Diabetes-associated fat disorder traced to genetic mutation

Canadian researchers have discovered that Dunnigan-type familial partial lipodystrophy (FPLD), a body-fat disorder that often leads to diabetes, is caused by a mutation of the lamin gene (LMNA) on human chromosome 1q21-22. FIGURE

Figure. Schematic diagram of the human lamin A/C (LMNA) gene, showing the position of the FPLD mutation. The mutation is in the eighth exon, and alters the DNA sequence that would normally encode the amino acid arginine (R) at position 482. The mutation encodes glutamine (Q) instead. Hence, the mutation is designated R482Q.

The finding, by Drs. Robert Hegele and Henian Cao of the John P. Robarts Research Institute in London, Ont., is the first definitive indication that degenerative disorders of fat cells can be caused by mutations. Hegele says it may point the way to a better understanding of diabetes, as well as of fat distribution in healthy individuals, and of the lipodystrophy that occurs in patients receiving protease inhibitors for AIDS.

"Central fat leads to diabetes. These people [FPLD patients] have an extreme form of central fat. If we can understand better the mechanism of disease in these people, it could be applicable to the more garden-variety form of obesity," he says.

In the Jan. 1 issue of Human Molecular Genetics (available early online at www3.oup.co.uk/hmg/), Hegele and Cao report using Robarts' DNA sequencing technology to find the mutation responsible for FPLD (LMNA R482Q) in the lamin gene that codes for 2 proteins, lamin A and lamin C.

Patients with FPLD (www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?151660) have normal fat distribution at birth. Following puberty, fat accumulates around their neck, shoulders, the "buffalo hump" area between the shoulders, and the genitalia. At the same time, fatty tissue atrophies in the limbs and buttocks, giving those affected a lean and muscular appearance. The disorder is also often associated with profound insulin resistance and diabetes, high blood pressure and cholesterol, and heart disease.

Hegele, an endocrinologist at the London Health Sciences Centre and director of Robarts' Blackburn Cardiovascular Laboratory, and Cao, a research fellow, used a rapid genotyping test to locate the LMNA R482Q mutation in 22 FPLD-affected patients. The mutation was not found in 23 family members unaffected by FPLD, or in 1000 control subjects representing people of Caucasian (276), South Asian (243), African (169), Chinese (160), Oji-Cree (76), and Inuit (76) descent.

The search for an FPLD-causing mutation had been previously pinpointed by other researchers to a 120-gene section of chromosome 1. Aware that another disease causing heart difficulties and loss of muscle cells had been traced to mutations in the LMNA gene, Hegele and Cao decided to focus their research there.

In the Human Molecular Genetics paper, the Robarts researchers report that they have applied for a patent on "novel concepts and materials derived from this work."