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Biomedical subjects

Reiko Horikawa

Publications and source records attributed to Reiko Horikawa.

At least 19 recordsLinked to original sources
PubMed2025

DHX37 variants in patients with 46,XY disorders or differences of sex development.

Here, using whole-exome sequencing of a cohort of 17 Japanese patients with 46,XY disorders or differences of sex development, we identified two pathogenic DEAH-box helicase 37 (DHX37) variants in three patients. We also identified a patient with a likely pathogenic variant in SOX9 and a rare likely benign variant in DHX37. This Data Report highlights the genetic and phenotypic diversity of DXH37 variants.

Journal Article↗
PubMed2006

Replacement of alanine with asparagic acid at position 203 in human steroidogenic acute regulatory protein impairs the ability to enhance steroidogenesis in vitro.

Steroidogenic acute regulatory protein (StAR) is a 30-kDa phosphorylated protein that rapidly appears in mitochondria of steroidogenic cells following tropic stimulation, and is required in the acute regulation of steroidogenesis. It was reported that mutations in the STAR gene encoding StAR cause congenital lipoid adrenal hyperplasia (CLAH), an autosomal recessive disorder characterized by impaired synthesis of all adrenal and gonadal steroid hormones. We previously reported a D203A polymorphism in the STAR gene in Japanese patients with CLAH as well as in normal Japanese subjects. In the present study, we analyzed the ability of the A203 StAR and D203 StAR to stimulate steroidogenesis using the in vitro functional expression system. The A203 StAR caused a twelve-fold increase in pregnenolone secretion over COS-1 cells transfected with an NH2-cholesterol side-chain cleavage enzyme (P450scc)-adrenodoxin reductase-adrenodoxin-COOH fusion protein expressing plasmid (F2) and an empty vector, whereas the D203 StAR increased pregnenolone production no more than threefold. Western blot analysis detected mainly two species of StAR consisting of the 37-kDa precursor and the 30-kDa mature form. Together, these results indicate that the alanine at position 203 in human StAR is functionally important and that the D203 StAR is extremely unlikely to be a polymorphism.

Alanine↗
PubMed2006

Urine steroid hormone profile analysis in cytochrome P450 oxidoreductase deficiency: implication for the backdoor pathway to dihydrotestosterone.

CONTEXT: Although the "backdoor" pathway to dihydrotestosterone has been postulated in the fetal-to-early-infantile period of patients with cytochrome P450 oxidoreductase deficiency (PORD), clinical data in support of this pathway remain limited. OBJECTIVE: The objective of this study was to obtain clinical evidence for the presence of the backdoor pathway in PORD. SETTING: This was a collaboration study between laboratories and hospitals. SUBJECTS: Twenty-two Japanese patients with molecularly confirmed PORD and 1763 control subjects participated in this study. INTERVENTION: Urine steroid profile analysis was performed by gas chromatography/mass spectrometry. In five patients and 776 control subjects, urine samples were obtained before 12 months of age. MAIN OUTCOME MEASURE: The main outcome measure was identification of a urine steroid(s) indicating the backdoor pathway. RESULTS: In the PORD patients, pregnanediol, pregnanetriolone, and pregnanetriol were obviously elevated, and the urine steroid ratios reflecting CYP17A1 and CYP21A2 activities were decreased throughout the examined ages. Furthermore, etiocholanolone and 11-hydroxyandrosterone, which should originate almost exclusively from androstenedione in the conventional "frontdoor" pathway, were grossly normal or somewhat decreased since early infancy, whereas androsterone, which can be derived not only from androstenedione and dihydrotestosterone in the conventional frontdoor pathway but also from 5alpha-pregnane-3alpha,17alpha-diol-20-one in the backdoor pathway, was increased during early infancy and remained grossly normal thereafter. Thus, the androsterone to etiocholanolone ratio was increased during early infancy and remained grossly normal thereafter. 5alpha-Pregnane-3alpha,17alpha-diol-20-one was elevated throughout the examined ages. CONCLUSIONS: The increased androsterone excretion during early infancy, as compared with the etiocholanolone and 11-hydroxyandrosterone excretions in the same period, suggests the presence of the backdoor pathway in PORD.

Adolescent↗
PubMed2006

Hearing loss in Turner syndrome.

OBJECTIVE: To address the characteristics of hearing loss in patients with Turner syndrome (TS), we evaluated hearing levels of patients with TS and analyzed causative factors. STUDY DESIGN: Thirty-three patients with TS (8 to 40 years of age) were studied through the use of audiological measurements, and causative factors were explored. RESULTS: Twenty cases (35 of 66 ears tested) showed high-frequency (8 kHz) sensory neural hearing loss (HFQ-SNHL). Fifteen cases (26 ears) and 15 cases (24 ears) of the impaired 20 cases were unresponsive to distortion-product otoacoustic emissions and transient-evoked otoacoustic emissions, respectively. HFQ-SNHL showed little relation to the history of middle ear infection and puberty, although middle ear infections were seen in 11 of the 20 cases. The hearing thresholds at high frequencies were correlated with age and body height (P < .001). The age-dependent increase in hearing thresholds in the high frequencies was more apparent in patients with TS with monosomic 45, X than in those with the mosaic type (P < .05). CONCLUSIONS: More than 60% of patients with TS had HFQ-SNHL. Because the increase in hearing threshold at high frequencies was shown to depend on karyotype and aging, regular otological examination is important for the determination of proper treatment.

Acoustic Impedance Tests↗
PubMed2006

Current role of liver transplantation for methylmalonic acidemia: a review of the literature.

To evaluate the current role of liver transplantation (LT) for methylmalonic acidemia (MMA), we reviewed the literature on outcomes of this treatment, and describe three of our own cases of living-donor liver transplantation (LDLT). The total number of LT cases identified was 18. Transplantation mode was deceased donor LT in 12, including five combined liver-kidney transplantations (CLKT) from deceased donors, and LDLT in six. Three hospital mortalities were noted, because of metabolic decompensation, sepsis and aspergillosis. Although mean postoperative serum MMA level decreased to 13.8% +/- 9.2% (range 1.25-26.1%) of preoperative levels, four patients (22.2%) had renal insufficiency after isolated LT and three (16.7%) had postoperative neurological disability. Continuing metabolic damage to the kidney and brain may occur even after successful LT. Further evaluation is required to determine the long-term suitability of this treatment modality.

Adolescent↗
PubMed2006

Cytochrome P450 oxidoreductase deficiency in three patients initially regarded as having 21-hydroxylase deficiency and/or aromatase deficiency: diagnostic value of urine steroid hormone analysis.

In this study, we report on three Japanese patients with cytochrome P450 oxidoreductase (POR) deficiency (PORD). Case one was a 46,XY patient who was found to have mildly increased 17alpha-hydroxyprogesterone (17-OHP) by the neonatal mass screening. There was no maternal virilization during pregnancy, and he had no skeletal or genital abnormality. Thus, he was initially diagnosed as having nonclassical 21-hydroxylase deficiency (21-OHD). Cases two and three were 46,XX patients who were identified because of severely virilized external genitalia and maternal virilization during pregnancy. In case two, the neonatal mass screening was normal, and she had no skeletal abnormality except for mild adduction of bilateral third toes. Thus, she was initially diagnosed as having aromatase deficiency. In case three, the neonatal mass screening showed moderately increased 17-OHP, and no skeletal lesion other than rigid second metacarpophalangeal joints was identified in early infancy. Thus, she was initially suspected as having 21-OHD and/or aromatase deficiency. Subsequently, endocrine studies including urine steroid hormone analysis were performed for the assessment of glucocorticoid treatment in case one and for the virilized genitalia in cases two and three, showing adrenal and/or gonadal dysfunction characteristic of PORD. Thus, molecular analysis of POR was carried out, demonstrating homozygosity for R457H in cases one through three. The results imply that clinical features in PORD can be similar to those in 21-OHD or aromatase deficiency, and that comprehensive assessment of the pregnant course, physical examination, and adrenal and gonadal function studies is essential for the precise diagnosis of PORD.

17-alpha-Hydroxyprogesterone↗
PubMed2004

Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients.

We report on molecular and clinical findings in 10 Japanese patients (four males and six females) from eight families (two pairs of siblings and six isolated cases) with Antley-Bixler syndrome accompanied by abnormal genitalia and/or impaired steroidogenesis. Direct sequencing was performed for all the 15 exons of cytochrome P450 oxidoreductase gene (POR), showing two missense mutations (R457H and Y578C), a 24-bp deletion mutation resulting in loss of nine amino acids and creation of one amino acid (L612_W620delinsR), a single bp insertion mutation leading to frameshift (I444fsX449), and a silent mutation (G5G). R457H has previously been shown to be a pathologic mutation, and computerized modeling analyses indicated that the 15A>G for G5G could disturb an exonic splicing enhancer motif, and the remaining three mutations should affect protein conformations. Six patients were compound heterozygotes, and three patients were R457H homozygotes; no mutation was identified on one allele of the remaining one patient. Clinical findings included various degrees of skeletal features, such as brachycephaly, radiohumeral synostosis, and digital joint contractures in patients of both sexes, normal-to-poor masculinization during fetal and pubertal periods in male patients, virilization during fetal life and poor pubertal development without worsening of virilization in female patients, and relatively large height gain and delayed bone age from the pubertal period in patients of both sexes, together with maternal virilization during pregnancy. Blood cholesterol was grossly normal, and endocrine studies revealed defective CYP17A1 and CYP21A2 activities. The results suggest that Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis is caused by POR mutations, and that clinical features are variable and primarily explained by impaired activities of POR-dependent CYP51A1, CYP17A1, CYP21A2, and CYP19A1.

Abnormalities, Multiple↗
PubMed2004

Aire downregulates multiple molecules that have contradicting immune-enhancing and immune-suppressive functions.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a systemic disease with autoimmune characteristics caused by mutations in a single gene called AIRE. Although a defect in negative selection has been emphasized for the pathogenesis of the autoimmune symptoms on the basis of studies of Aire-targeted mice, the function of the gene in the peripheral immune system and the cause of immunodeficiency noted in the disease have not been clarified yet. In this study, we demonstrated using murine Aire transfectants that Aire downregulates IL-1 receptor antagonist (IL-1Ra), which is important for immune suppression, and major histocompatibility complex (MHC) class II molecules, which are critical for acquired immunity. It was surprising to learn that Aire, which has been supposed to positively regulate transcription, downregulates multiple molecules. This downregulation of IL-1Ra and MHC class II molecules seems to be caused by the competition for transcriptional coactivator, CREB-binding protein (CBP), and may explain part of the contradictory (i.e., both autoimmune and immunodeficient) nature of APECED.

Animals↗
PubMed2004

Genetic testing of glycogen storage disease type Ib in Japan: five novel G6PT1 mutations and a rapid detection method for a prevalent mutation W118R.

We devised a simple method using a TaqMan fluorogenic probe for detection of a prevalent G6PT1 mutation W118R among Japanese patients with glycogen storage disease type Ib. The W118R mutation was detected in three of six newly diagnosed Japanese patients. The W118R-negative alleles were screened for causative mutations by sequencing analysis, revealing five novel mutations. The genetic tests using the simple TaqMan method coupled with sequencing analysis would facilitate the early diagnosis of this disorder.

Adult↗
PubMed2004

Genitourinary phenotype in XX patients with distal 9p monosomy.

Although testicular development has been shown to be variably impaired in XY patients with distal 9p monosomy, ovarian and other genitourinary phenotype has poorly been studied in XX patients monosomic for the distal 9p region. Thus, we studied a 13-month-old infant with 46,XX,der(9)t(9;10)(p23;p13) (case 1) and an 11-year-old girl with 46,XX,der(9)t(9;16)(p23;q22) (case 2). Case 1 had primary hypogonadism (basal serum follicle stimulating hormone [FSH], 40.0 mIU/mL; leteinizing hormone [LH], 1.2 mIU/mL; estradiol [E2], <10 pg/mL), whereas case 2 had age-appropriate pubertal development (breast, Tanner stage 4; pubic hair, Tanner stage 3; menarche 11.7 years of age) and hormone values (FSH, 7.3 mIU/mL; LH, 6.7 mIU/mL; E2, 47 pg/mL). In addition, case 1 had hypoplastic labia majora, short distance between the vaginal orifice and the anus, and five renal cysts, and case 2 had anal atresia, short distance between the vaginal orifice and the anus, bilateral hydronephrosis of grade 3 with probable ureteropelvic junction stenosis, and renal dysfunction (serum creatinine, 1.52 mg/dL; urea nitrogen, 34.5mg/dL). Fluorescence in situ hybridization analysis for five regions and microsatellite analysis for 10 loci on 9p confirmed hemizygosity for the distal 9p region with the breakpoints between IFNA and D9S285 in case 1 and between D9S168 and D9S286 in case 2. The results, in conjunction with the previous data in XX patients with molecularly defined distal 9p monosomy, are consistent with the presence of a gene(s) involved in the development of indifferent gonad or subsequent ovarian differentiation in a approximately 11 Mb region distal to D9S168. In addition, it is possible that a gene(s) for anoperineal and renal development also maps distal to D9S168 and that for external genital development maps distal to D9S285 at the position approximately 16 Mb from the 9p telomere.

Adult↗
PubMed2004

Growth hormone treatment in short Japanese children born small for gestational age.

Recent reports have shown that high-dose growth hormone (GH) treatment in short children born with small for gestational age (SGA) resulted in a pronounced acceleration of linear growth. We describe the results of multicenter trials of recombinant human GH (rhGH) treatment in short SGA children in Japan. Two clinical studies were performed and the results were combined. Study 1 comprised 104 SGA children and study 2 comprised 61 SGA children. The patients were divided into three groups: group 1 consisted of 20 patients (13 boys and 7 girls) who received rhGH 25 microg/kg per day six or seven times per week in the first year and 50 microg/kg per day in the second year and thereafter; group 2 consisted of 48 patients (28 boys, 20 girls) who received rhGH 45/50 microg/kg per day; group 3 consisted of 44 patients (28 boys, 16 girls) who received 90/100 microg/kg per day. The mean increments in height SDS were 0.46, 0.67 and 0.94 SD in boys and 0.49, 0.79 and 0.93 SD in girls in groups 1, 2 and 3, respectively. The mean increment in height SDS at 2 years in group 3 was significantly greater than that in group 1, but it was not significantly different from that in group 2 in boys and girls. Our data demonstrated that high-dose GH administration significantly improved height velocity and height SDS in short SGA children. Additional studies are necessary to optimize a long-term GH treatment regimen and combined luteinizing hormone releasing hormone analog treatment for final height. Careful observation is also necessary to assess the metabolic effects of high-dose GH, especially on carbohydrate metabolism.

Asian People↗
PubMed2004

Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients.

We report on the clinical and molecular findings in 25 males and three females with Kallmann syndrome (KS) aged 10-53 yr. Ten males were from five families, and the remaining 15 males and three females were apparently sporadic cases. Molecular studies were performed for Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, also known as KAL2) by sequence analysis for all the coding exons, by PCR-based deletion analysis, and by fluorescence in situ hybridization (FISH) analysis, showing six novel and two recurrent intragenic KAL1 mutations in seven familial and four sporadic male cases and two novel intragenic FGFR1 mutations in two sporadic male cases. In addition, submicroscopic deletions at Xp22.3 involving VCX-A, STS, KAL1, and OA1 were identified in three familial cases and one sporadic male case affected by a contiguous gene syndrome. Clinical assessment in the 15 males with KAL1 mutations showed normal and borderline olfactory function in two males and right-side dominant renal lesion in seven males, in addition to variable degrees of hypogonadotropic hypogonadism (HH) in all the 15 males and olfactory dysfunction in 13 males. The two males with FGFR1 mutations had HH and anosmia and lacked other features. Clinical features in the remaining 11 cases with no demonstrable KAL1 or FGFR1 mutations included right renal aplasia in one female, cleft palate in one male, cleft palate and perceptive deafness in one male, and dental agenesis and perceptive deafness in one male, in addition to a variable extent of HH and olfactory dysfunction. The results suggest the following: 1) KAL1 mutations might be more prevalent in the Japanese patients than previously estimated in the Caucasian patients and can be associated with apparently normal olfactory function; 2) FGFR1 mutations account for approximately 10% of KS patients, as previously reported in the Caucasian patients, and can result in HH and olfactory dysfunction-only phenotype; and 3) renal aplasia, which is characteristic of KAL1 mutations, and cleft palate and dental agenesis, which are characteristic of FGFR1 mutations, can occur in patients without KAL1 and FGFR1 mutations.

Adolescent↗
PubMed2004

Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome.

We report on PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11) mutation analysis and clinical assessment in 45 patients with Noonan syndrome. Sequence analysis was performed for all of the coding exons 1-15 of PTPN11, revealing a novel 3-bp deletion mutation and 10 recurrent missense mutations in 18 patients. Clinical assessment showed that 1) the growth pattern was similar in mutation-positive and mutation-negative patients, with no significant difference in birth length [-0.6 +/- 2.2 sd (n = 10) vs. -0.6 +/- 1.4 sd (n = 21); P = 0.95], childhood height [-2.6 +/- 1.1 sd (n = 14) vs. -2.1 +/- 1.6 sd (n = 23); P = 0.28], or target height [-0.4 +/- 0.9 sd (n = 14) vs. -0.2 +/- 0.7 sd (n = 17); P = 0.52]; 2) pulmonary valve stenosis was more frequent in mutation-positive patients than in mutation-negative patients (10 of 18 vs. 6 of 27; P = 0.02), as was atrial septal defect (10 of 18 vs. 4 of 27; P = 0.005), whereas hypertrophic cardiomyopathy was present in five mutation-negative patients only; and 3) other features were grossly similar in the prevalence between mutation-positive and mutation-negative patients, but hematological abnormalities, such as bleeding diathesis and juvenile myelomonocytic leukemia, were exclusively present in mutation-positive patients (5 of 18 vs. 0 of 27; P = 0.007). The results suggest that PTPN11 mutations account for approximately 40% of Noonan syndrome patients, as has been reported previously. Furthermore, assessment of clinical features, in conjunction with data reported previously, implies that the type of cardiovascular lesions and the occurrence of hematological abnormalities are different in mutation-positive and mutation-negative patients, whereas the remaining findings are similar in the two groups of patients.

Adolescent↗
PubMed2004

Novel compound heterozygous AIRE mutations in a Japanese patient with APECED.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder defined by the presence of two of three conditions, namely, Addison's disease, hypoparathyroidism, and mucocutaneous candidiasis. APECED is caused by alteration in a single gene, named the autoimmune regulator (AIRE) gene. We report AIRE gene mutations in a Japanese female with APECED. The patient is a 22-year-old Japanese female who was diagnosed with Addison's disease, hypoparathyroidism, and mucocutaneous candidiasis at age 8 years. Sequence analysis of the AIRE gene revealed novel compound heterozygous mutations. One was 1471 delCinsTT in exon 11 (GenBank accession no. AB006682), which leads to a frameshift and premature truncation of a 502 amino acid protein. The other was a G-->A transition at IVS11+1. Her mother was heterozygous for 1471 delCinsTT and was normal homozygous for IVS11+1. We found novel compound heterozygous mutations in the AIRE gene of a Japanese female with APECED.

Addison Disease↗
PubMed2004

[Congenital lipoid adrenal hyperplasia].

Congenital lipoid adrenal hyperplasia(CLAH) is known as the severest form of congenital adrenal hyperplasia, which is characterized by the lack of biosynthesis of all steroid hormones and its metabolites due to the failure in converting cholesterol to pregnenolone, the first and rate-limiting step of steroid synthesis. The genetic etiology has been identified; trafficking defect of cholesterol to mitochondria due to defect of StAR gene, and conversion defect of cholesterol to pregnenolone at mitochondrial membrane due to the defect of CYP11A, cholesterol side chain cleavage enzyme. The advancement of genetical analysis has revealed that the clinical feature is not only defined as severe salt-loosing and complete failure of musculinization, but also as relatively mild or late-onset form. Spontaneous puberty may exhibit to 46,XX patients while 46,XY subjects will never show pubertal signs. It suggested that 1) it may take more time to deposit lipid particles to cause irreversible damage to ovary than to testis, 2) there exists the other ways in cholesterol trafficking which rescue the StAR deficiency.

Adrenal Hyperplasia, Congenital↗
PubMed2003

The comparison of the effects of short-term growth hormone treatment in patients with achondroplasia and with hypochondroplasia.

The effects of recombinant human growth hormone (rhGH) treatment for three years were compared in patients with achondroplasia (ACH) and hypochondroplasia (HCH), whose diagnosis had been confirmed by DNA analysis of the fibroblast growth factor receptor 3 gene. Height SDS (H-SDS) and height velocity SDS (HV-SDS) using the standard for ACH significantly improved during three-year treatment as compared with that before treatment in both ACH and HCH except HV-SDS in the third year. The improvement was much greater in HCH than in ACH. The mean increase H-SDS using the standard for ACH in three years in ACH (from -0.2 SD to 0.1 SD) is almost negligible but that in HCH (from 1.2 SD to 2.6 SD) can be estimated as effective clinically. It can be concluded short-term GH treatment in HCH is effective to increase growth rate and H-SDS, but it has little effect in ACH. Further studies would be required to confirm the other beneficial effects of GH treatment such as increase in bone mineral density in ACH and HCH and the effect on the final height.

Achondroplasia↗
PubMed2003

[Growth hormone treatment in children with short stature due to IUGR].

Most of the children with intrauterine growth retardation show fair catch-up growth by two years of age, while approximately 10% of them fails the catch-up and remains short as adult. Growth hormone has been applied to those who stay short (height<-2SD of mean) in relatively high dose, and favorable results come out in terms of not only height but also psychosocial positiveness. The long-term out come, however, should be carefully monitored, especially the effect of early pubertal onset for height and pubertal height gain on the final height, and metabolic effect of long-term pharmacological dose of GH exposure from early childhood, such as glucose intolerance.

English Abstract↗