MUTATION AND LOSS OF AMBULATION

Genetic Variant in Duchenne MD Linked to Earlier Loss of Ambulation, Study Finds

The expressivity of Mendelian diseases can be influenced by factors independent from the pathogenic mutation: in Duchenne muscular dystrophy (DMD), for instance, age at loss of ambulation (LoA) varies between individuals whose DMD mutations all abolish dystrophin expression. This suggests the existence of trans-acting variants in modifier genes.

DMD is caused by mutations in the gene that encodes dystrophin, a protein that plays an important role in the proper functioning of muscle cells. However, changes in the coding sequence of certain genes – changes which are called polymorphisms – may influence the development of the disease in patients, and are called disease modifiers.

Previous studies have identified polymorphisms in two genes – SPP1, encoding osteopontin, and LTBP4, encoding TGFβ-binding protein 4 – establishing them as Duchenne MD modifiers. To identify other DMD modifiers that could influence the when ambulation is lost in patients; researchers analyzed the DNA of a group of 109 Duchenne patients with European or European-American ancestry from the Cooperative International Research Group Duchenne Natural History Study. The team focused on 438 polymorphisms in 384 genes previously implicated in DMD.

A minor variant, known as rs1883832, was found on the CD40 gene, which encodes a protein of the immune system. This variant causes a reduction in the expression levels of the protein, altering the function of the immune system. It was associated with an earlier loss of ambulation in patients who carried it.

 

Source : Belo et al., 2016