Recent observations have suggested that the pathological mutations in human P-450(C21) deficiency are generated through gene conversion-like events between the functional gene [P-450(21)B] and the pseudogene [P-450(C21)A]. To address this point more extensively, we investigated the effects of the base changes in the A pseudogene on the P-450(21) activity by using the COS cell expression system. In addition to the defective mutations found previously in the pseudogene, four single base changes with amino acid substitutions of Pro(30), Ile(172), Val(282), or Arg(356) were further identified as causing complete [Arg(356)] or partial [Pro(30), Ile(172), and Val(282)] inactivation of P-450(C21). Blot hybridization analysis of patient DNAs using oligonucleotide probes specific for these mutations revealed that the splicing mutation in the 2nd intron was distributed most frequently in both simple-virilizing and salt-wasting forms. The mutation Ile(172) seemed to be frequent in patients with the less severe simple-virilizing form, whereas the mutation Arg(356), together with other most serious mutations reported previously, was preferentially associated with salt-wasting, the most severe form of the disease. In combination with the present results of the effects of various mutations on the P-50(C21) activity, a survey of the distribution of the various mutations in the patient genomes so far reported suggests that the heterogeneous clinical symptoms of this genetic disease are somehow related to the degree of attenuation of the activities of the mutated gene products.
Four steroid 21-hydroxylase B [P-450(C21)B] genes (designated P.7, P.10-1, P.10-2, and P.3) from three P-450(C21)-deficient patients were isolated to analyze their structures and functions. Several base changes were observed in the sequences of the four P-450(C21)B genes as compared to that of the functional B gene. Many of these base changes were identical to those of the P-450(C21)A pseudogene. The three DNAs (P.10-1, P.10-2, and P.3) produced no P-450(C21) activity in a functional assay for P-450(C21) by the COS cell expression system, while the P.7 DNA expressed the activity.The P.10-1 and P.10-2 DNAs were shown to have a point mutation in the second intron, causing aberrant splicing. The P.3 DNA carried three clustered missense mutations in the sixth exon, which impaired P-450(C21) activity. AM these critical mutations could be seen in the corresponding site of the P-450(C21)A pseudogene. These data strongly suggest the involvement of gene conversion in this genetic disease.Steroid 21-hydroxylase [P-450(C21), steroid 21-monooxygenase; steroid, hydrogen-donor:oxygen oxidoreductase (21-hydroxylating), EC 1.14.99.10] deficiency (1, 2) is the most frequent cause (=95%) ofcongenital adrenal hyperplasia, one of the most common inborn errors of metabolism, affecting -1 in 15,000 births. This disease is inherited as a monogenic autosomal recessive trait closely linked to HLA major histocompatibility complex (3). P-450(C21) is involved in the conversion of progesterone and 17-hydroxyprogesterone to ll-deoxycorticosterone and ll-deoxycortisol, the intermediate steps in mineralocorticoid and glucocorticoid biosynthesis, respectively (4). By the defect of the P-450(C21) gene, synthesis of aldosterone and/or cortisol is impaired and 17-hydroxyprogesterone consequently accumulates, leading to excess production of androgen. These hormonal conditions develop three types of clinical symptoms, referred to as the salt-wasting, simple-virilizing, and nonclassical forms (5).Recent gene cloning analysis showed that there are two P450(C21) genes-P-450(C21)A and P-450(C21)B-each of which is located immediately adjacent to the 3' end ofthe two genes encoding the fourth component of complement, C4A and C4B, which reside in the class III region of the HLA complex (6, 7). The B gene characterized by the 3.7-kilobase (kb) Taq I fragment of the genomic DNA is functional, whereas the A gene of the 3.2-kb Taq I fragment is a pseudogene harboring at least three deleterious mutations in the coding sequence (8, 9). Nonetheless, the two genes are extremely homologous (-98%) even in the introns and the 5'-flanking sequence, suggesting their concerted evolution by exchanging genetic information with each other (8).Genomic blot analysis of P-450(C21)-deficient patients by using cloned DNAs as probes (10-13) revealed that some patients had the B gene either totally deleted or converted to the A gene. Further analysis with oligonucleotide probes specific for the three deleterious sequences in the A gene could show that at least one alle...
One hundred and sixty-one children with idiopathic GH deficiency who received GH treatment were followed until they reached their final height. Final height was found to be influenced by gonadal function. In 108 patients who had spontaneous puberty (91 boys and 17 girls; group A), the mean final height was 151.8 +/- 6.6 (+/- SD) cm in boys and 141.7 +/- 7.4 cm in girls. In 29 patients with combined GH and gonadotropin deficiency (23 boys and 6 girls; group C), whose pubertal development was induced artificially at age 19.5 +/- 2.1 yr in the boys and 18.6 +/- 1.8 yr in the girls, the mean final height was 163.7 +/- 3.9 cm in boys and 151.0 +/- 5.1 cm in girls. The differences in final height between groups A and C were significant in both boys and girls. The shorter final height in group A was caused by the shorter pubertal duration and smaller pubertal height gain than those in normal children. In 24 patients (17 boys and 7 girls; group B) who developed early signs of puberty, gonadal suppression therapy with cyproterone acetate and/or medroxyprogesterone acetate was given. The mean SD score of the final height in these 24 patients was -2.1 +/- 0.6, significantly higher than that in group A. This beneficial effect of gonadal suppression treatment on final height was caused by increases in the duration of puberty and the pubertal height gain.
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