Genetic Basis For Rare Autosomal Dominant Inclusion Body Disease Identified

NEW YORK (Reuters Health) - Scientists have identified a gene responsible for hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), a rare, progressive, and ultimately fatal autosomal dominant disorder.

The culprit is a mutant valosin-containing protein (VCP), Dr. Virginia E. Kimonis and colleagues report in the March 21st advance online issue of Nature Genetics.

Characteristically, individuals affected with IBMPFD develop proximal and distal muscle weakness, early onset Paget disease of bone, and premature frontotemporal dementia. "This is a devastating disorder associated with a considerable amount of disability and early demise," Dr. Kimonis told Reuters Health.

Although IBMPFD maps to chromosome 9p21.1-p12, the genetic basis for the disease was unknown until now.

Dr. Kimonis, from Children's Hospital, Boston, and colleagues used a candidate-gene approach to investigate 13 families with IBMPFD linked to chromosome 9. They found six missense mutations in the gene encoding VCP was present exclusively in all 61 affected individuals.

"Haplotype analysis identified descent from two founders in two separate North American kindreds accounted for IBMPFD in roughly 50% of affected families," according to the team.

VCP, which is also known as CDC48 or p97, plays "multiple important roles" in the cell, Dr. Kimonis explained, including activities involving cell cycle control, membrane fusion, and targeted protein degradation via the ubiquitin-based pathway. "The protein is essential for cellular viability, where cells lacking VCP die," she said.

The identification of VCP as the cause of IBMPFD has "important implications for other inclusion body diseases including myopathies, dementias, and Paget disease of bone, as it may define a new common pathological ubiquitin-based pathway," Dr. Kimonis and colleagues write.

"Ultimately, studying the common biochemical link may offer a new avenue of therapeutic research, which is our great hope," Dr. Kimonis said.

Source: Nat Genet 2004. [ Google search on this article ]