Advances in the molecular biology of diseases of the immune system are rapidly unfolding in many areas Immunologists have become aware that many of the rare congenital immunodeficiency patients they encounter have specific genetic defects, many of them X-linked. Two X-linked genes, those for properdin and cytochrome b-245 beta chain, have been cloned and proven to cause, respectively, a complement system disorder, properdin deficiency, and the phagocyte-killing defect chronic granulomatous disease. There are at least five other genetic loci responsible for X-linked diseases involving lymphocytes. These appear to be disorders of distinct gene products which may be required for development, survival, or function of particular lymphocyte lineages. None of these genes have been cloned, and there are no biochemical or immunological indicators as to the primary pathogenesis. Linkage analysis has been used to establish a regional localization for each gene defect. Further genetic clues, such as affected individuals with chromosomal translocations or deletions, have not been detected except in chronic granulomatous disease and, recently, X-linked lymphoproliferative syndrome.
The amyloidoses are diseases characterized by the extracellular accumulation of insoluble protein fibrils. From the initial pathologic description by Virchow in the mid-19th century until the early 1970s, the idea of a single amyloid substance was dominant, and the systemic amyloid syndromes were classified on clinical grounds, i.e., the anatomic distribution of amyloid deposition and the associated clinical findings. The most widely accepted nosology acknowledged only three basic types of systemic amyloidosis, “secondary,” “familial,” and “primary” (in addition to rare forms of amyloidosis localized to a single organ). Thus, deposits of amyloid material in the kidney, liver, and spleen in association with chronic inflammatory processes such as tuberculosis and rheumatoid arthritis were termed “secondary amyloidosis.” Familial amyloidosis was recognized by its distinctive clinical manifestations and the positive family history. All other types of amyloidosis, except that associated with the neoplasm multiple myeloma, were termed “primary,” in the sense of “idiopathic”; this category included unrecognized inherited forms, “secondary” amyloidosis without an identified cause, and localized amyloidoses. The failure of many instances of amyloid deposition to fit neatly into the prescribed clinical and histologic categories should have suggested that the notion of a unique amyloid substance was conceptually inadequate.
Huntington's disease (HD) research is aimed at understanding the root cause of the disorder, for the thrill of uncovering new biology, and for the serious purpose of finding effective therapeutic agents. Molecular genetics has revealed the disease trigger, an inherited unstable CAG expansion in a novel 4p16.3 gene (HD), that lengthens a polyglutamine segment in huntingtin. Now studies with HD patients and model systems that are genetic HD replicas are homing in on the trigger mechanism and the first formative steps that cast HD as a distinct clinical entity. At the same time, assays at the biochemical, cellular, and whole organism levels are starting to yield potential disease modifying genes and candidate drugs. These can be prioritized by testing in a panel of genetic and phenotypic HD mouse models to yield analytical tools for dissecting the early and late stages of the disease process and to maximize the chance of success in trials with HD patients.
Orthologs and paralogs are two fundamentally different types of homologous genes that evolved, respectively, by vertical descent from a single ancestral gene and by duplication. Orthology and paralogy are key concepts of evolutionary genomics. A ...Read More
