Shigeki Uehara

XY gonadal dysgenesis can be classified as either complete or incomplete according to gonadal morphology. The disease is a sex-reversal disorder resulting from embryonic testicular regression sequences and is induced by mutations in the sex-determining region Y (SRY) gene. The incidence of SRY mutations is thought to be approximately 20%. As the disease is characterized by a frequent complication of gonadal tumors, patients are usually advised to undergo prophylactic gonadectomy. In this study, we searched for mutations in SRY open reading frames from three patients with the complete form of XY gonadal dysgenesis, and detected missense mutations in two patients. Combined with the results of our previous study, in which SRY abnormalities were also detected in two out of three complete-type patients, the final incidence of SRY abnormalities was 67% (four of six patients), which is much higher than previously thought. The incidence of gonadal tumor formation in patients with SRY abnormalities was 50% (two of four patients), which is similar to the result of a metanalysis of patients with SRY abnormalities that revealed an incidence of 52.5%. Therefore, it is possible that the lower incidences of SRY abnormalities previously reported were caused by the inclusion of patients with the incomplete form or other sex-reversal disorders. Moreover, our results suggest that clinicians should carefully examine patients with SRY abnormalities.

To investigate X-chromosome inactivation (XCI) in human trophoblasts during early pregnancy, tropho-blast genomic DNA was extracted and analyzed for a Bst XI restriction endonuclease site polymorphism in the X-linked phosphoglycerate kinase gene, after digestion with methylation-sensitive Hpa II (control samples were digested instead with Afa I). Six villous trophoblast DNA samples were informative for the polymorphism (ie, heterozygous) and were derived from women homozygous for the polymorphism. These samples were then evaluated for XCI. In five of the six samples with Hpa II predigestion, the sizes of the two heterozygous band peaks differed; maternal X-chromosome (X^M)-derived alleles showed smaller peak sizes than paternal X-chromosome (X^P)-derived alleles, but the differences varied in degree. In samples obtained by microdissection from formalin-fixed, paraffin-embedded tissues (30 samples from different anchoring villi, and 38 samples from different branch villi), monoclonal band patterns of X^P-derived alleles were observed more frequently than those of X^M-derived alleles, but almost half of the samples showed polyclonal pat-terns. Our results suggest that a skewing of XCI exists in the human trophoblast; however, the degree of non-randomness due to predominant X^P inactivation appears to be restricted. It is probable that transcription of the X inactivation center (XIC) begins earlier in mice than in humans.

The autosomal recessive disease 17α-hydroxylase/17, 20-lyase deficiency is characterized by mutation of the P450c17 enzyme, which catalyzes 17α-hydroxylation and 17, 20-lysis in the steroidogenic pathways. Although 17 mutations of this enzyme have been reported, only a few of them resulted in a completely unambiguous phenotype of female external genitalia in 46, XY individuals. We report here a Japanese patient with a 46, XY karyotype, who showed such a unambiguous female external genitalia. Nucleotide sequencing of the P450c17 gene revealed the patient to be a compound heterozygote carrying two different mutations (PHE53/54DEL in exon 1 and HIS373LEU in exon 6). As these mutations have been previously detected in unrelated Japanese patients, it is confirmed that these mutations accumulate regionally. Since these mutations could be screened by a multiple genotyping method, the method is applicable when 17α-hydroxylase/17, 20-lyase deficiency is suspected in Japanese patients.

We describe a unique patient with complete androgen insensitivity syndrome and a 47,XXY karyotype. Androgen receptor assay using cultured pubic skin fibroblasts showed no androgen‐binding capacity. Sequence analysis of the androgen receptor gene demonstrated two nonsense mutations, one in exon D and one in exon E. Microsatellite marker analysis showed that the patient is homozygous for all five Xq loci examined. The results suggest that the long‐arms of the two X chromosomes are identical, i.e., uniparental isodisomy at least for Xq, and carry the same mutations in the androgen receptor gene. This explains how complete androgen insensitivity syndrome occurred in this 47,XXY individual. Am. J. Med. Genet. 86:107–111, 1999.

Carbamoyl phosphate synthetase deficiency is a type of an inborn error of metabolism with a poor prognosis. Carbamoyl phosphate synthetase is a liver-specific enzyme, and its deficiency can only be diagnosed by enzyme assay using liver biopsy specimens. A pregnant woman at risk for carbamoyl phosphate synthetase deficiency was evaluated for the purpose of prenatal diagnosis of the condition. Fetal liver biopsy was performed at the 22nd week of gestation. The results of enzyme assays on fetal liver biopsy revealed normal enzymatic activity and the diagnosis of carbamoyl phosphate synthetase deficiency was ruled out prenatally. Methods and safety of fetal liver biopsy are discussed. Measurements of activity of liver-specific enzymes were evaluated with respect to methodology and manner of assessment. Prenatal diagnosis of deficiencies in liver-specific enzymes, which have hitherto been considered difficult to detect before birth, has now become possible.

UEHARA, S., AKAI, Y., TAKEYAMA, Y., TAKABAYASHI, T., OKAMURA, K. and YAJIMA, A. Pericentric Inversion of Chromosome 9 in Prenatal Diagnosis and Infertility. Tohoku J. Exp. Med., 1992, 166 (4), 417-427-In order to evaluate the relation between pericentric inversion of chromosome 9 (inv(9)) and clinical problems, the characteristics of inv(9) were investigated on the basis of chromosomal analyses of fetuses and infertile couples. The incidence of such inversion in fetuses with parents having an offspring who suffered from various clinical problems was significantly higher than the basic incidence obtained in fetuses karyotyped by reason of advanced maternal age. In the chromosomal examination of the parents whose fetuses were diagnosed as inv(9), it was revealed that either parent might be the carrier. Furthermore, in the inv(9) carrying fetuses, the number of females was significantly greater than that of males. Analysis of infertile couples revealed that the incidence of such inversion in males was significantly higher than the basic incidence mentioned above. Moreover, infertile couples with an inv(9) carrier showed a significantly higher incidence of intrauterine fetal death, compared with infertile couples with a translocation carrier or those in which the etiology was unknown. These results indicate that inv(9) may often cause clinical problems in offspring of the carrier and infertility with unknown mechanisms related to sex.