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We identified two novel mutations of the aquaporin-2 (AQP2) gene in a sporadic Japanese patient diagnosed with an autosomal recessive nephrogenic diabetes insipidus (NDI). The patient, a Japanese boy, was referred to our clinic at the age of 5 months because of unexplained recurrent fever. He was diagnosed with NDI by clinical, biochemical and endocrine findings. Molecular analysis demonstrated that he was a compound heterozygote for two mutations. One mutation consisted of a two base deletion in exon 1 (197, 198 delCA). This deletion caused a frameshift in the open reading frame, resulting in a premature stop codon 186 bases downstream in exon 1. The second mutation was a G to A transition of the terminal exon splice site (1502-1G-->A). To date, several mutations in the AQP2 gene have been described, however no splicing mutation in the AQP2 gene has been identified. The deletion mutation described in this case study was inherited patemally and the splicing site mutation was inherited maternally, indicating an autosomal recessive inheritance. In the present case study, we identified two new mutations in the AQP-2 gene. Previous studies have shown that there is no hot spot for mutations in the AQP-2 gene, and thus genetic analysis for individual patients is helpful for genetic counseling and early diagnosis.

Congenital lipoid adrenal hyperplasia (lipoid CAH) is the most severe form of CAH in which the synthesis of all gonadal and adrenal cortical steroids is markedly impaired. Lipoid CAH may be caused by the defect in either the steroidogenic acute regulatory (StAR) protein or the P450scc. More than 34 different mutations in StAR gene have been identified. Clinically, most of the patients manifest adrenal insufficiency from 1 day to 2 months of age, but some patient show delayed onset of adrenal insufficiency. Affected 46, XY subjects do not show pubertal development, whereas affected 46, XX subjects undergo spontaneous feminization, breast development and cyclical vaginal bleeding at the usual age of puberty. X-linked adrenal hypoplasia congenital (AHC) is a rare congenital adrenal disorder characterized by severe adrenal insufficiency and hypogonadotropic hypogonadism. More than 80 different several intragenic mutations of DAX-1 have been identified. The failure of pubertal development may be caused by either abnormal hypothalamic or pituitary regulation of gonadotropin secretion. In addition, although the testicular steroidogenesis is largely intact, the functional maturity of Sertoli cells and also spermatogenesis are impaired. The type of mutation does not predict clinical phenotype. Thus, unified mechanism how DAX-1 gene defect gives rise to adrenal insufficiency, hypothalamic/pituitary hypogonadism and impaired spermatogenesis remains established.

Pseudohypoparathyroidism Ia (PHP-Ia), is an inherited disease with clinical hypoparathyroidism caused by parathyroid hormone resistance (PTH), and shows the phenotype of Albright hereditary osteodystrophy (AHO), including short stature, obesity, round face, brachydactyly, and subcutaneous ossification. This disease is caused by mutation that inactivates the alpha-subunit of Gs, the stimulatory regulator of adenylyl cyclase. Here, a novel frameshift mutation (delG at codon 88) in exon 4, and a missense mutation (R231H) in exon 9 of the Gsalpha gene were identified in two Japanese patients with sporadic PHP-Ia. Deletion of a G in exon 4 at codon 88 in the first patient produced a premature stop codon, resulting in the truncated protein. The second patient had a previously reported R231H mutation. Because this amino acid is located in a region, switch 2, that is thought to interact with the betagamma subunit of Gsalpha protein, this mutation may impair Gs protein function. We report here one novel Gsalpha mutation, and note that mutations in Japanese patients with PHP-Ia are probably heterogeneous.

X-linked hypophosphatemic rickets (XLH) is an X-linked dominant disorder characterized by renal phosphate wasting, abnormal vitamin D metabolism, and defects of bone mineralization. The phosphate-regulating gene on the X-chromosome (PHEX) that is defective in XLH has been cloned, and its location identified at Xp22.1. It has been recognized to be homologous to certain endopeptidases. So far, a variety of PHEX mutations have been identified mainly in European and North American patients with XLH. To analyze the molecular basis of four unrelated Japanese families with XLH, we determined the nucleotide sequence of the PHEX gene of affected members. We detected a new nonsense mutation (R198X) in exon 5, a new 3 nucleotides insertion mutation in exon 12 and a new missense mutation (L160R) in exon 5 as well as a previously reported nonsense mutation in exon 8 (R291X). These results suggest that: 1) PHEX gene mutations are responsible for XLH in Japanese patients, and 2) PHEX gene mutations are heterogeneous in the Japanese population similarly to other ethnic populations.

The Wilms' tumor suppressor gene, WT1, plays an important role in the development of the urogenital system and also subsequent normal function of this system. Recently, the splice mutations in intron 9 of WT1 gene have been detected in Frasier syndrome, which is characterized by streak gonads, pseudohermaphroditism, slowly progressive nephropathy and frequent development of gonadoblastoma. Here to elucidate the molecular basis in a Japanese patient of Frasier syndrome, WT1 gene was analyzed by polymerase-chain-reaction (PCR) and direct sequencing. We identified the splice junction mutation in intron 9 of WT1, which is recognized as a mutation hot-spot in intron 9. This finding concludes that 1) the mutation in intron 9 might be the cause of Frasier syndrome, and 2) the mutation hot-spot in Japanese and Caucasian patients is similar.