The complement component C4 genes located in the major histocompatibility complex (MHC) class III region exhibit an unusually complex pattern of variations in gene number, gene size, and nucleotide polymorphism. Duplication or deletion of a C4 gene always concurs with its neighboring genes serine/threonine nuclear protein kinase RP, steroid 21-hydroxylase (CYP21), and tenascin (TNX), which together form a genetic unit termed the RCCX module. A detailed molecular genetic analysis of C4A and C4B and RCCX modular arrangements was correlated with immunochemical studies of C4A and C4B protein polymorphism in 150 normal Caucasians. The results show that bimodular RCCX has a frequency of 69%, whereas monomodular and trimodular RCCX structures account for 17.0 and 14.0%, respectively. Three quarters of C4 genes harbor the endogenous retrovirus HERV-K(C4). Partial deficiencies of C4A and C4B, primarily due to gene deletions and homoexpression of C4A proteins, have a combined frequency of 31.6%. This is probably the most common variation of gene dosage and gene size in human genomes. The seven RCCX physical variants create a great repertoire of haplotypes and diploid combinations, and a heterozygosity frequency of 69.4%. This phenomenon promotes the exchange of genetic information among RCCX constituents that is important in homogenizing the structural and functional diversities of C4A and C4B proteins. However, such length variants may cause unequal, interchromosomal crossovers leading to MHC-associated diseases. An analyses of the RCCX structures in 22 salt-losing, congenital adrenal hyperplasia patients revealed a significant increase in the monomodular structure with a long C4 gene linked to the pseudogene CYP21A, and bimodular structures with two CYP21A, which are likely generated by recombinations between heterozygous RCCX length variants.

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Serum pancreatic polypeptide (PP), gastric inhibitory polypeptide (GIP), insulin and glucose responses to meal stimulation were studied in 10 normal weight patients, 13 normal obese patients and 7 patients with Prader-Willi syndrome (PWS) associated obesity. Serum and plasma concentrations of PP, glucose, insulin and GIP were obtained at 15 min intervals from 0-180 min. after a 275 K calorie meal. Basal and peak responses of glucose, for patients with PWS were significantly lower when compared to normal or obese controls. Basal and peak insulin responses in PWS were significantly greater than those of the normal controls but still less than those of the obese controls. Basal GIP concentrations in the patients with PWS were significantly less than normals and their peak response was less than the obese control group. No significant differences in basal or peak PP responses were noted between normal and obese controls. All 7 patients with PWS had abnormal PP responses. Five failed to show significant PP release after the stimulation; one had a peak response to 130 pg/ml while the 7th patient (PB) had an exaggerated response to 2000 pg/ml. The 6 patients with low or no response had basal PP values of 62 +/- 12 pg/ml and a mean PP peak response of 78 +/- 15 pg/ml. This observation of blunted PP response in a human model of hyperphagia and obesity parallels the animal models and suggests PP may have a significant role in appetite control.