Unique Approach Leads to Identifying Gene for Rare Disorder


A Children's Hospital investigator has led a study that used a novel laser microdissection and proteomics approach to identify the gene behind a rare condition that leads to progressive muscular weakness.

Identifying the genes responsible for reducing body myopathy (RBM) through traditional genetic techniques has posed a challenge for investigators because of the rarity of the condition. Although this condition was described more than 30 years ago, the gene that causes RBM had remained elusive because most of the patients found subsequently were "sporadic"-- there were no larger families to use for more conventional linkage analysis to identify the responsible gene.

As a new patient with RBM was diagnosed in the Neuromuscular Program at Children's Hospital by Carsten Bönnemann, M.D., Division of Neurology, Dr. Bönnemann and his colleagues began to consider alternative ways to identify the genes responsible for the debilitating and often fatal condition.

Reducing bodies are aggregates of proteins that progressively form inclusions in the muscle cells, at times leading to rapidly advancing loss of muscle strength. Figuring that knowledge about the major component stored in the inclusions could yield crucial information about the gene underlying RBM, Dr. Bönnemann and his team used an unusual approach to get at this information – laser microdissection of the reducing bodies out of biopsy material followed by proteomic analysis.

Using this approach the research team found that a protein referred to as Four-and-a-Half-LIM-Domain-1 (FHL1) was the predominant component in the aggregates in the COP patient as well as in another patient recently diagnosed at the Unversity of Utah. They went on to show mutations in the FHL1 gene itself lead to RBM in sporadic as well as in additional familial cases. The FHL1 protein is expressed predominantly in skeletal muscle but can also be found in cardiac muscle. The group showed in cell culture that the mutated FHL1 protein is prone to aggregate into conspicuous inclusions, recapitulating what is seen in the muscle from patients.

"We believe this is the first example in which this type of analysis has directly led to the identification of a disease gene," says Dr. Bönnemann, who took full advantage of the advanced technologies offered through the Hospital's Core Facilities to pursue identification of the gene.

Dr. Bönnemann believes the same approach could also prove to be useful in other conditions with prominent intracellular inclusions that are seen in many neurodegenerative disorders.

Joachim Schessl, M.D., and Yaqun Zou, M.D. were Children's Hospital co-authors on the study, which was published in a recent issue of The Journal of Clinical Investigation.