(Editor’s Note: The following is a summary of an abstract originally published in The American Journal of Human Genetics)
Neurological disorders such as Alzheimer’s, Parkinson’s and Lou Gehrig’s disease may share a common gene. Researchers identified the gene while conducting studies on the disorder Charcot-Marie-Tooth disease, (CMT). This is one of the most commonly inherited conditions in humans, where gene defects affect peripheral nerves, leading to progressive weakness and atrophy of muscles.
The gene is responsible for neurofilament light, a protein essential to the structure and function of nerve cell processes. Knowledge of this gene, as well as three other genes already known to be involved in CMT, lends important insight into the workings of the peripheral nervous system. By understanding the mutations in CMT-causing genes, scientists also hope to gain a similar understanding of disorders like Alzheimer’s disease, which share this genetic link.
Charcot-Marie-Tooth (CMT) disease is the most common inherited motor and sensory neuropathy. The axonal form of the disease is designated as “CMT type 2” (CMT2). Although four loci known to be implicated in autosomal dominant CMT2 have been mapped thus far (on 1p35-p36, 3q13.1, 3q13-q22, and 7p14), no one causative gene is yet known. A large Russian family with CMT2 was found in the Mordovian Republic (Russia). Affected members had the typical CMT2 phenotype. Additionally, several patients suffered from hyperkeratosis, although the association, if any, between the two disorders is not clear. Linkage with the CMT loci already known (CMT1A, CMT1B, CMT2A, CMT2B, CMT2D, and a number of other CMT-related loci) was excluded. Genomewide screening pinpointed the disease locus in this family to chromosome 8p21, within a 16-cM interval between markers D8S136 and D8S1769. A maximum two-point LOD score of 5.93 was yielded by a microsatellite from the 5 region of the neurofilament-light gene (NF-L). Neurofilament proteins play an important role in axonal structure and are implicated in several neuronal disorders. Screening of affected family members for mutations in the NF-L gene and in the tightly linked neurofilament-medium gene (NF-M) revealed the only DNA alteration linked with the disease: a A998C transversion in the first exon of NF-L, which converts a conserved Gln333 amino acid to proline. This alteration was not found in 180 normal chromosomes. Twenty unrelated CMT2 patients, as well as 26 others with an undetermined form of CMT, also were screened for mutations in NF-L, but no additional mutations were found. It is suggested that Gln333Pro represents a rare disease-causing mutation, which results in the CMT2 phenotype.