Researchers identify second gene responsible for rare syndrome associated with skeletal defects

UT Southwestern Medical Center at Dallas researchers have discovered a second gene responsible for a rare syndrome that causes the loss of bone from the lower jaw, fingers, toes and collarbone.

The researchers isolated the gene, zinc metalloproteinase (ZMPSTE24), in a patient who had all of the classic characteristics of mandibuloacral dysplasia (MAD) but did not have a mutation in the LMNA gene, previously reported as a cause of the disorder.

In addition to causing MAD, mutations in this newly discovered gene may also lead to progeroid features, or premature aging, generalized loss of body fat and early death, the researchers report. The study appears in today’s publication of the journal Human Molecular Genetics and also is available online.

“It was known that a mutation in LMNA caused MAD, but in several of the individuals that we studied LMNA was normal,” said Dr. Abhimanyu Garg, professor of internal medicine and the study’s senior author. “This led us to look at other genes that were associated with lamin A production. We considered ZMPSTE24 as a candidate gene based on recent reports that deletion of this gene in mice resulted in the development of similar physical features of the human form of MAD.”

The LMNA gene encodes two proteins, lamin A and lamin C, which are components of the membrane of the cell nucleus. The zinc metalloproteinase enzyme is essential for producing the active form of lamin A. Besides MAD, LMNA mutations are linked to several conditions including a body-fat disorder called familial partial lipodystrophy, muscular dystrophy, cardiomyopathy and a premature aging disorder called progeria.

“It is likely that minor changes in these genes may predispose individuals to premature aging, a change of body-fat distribution, as well as osteoporosis,” said Dr. Garg.

The researchers studied six individuals with MAD and found a mutation in LMNA in two. Of the remaining four individuals, who did not have a mutation in the LMNA gene, one was found to have mutations in ZMPSTE24. Dr. Garg is currently searching for mutations in other genes that are involved in processing of lamin A in three of the patients who did not have mutations in either LMNA or ZMPSTE24.

Other researchers contributing to the study were Dr. Anil Agarwal, assistant professor of internal medicine and lead author of the study, and Dr. Richard Auchus, assistant professor of internal medicine, both from UT Southwestern; and a scientist from the University Hospital of Leuven in Belgium.

The study was funded by the National Institutes of Health and Southwestern Medical Foundation.