Advances in Human Genetics最新文献

IgA deficiency is one of the most common of all immune defects. While it is often not associated with clinical illness, presumably due to compensation from other sectors of the immune system, IgA-deficient individuals are distinctly more likely to become ill and have one or more of specific groups of diseases. While the unifying immunologic perturbation in IgA deficiency is a lack of mature IgA-secreting B cells, a host of other, usually minor, immunologic abnormalities have been reported in such patients. IgA deficiency can be inherited in an autosomal dominant or autosomal recessive fashion, but most individuals who are IgA deficient have no other affected family members. From a genetic point of view, IgA deficiency has been associated with three chromosomes, 18, 14, and 6. Many IgA-deficient individuals who have cytogenically detectable abnormalities of chromosome 18 have been reported, but all the individuals with these defects have severe congenital defects of other kinds. Obscuring the relationship between chromosome 18 and IgA deficiency is the fact that both short- and long-arm deletions have been reported in IgA deficiency. The chromosome deletions in the individuals who are IgA deficient thus appear to have no common pattern. While a rare individual can be IgA1 deficient on the basis of heavy-chain deletions of alpha 1 genes in concert with other heavy-chain genes on chromosome 14, such individuals are quite rare, and from a clinical point of view, those reported have usually been healthy. Absence of both IgA1 and IgA2 genes (presumably in concert with other heavy-chain genes) has never been reported. For chromosome 6, a more complex puzzle emerges. IgA-deficient individuals have been reported to have one of a few specific HLA haplotypes. While many individuals with these supratypes are not IgA deficient, these findings encourage the notion that the secretion of IgA could be at least partly controlled by genes residing in the major histocompatibility locus.

As diverse as the group of inherited structural defects and giant platelet disorders presented in this chapter may seem, there is a common thread that ties them together. All appear to represent some form of membrane aberration. Sometimes only a small inclusion identifies the membrane defect, sometimes a massive increase in size. In others, whole populations of organelles are missing or surface membranes lack specific glycoproteins essential for their function. All of them are born in the deep recesses of a hidden cell, the bone marrow megakaryocyte. Getting the megakaryocyte out into the light of day, or at least into a culture medium, should certainly lead to the solution of many, if not all, of the disorders of platelet membranes and membrane disorders. We have not been completely successful in our efforts to study the megakaryocyte in vitro. As a result, we do not yet understand the normal megakaryocyte, much less normal platelet. The megakaryocyte presents one of the greatest of challenges to our understanding of membrane biology. As our knowledge of how its cytoplasm fills with interiorly and exteriorly derived membranes, and the mechanisms underlying their organization into platelet surfaces, channels of the OCS and DTS, membrane complexes, and five kinds of organelles become clear, our ability to define the basic nature and inheritance of defects will improve rapidly. Within the next decade most aspects of platelet molecular genetics and cell biology will be solved.