Biennial and Annual Report on the Rare Diseases Research Activities at the National Institutes of Health FY 2004

National Institute of General Medical Sciences (NIGMS)

Overview of Rare Diseases Research Activities

The National Institute of General Medical Sciences (NIGMS) supports broad-based fundamental research that is not targeted to any specific organ system or disease. Examples include studies on the structure and function of organelles and membranes at the cellular and molecular level; investigations into the replication, organization, and function of the genome in organisms ranging from bacteria to man; development of new and improved instrumentation and technology for application to biological problems; studies on basic bio-related organic chemistry for the elucidation of biosynthetic pathways and the development of new synthetic strategies for molecules of biological interest; and investigations of basic pharmacological mechanisms at levels ranging from the receptor to the molecular. In general, support of investigations related to specific diseases, unless of wide applicability across disease or organ system lines, is not the responsibility of the NIGMS but rather would be assigned to one of the categorical Institutes.

Human Genetic Cell Repository

The NIGMS Human Genetic Cell Repository provides a valuable resource for investigators studying genetic disorders. The Repository, located at the Coriell Institute for Medical Research in Camden, NJ, collects, characterizes, maintains, and distributes cell lines and DNA samples from patients and families with a wide variety of genetic disorders and from normal persons whose tissues serve as controls. More than 9,200 unique cell lines, representing over 700 different diseases, and 4,000 DNA samples are available to qualified investigators. The Repository stimulates research on rare diseases by providing access to cell lines, both fibroblasts and transformed lymphoblasts, and DNA samples derived from these cell lines, that otherwise are not readily available. Among the cell lines requested most frequently in the last year are those from patients with rare diseases such as xeroderma pigmentosum, ataxia-telangiectasia, Fanconi anemia, cystic fibrosis, fragile X-linked mental retardation, Niemann-Pick disease, Friedreich ataxia, familial breast cancer, osteogenesis imperfecta, and Down syndrome. Recent acquisitions to the collection include samples from patients with the following rare disorders: adrenoleukodystrophy, Alexander disease, Alpers syndrome, ATP synthase deficiency, Caravan disease, Ehlers-Danlos syndrome (Types III, IV, unclassified), fascioscapulohumeral muscular dystrophy, RETT syndrome, osteogenesis imperfecta, hypochondroplasia, glycogen storage disease types VIII and IX, and Salla disease. These cell lines, as well as those previously acquired, are used for biochemical, cellular, and molecular studies to help elucidate the causes of genetic defects. The Repository has a growing collection of cell lines in which the mutation has been characterized at the molecular level. These include the newly acquired samples from patients with adrenoleukodystrophy, Alexander disease, Bloom syndrome, galactosemia, and osteogenesis imperfecta as well as cell lines with recently characterized mutations from patients with cystinuria, familial dysautonomia, and multiple Nieman-Pick C variants.

In addition, the Repository houses an expanding collection of chromosomally aberrant human cell lines. It also supplies DNA isolated from complete panels of well-characterized human-rodent somatic cell hybrids and from chromosome-specific somatic cell hybrid panels for nearly every human chromosome. The Repository also houses sets of cell lines (and DNAs derived from them) that represent the CEPH family collection and other extended families, the National Human Genome Research Institute’s DNA Polymorphism Discovery Resource and International HapMap Project, and other identified populations that represent the genetic diversity of humans. These samples will help researchers map and identify genes that are involved in the etiology of complex genetic diseases.

Recent Scientific Advances in Rare Diseases Research

Unstable DNA Repeats in Neurodegenerative Disorders

Over a dozen inherited neuromuscular degenerative diseases, including Huntington’s disease (HD), myotonic dystrophy, Friedreich’s ataxia, and fragile X syndrome, are associated with the presence of long tracts of trinucleotide repeats (TNRs) in genomic DNA. There are normally fewer than 30 repeats in any particular chromosomal allele, but affected individuals may have several hundred repeat units at a disease-causing gene locus. A process by which the length of TNR tracts may rapidly expand to several hundred copies in a single generation was addressed in work supported by NIGMS that was reported last year. Now, another group of NIGMS-supported researchers has reported their insights into the details of the pathogenic mechanisms involving these repeat structures that can not only compromise chromosomal integrity but also lead to immediate cell death in these human diseases.

The investigators initially observed, using a yeast model system, that just the presence of TNRs in growing cells is associated with activation of the DNA damage cell cycle checkpoint response. It appears that the unusual DNA structures that can arise during the replication of triplet repeats, particularly long repeat tracts, are seen as chromosome defects by the DNA damage control monitor. If these apparent lesions are not repaired quickly and efficiently, the activated cell cycle checkpoint machinery triggers the programmed cell death (apoptosis) pathway. The mechanisms of this cellular response, which serves to prevent the reproduction of cells with chromosomal defects, are conserved in yeast and humans. Overactivation of the checkpoint mechanism, in cells that are already stressed to repair multiple possible defects, represents an obvious explanation for the death of neurons and muscle cells in HD and myotonic dystrophy and other TNR diseases. Future work to characterize checkpoint mechanisms may provide approaches for limiting the severity of TNR expansions and the manifestation of the associated pathologies.

Polyglutamine Protein Inhibition of Proteosomes in Neurodegenerative Diseases

The long tracts of TNRs that are present in the chromosomal DNA sequences of patients suffering from hereditary neurodegenerative disorders can compromise cell function through a spectrum of pathogenic mechanisms ranging from the disruption of chromosome replication to the cytoplasmic accumulation of massive, toxic aggregates of defective proteins. HD and spinocerebellar ataxia (SCA) are associated with expansion of CAG nucleotide repeats in coding regions of the genes coding for the huntingtin and ataxin-1 kinase proteins, respectively. Transcription and translation of the CAG codons results in the incorporation of long polyglutamine stretches in these peptides. NIGMS-funded researchers have confirmed that the toxic protein clumps observed in cells from these patients originate initially as result of the self-aggregation of polyglutamine containing huntingtin and ataxin-1 proteins, but they add that the aggregation is exacerbated as the toxic protein complexes irreversibly bind to and inhibit the function of proteosomal.

Proteasomes are the molecular machines that are responsible for the normal turnover of proteins that is central to cell homeostasis. In healthy cells, proteins perform their various functions and then, through the action of the proteasome, are degraded and cleared. The new results indicate that in HD, SCA, and other polyglutamine diseases, the inhibition of these machines not only prevents the complete degradation of the polyglutamine peptides but also impairs the normal degradation of other aged and damaged proteins that then become entangled in the expanding aggregates. A detailed understanding of the distinct biophysical properties and molecular interactions that result in differences in the rate of complex formation and in the degree of proteosomal compromise with huntingin and ataxin-1 may enable researchers to account for differing presentation of the disease processes. This basic knowledge could lead to interventions for these currently untreatable conditions.


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Last Reviewed: July 22, 2005