Genetic Pioneers at BCM Uncover Triplications in Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth Disease GeneticsMore is not always better, especially when it comes to genes. Genomics pioneer Dr. James Lupski, along with Dr. Pengfei Liu and other members of his laboratory at Baylor College of Medicine in Houston, made new insight on the genetic disorder Charcot-Marie-Tooth (CMT) disease (of which Dr. Lupski found the cause in 1991) and reported the findings in The American Journal of Human Genetics. CMT is a rare genetic disorder usually caused by a 1.4 Mb recurrent duplication of the gene CMT1A, but Dr. Lupski’s new study revealed that sometimes triplications of the CMT1A gene occur, resulting in an overabundance of the CMT protein and a more severe form of the disorder.

Triplications and duplications are not a new concept: fly geneticist Calvin Bridges posited the idea in the 1930s when he found that fruit flies’ eye sizes are reduced when a duplication of a certain chromosome is present; if three sets of the gene exist, then flies’ eyes become even smaller. Further into the future, after Dr. Lupski discovered CMT gene duplications in 1991, he found that “sometimes, in a family, the mother or father is affected and one of the children is affected with more severe symptoms of the disease. We thought it was a normal variation. But when we looked at it carefully, we found that the parent had a duplication and the child had a triplication.”

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When the research team looked at the chromosomes of 20,661 individuals, they identified 2,752 with duplicated CMT1A and five with triplicated CMT1A. This means that triplications occur at a rate as high as ~1:550, even greater than the rate of duplications. The reason there are not more people with triplications than duplications, despite the higher rate, is because a duplication has to occur before a triplication can occur. In scientific terms, “We believe the triplication is formed by a mechanism similar to the one that results in duplication – non-allelic homologous combination,” said Dr. Liu. “We can say that the presence of duplication predisposes the chromosome to triplication. Duplication makes the chromosome unstable.” The chromosomal instability leads to non-allelic homologous replication during meiosis.

Dr. Liu believes their findings show that there may be individuals with four or more copies of the CMT1A gene, and that the triplication principles may apply to other disorders caused by duplications, not just CMT.

CMT is a rare genetic disease with four main variations – CMT1, CMT2, CMTX, and CMT4 – that are categorized based on autosomal dominance. Individuals with CMT have weakness and deterioration of muscles in the lower legs due to an abnormal myelin sheath. Treatment for CMT is symptomatic, and individuals are usually diagnosed using multiplex-ligation-dependent probe amplification, although more sensitive techniques, such as chromosome microarray analysis, might be better for detection of severe forms of the disease.

Funding for this work came from: National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (Grant R01NS058529, Grant R01NS066927; Texas Children’s Hospital General Clinical Research Center (Grant M01RR00188); Intellectual and Developmental Disabilities Research Centers (Grant P30HD024064); Vanderbilt Institute for Clinical and Translational Research fund (Grant VR1687) and Vanderbilt National Center for Advancing Translational Sciences award  (Grant UL1TR000445).

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