No abstract

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.

The frequent variations of human complement component C4 gene size and gene numbers, plus the extensive polymorphism of the proteins, render C4 an excellent marker for major histocompatibility complex disease associations. As shown by definitive RFLPs, the tandemly arranged genes RP, C4, CYP21, and TNX are duplicated together as a discrete genetic unit termed the RCCX module. Duplications of the RCCX modules occurred by the addition of genomic fragments containing a long (L) or a short (S) C4 gene, a CYP21A or a CYP21B gene, and the gene fragments TNXA and RP2. Four major RCCX structures with bimodular L-L, bimodular L-S, monomodular L, and monomodular S are present in the Caucasian population. These modules are readily detectable by TaqI RFLPs. The RCCX modular variations appear to be a root cause for the acquisition of deleterious mutations from pseudogenes or gene segments in the RCCX to their corresponding functional genes. In a patient with congenital adrenal hyperplasia, we discovered a TNXB-TNXA recombinant with the deletion of RP2-C4B-CYP21B. Elucidation of the DNA sequence for the recombination breakpoint region and sequence analyses yielded definitive proof for an unequal crossover between TNXA from a bimodular chromosome and TNXB from a monomodular chromosome.Besides the immunoglobulins, complement component C4 is probably the most polymorphic serum protein. There are two isotypes, C4A and C4B, that manifest remarkable differences in chemical reactivities and serological properties (reviewed in Ref. 1). More than 34 allotypes for C4A and C4B have been demonstrated by agarose gel electrophoresis, based on gross differences in electric charge (2). Similar to the protein, the complement C4 genes are unusually complex with frequent variations in gene size and gene number. In addition, the genes surrounding C4A or C4B also exhibit considerable variations. These neighboring genes include RP1 or RP2 at the 5Ј region, CYP21A, or CYP21B and TNXA or TNXB at the 3Ј region ( Fig.

Our results indicate that isolated 46,XY and 46,XX DSD can be assigned to two separate regulatory regions, XYSR and XXSR, far upstream of SOX9. The 1.9 kb SRY-responsive subfragment from the XYSR might constitute the core of the Sertoli-cell enhancer of human SOX9, representing the so far missing link in the genetic cascade of male sex determination.

To elucidate further pituitary influence on testicular function, we studied the effect of PRL, GH, and LH alone or in various combinations on the maintenance of testicular LH receptor concentration and testosterone synthesis in response to LH (testicular responsiveness) in hypophysectomized adult rats. Hypophysectomy reduced LH receptor concentration by 80% and testicular responsiveness to LH by 70% 7 days after surgery. Treatment with PRL (75 or 150 iig/day) or with GH (75 or 150 iig/day) initiated within 6 h after surgery and continued twice daily for 6 days partially prevented the loss of LH receptors. The effect of PRL (150 jug/day) plus GH (150 /xg/day) on LH receptor concentration was additive. The combination of LH (5 jug/day), PRL, and GH prevented any loss of LH receptors after hypophysectomy. A positive effect of LH on its receptor occurred in the presence of PRL. Treatment of hypophysectomized rats with 5 /ng LH plus 150 /ng PRL enhanced the effect observed with PRL alone (1.31 pmol/testis vs. 1.68 pmol/testis, P < 0.05). We previously reported that administration of 5, 25, or 50 /xg LH/day to hypophysectomized rats caused a further