CMT1B results from mutations in the Myelin Protein Zero (MPZ) gene.  Mutant MPZ causes neuropathy by different mechanisms that depend on the particular mutation.  One frequent mechanism is that the mutant protein is retained in the endoplasmic reticulum (ER) of the cell that makes myelin, the Schwann cell. The ER retention activates a process known as the Unfolded Protein Response (UPR), which alters transcription in the cell, resulting in demyelination.

In 2014, the CMTA funded a project to create reporters of cellular pathways suspected of a causative role in CMT1B. The lab of Dr. James Inglese at the NIH, in collaboration with Dr. Michael Shy’s lab at the University of Iowa and the laboratory of Dr. Lawrence Wrabetz at the University of Buffalo, is working to develop cell-based assays that detect the activation of the UPR.

A CMT1B stem cell effort is also in progress, aimed at determining how many of the mutations in the Myelin Protein Zero (MPZ) gene cause neuropathy. Patient skin cells representing different mutations in MPZ, banked at the University of Iowa, have been sent to the New York Stem Cell Foundation for transformation into induced pluripotent stem cell lines (iPSCs). Future studies with these cells are aimed at further differentiating them into mature Schwann cells that can be used to investigate how correction of the patient defect can be achieved.