 mls). Futhermore, morphological analysis also replicated the

R98C pathological findings, namely abnormaily thin myelin in heterozygous

animals and severe dysmyelination in homozygous mice.

Conclusions Relevance: Despite its beneficial effects in the PO S63del mouse,

another model of early onset CMT 1B, CHOP ablation did not influence the

clinical, neurophysiological or pathological phenotype of the PO R98C knockin

model, suggesting that

other pathways likely play a role in the toxic gain of function seen in this

model of CMT lB.

Further investigation aiming to better characterize the UPR response and

apoptosis in CHOP knockout animals is underway.