National Institute on Aging (NIA)

Overview of NIA Rare Diseases Research Activities

NIA conducts and supports biomedical, social, and behavioral research; training; health information dissemination; and other programs with respect to the aging process. The Institute does not focus on rare diseases per se; however, certain rare conditions and diseases are studied as they relate to the process or diseases of aging. Of particular interest are progeroid syndromes (e.g., Werner's syndrome, Bloom's syndrome, and Cockayne's syndrome) that have implications for age-related diseases.

Recent Scientific Advances in Rare Diseases Research

Molecular Basis of Werner's Syndrome Werner's syndrome is an inherited recessive disease that has been termed a "progeroid syndrome" because it prematurely manifests many clinical symptoms resembling aging. The gene for this disorder (WRN) has been shown to code for a RecQ class helicase. Investigators have reported that the WRN protein is located in the nucleolus in human cells. In addition to its helicase activity, the WRN protein also has a 3 - to 5 -exonuclease activity that may facilitate the accuracy of DNA replication or homologous recombination. The yeast homolog of this gene, SGS1, shares significant homology with BLM, the gene whose defect is responsible for Bloom's syndrome. Studies have also found that yeast carrying a mutation in the SGS1 gene shows a progressive enlargement and fragmentation of the nucleolus and senesce prematurely. The phenomenon is apparently caused by the generation of extrachromosomal rDNA circles (ERCs), which accumulate in the mother cell as a result of improper segregation during cell division. ERCs may be the "molecular clock" for yeast cells. Further research will explore the relationship of this finding to normal human aging and the premature aging seen in Werner's syndrome.

Cockayne's Syndrome (CS), also called a segmental progeria, is a human disorder associated with clinical features of premature aging. These individuals suffer from mental retardation, cachectic dwarfism, hypersensitivity to ultraviolet irradiation, and other DNA-damaging agents. There are two genetic complementation groups-A and B (CS-A and CS-B). NIA intramural scientists have demonstrated that Cockayne's syndrome individuals have a deficiency in basal transcription in vivo. The CS-B gene sequence contains a helicase domain, but the gene does not appear to have helicase activity in vitro. It does, however, have ATPase activity. The CS-B protein appears to have several significant protein interactions, and CS-B may have separate critical function in DNA repair and basal transcription.

Rare Diseases Research Initiatives

Ongoing rare diseases research projects include studies of connective tissue metabolism in Hutchinson-Gilford progeria; genetic studies of Cowden's syndrome, including an investigation of the role of retinoic acid and its nuclear receptors in the disease; and several studies of the Werner syndrome gene and gene product. Intramural scientists are continuing their study of premature aging disorders, including studies of DNA repair and transcription in Bloom's syndrome, Cockayne's syndrome, and Werner's syndrome. In addition, a study has been initiated of glypican 3 action in overgrowth syndromes such as Simpson-Golabi-Behmel syndrome.