The aim of this research will be to study genetic control of human protein structure, primarily those proteins in serum. Biochemical characterization of the Group-Specific component (Vitamin D-binding protein), a recently discovered Type IV basement membrane collagen protein found in human plasma, ceruloplasmin, Alpha1-antitrypsin and haptoglobin will be continued. Inherited diseases affecting the structure and processing of the plasma proteins which will be studied are cystic fibrosis (Vitamin D-binding protein) Alports' syndrome (Type IV basement membrane plasma protein), Wilson Disease (ceruloplasmin), Alpha1-antitrypsin deficiency and anhaptoglobinemia. The putative role of the Group-Specific component as a cytosol receptor of Vitamin D3 requires that the vitamin D-binding site on this protein be investigated. The Group-Specific component also offers a model for the investigation of glycosylation of threonine (and serine) 0-linkages. One of the amino acid substitutions characteristics of the Gcl genotype involves a lys arrow to the right thr alteration which is glycosylated and carries a terminal sialic acid residue which is absent in its allelomorph, Gc2. Such a model is needed in studying cystic fibrosis where 0-glycosylation is suspected of being abnormal in mucus, a complex and heterogeneous group of mucoproteins. A newly discovered Type IV basement membrane collagen protein in plasma will be studied. Isoelectric focusing and immunofixation will be employed to search for inherited polymorphisms affecting basement membrane collagen, and this protein will be characterized in Alport's syndrome, an often lethal disease affecting the glomerular basement membrane, and probably the basement membranes assciaated with the anterior lens and the auditory organelles. Inherited conditions associated with defects in synthesis or processing of the plasma proteins characterized here can eventually be studied molecularly by examining the leader or signal peptides and by utilization of oligodeoxynucleotide probes, designed from sequence information presently being made available in our laboratory, to examine the corresponding genomic DNA sequences.
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