Diabetes-associated fat disorder traced to genetic mutation

Date: Dec. 10, 1999
Time: 12:49 pm

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. 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, Hegele said in an interview this morning.

"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 told eCMAJ Today.

In the Jan. 1 issue of Human Molecular Genetics (subscription required) 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.

FPLD patients have normal fat distribution at birth, but 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 them 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 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 any of 1000 control subjects representing Caucasians (276), South Asians (243), Africans (169), Chinese (160), Oji-Cree (76), and Inuit (76).

The search for a 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 "novel concepts and materials derived from this work have been embodied in US patent application number C99-482."

-- David Helwig, London, Ont.

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