Exploring the Pathophysiology of CMT1G

“Exploringthe pathophysiology of CMT1G”
Charcot-Marie-Tooth
126,000
disease (CMT) is the most common inherited neurological disorders, affecting an estimated
individuals in the U.S. and 2.6 million people worldwide. CMT affects both sensory and motor nerves
in the peripheral nervous system. In patients with CMT, peripheral nerves slowly degenerate resulting in muscle
weakness and atrophy in the limbs as well as neuropathic pain. There is no cure for CMT, but physical and
occupational therapies, braces and other orthopedic devices, and orthopedic surgery may help with the disabling
symptoms of the disease. In addition, pain-relief drugs can be prescribed for severe nerve pain.
One subtype of CMT, CMT1G, is caused by dominant mutations in the Pmp2 gene, , encoding for a fatty
acid chaperone specifically expressed in Schwann cells, including the in-frame deletion (p.Ile50del) which was
associated to a severe and early onset demyelinating CMT1 disease.
In this project, we propose to examine how the mutation (p.Ile50del) in Pmp2 mouse gene causes a
demyelinating CMT1 disease. We will use CRISPR/Cas9 technology to generate a faithful knock-in mouse
model of CMT1G. We will then investigate two possible pathological gain-of-function. First, , like in some other
CMTs, CMT1G-related mutations could lead to aberrant protein folding, stability and localization of PMP2 and
be detrimental to Schwann cell functions. Second, we will investigate the possibility that the Pmp2 p.Ile50del
mutation alters the fatty acid chaperone function of PMP2 and impair fatty acid uptake in Schwann cells, limiting
myelin biosynthesis.
Determining whether the in-frame deletion mutation (p.Ile50del) alters PMP2 folding, stability, fatty acid
binding properties, fatty acid uptake and myelin lipid biosynthesis will further our understanding of the molecular
dysregulation associated to PMP2 mutations in CMT1G and offer core foundation for future investigations to test
the direct effect of those molecular dysregulations in the pathophysiology of CMT1G.

Grant Number: 5R03NS136069-02
NIH Institute/Center: NIH
Principal Investigator: SOPHIE BELIN