Study Reports Newly Identified CMT1X-Causing Gene Mutations

Four new mutations in the gene GJB1 have been identified, joining the growing list of mutations that can cause Charcot-Marie-Tooth disease (CMT).

The study, titled “New novel mutations in Brazilian families with X-linked Charcot-Marie-Tooth disease,” was published in the Journal of the Peripheral Nervous System.

CMT can be caused by mutations in over 90 known genes. The most common subtype is CMT1A, caused by alterations in the gene PMP22. The second-most common subtype is CMT1X, caused by mutations in the gene GJB1. More than 420 mutations in this gene have been described.

In this study, 12 CMT patients at the Hospital das Clínicas, Ribeirão Preto Medical School, University of São Paulo neurogenetics clinic, from five separate families, were included. The researchers noted that “all affected patients had the usual clinical and neurophysiological pattern,” though patients also tended to have “mild to moderate” disease, based on CMTNS disease scores.

The patients’ GJB1 genes were sequenced, and five mutations were identified. One of these was determined to be likely benign (i.e. not causing disease), but the other four were deemed likely causes of disease.

These four mutations are c.287C>T (p.A96V), c.431T>G (p.L144W), c.494T>A (p.L165Q), and c.578T>C (p.F193S). The first number/letter combination (c) indicates the specific substitution in the DNA sequence; the following number/letter combination in parentheses (p) indicates the corresponding protein-level change.

A few lines of evidence support the conclusion that these mutations cause CMT. First, in a cohort of 100 Brazilians without CMT tested as controls, none were detected. Additionally, males tended to be more severely affected than females, and affected males did not have affected male children.

This makes sense due to the GJB1 gene’s location on the X chromosome and a phenomenon called chromosome-X inactivation. Females have two copies of this chromosome (one from each parent); males have one X chromosome and one Y chromosome. So not only would males be expected to be more affected, as they have only one copy of the gene, but males also wouldn’t be able to pass on the disease to male children, as they would be passing on their Y chromosome instead.

The investigators concluded, “We described four novel GJB1 mutations in patients with CMTX1 in a Brazilian cohort of CMT cases, thereby increasing the already enormous [genetic] variability associated with this gene.”