Advances in molecular genetic understanding of disease processes has been extended to a number of phagocytic disorders. Most of these disorders were extensively characterized at the functional and
protein level prior to cloning of the relevant genes. Nucleotide sequence data has been essential for establishing the mechanism and mode of inheritance of genetically transmitted phagocyte disorders. Such data provides insights into the functionally important regions of affected
proteins and information regarding regulation of these genes and homologies to other known
proteins. From such data it is also possible to determine the evolutionary history of these genes.
Chronic granulomatous disease, a phenotypic classification of a heterogeneous group of defects in oxidative metabolism, has now been defined in terms of specific molecular defects. Cloning of the two subunits of
cytochrome b558 has led the way to characterization of the X-linked form and one of the autosomal recessive forms of this disease and confirmed the importance of this
protein in the phagocyte oxidative burst. The absence of
lactoferrin associated with hereditary
specific granule deficiency is a result of decreased transcription of the
lactoferrin gene in myeloid cells.
Myeloperoxidase deficiency is likely a result of a mutation of the gene coding for
myeloperoxidase. More precise understanding of expression of the
lactoferrin and
myeloperoxidase genes may be important in elucidating some of the underlying mechanisms in the pathogenesis of myeloid
malignancies. A rare
disorder, leukocyte adhesion deficiency, has provided a model for establishing the relationship between the several distinct alpha subunits and the shared common beta subunit of leukocyte adhesion
proteins. These
proteins have been shown to be genetically related to the superfamily of
extracellular matrix receptors termed '
integrins'. Because these
proteins have been highly conserved at the genetic level across a variety of species, comparison of nucleotide sequence data has illuminated some of the evolutionary history of these genes as they arose from ancestral genes. Studies of these adhesion
protein genes may contribute new information in the broader context of how the functions of these genes evolved.