PubMed Health⌕ Search

Biomedical subjects

R Fukuzawa

Publications and source records attributed to R Fukuzawa.

13 recordsLinked to original sources
PubMed2005

Imprinting, expression, and localisation of DLK1 in Wilms tumours.

BACKGROUND: Loss of imprinting (LOI) of the H19/IGF2 domain is a common feature of Wilms tumour. The GTL2/DLK1 domain is also imprinted and is structurally similar to H19/IGF2. The question arises as to whether DLK1 also undergoes LOI in Wilms tumour, or whether the LOI mechanism is restricted to the H19/IGF2 domain. AIM: To investigate the imprinting status of DLK1 in Wilms tumours with IGF2 LOI. The cellular localisation of DLK1 in the tumours was also examined. METHODS: DLK1 expression was measured by quantitative real time polymerase chain reaction (Q-PCR) in 30 Wilms tumours that had previously been classified according to whether they had IGF2 LOI, WT1 mutations, or 11p15.5 loss of heterozygosity. Allele specific expression of DLK1 was examined by direct sequencing using a DLK1 exon 5 polymorphism (rs1802710). Immunohistochemical analysis of DLK1 was performed on 13 tumours and two intralobar nephrogenic rests, in addition to two fetal kidneys and one fetal skeletal muscle sample. RESULTS: Ten of 30 tumours were heterozygous for rs1802710 and all tumours showed retention of imprinting of DLK1. Moderate to high expression of DLK1 was detected by Q-PCR in nine of 13 tumours with myogenic differentiation. Immunohistochemical expression of DLK1 was detected in the myogenic elements. CONCLUSION: LOI does not occur at the GTL2/DLK1 domain in Wilms tumour. This finding suggests that LOI at 11p15.5 does not reflect non-specific disruption of a shared imprinting mechanism. DLK1 expression in Wilms tumour might reflect the presence of myogenic differentiation, rather than an alteration of its imprinting status.

Alleles↗
PubMed2001

Pulmonary epithelial cell maturation in hyperplastic lungs associated with fetal tracheal agenesis.

BACKGROUND/PURPOSE: Cellular differentiation of pulmonary hyperplasia has not been reported in human cases. The authors studied surfactant protein expression and ultrastructure of pulmonary epithelial cells in fetal hyperplastic lungs associated with congenital tracheal agenesis. METHODS: The maturation of pulmonary epithelial cells was assessed by immunohistochemical examination for surfactant proteins (SP-A, mature SP-B, proSP-B, proSP-C, and SP-D) and transmission electron microscopy. As controls normal lung portions of 8 fetuses born at 21 weeks gestation were used. RESULTS: Mature SP-B and SP-D was detected in terminal airways in this case, but not in controls. In electron microscopy, lamellar bodies were recognized, and glycogen granules were less abundant in terminal airway cells. CONCLUSION: The differentiation of pulmonary epithelial cells appeared to be more advanced for the gestational age in pulmonary hyperplasia with congenital tracheal agenesis. J Pediatr Surg 36:1845-1848.

Adult↗
PubMed2001

A novel WT1 gene mutation associated with wilms' tumor and congenital male genitourinary malformation.

WT1 is located on the short arm of human chromosome 11 and consists of 10 coding exons. Mutations of this gene have been reported to be the cause of Wilms' tumor, congenital male genitourinary malformations, and/or renal disorders. We describe here a novel WT1 gene mutation, i.e. a point mutation at intron 7 (+2) in both the tumor and the germline cells of a patient with Wilms' tumor and congenital male genitourinary malformation, but without renal disorder. The position of the mutation is at a splice donor site of intron 7, which causes the splicing out of exon 7 and generates a truncated protein. This type of mutation in the WT1 zinc finger domain has not been reported before. The mutation is of paternal origin and is heterozygous in the germline cells. In the tumor cells, however, the maternal allele is largely lost, from 11p12 to 11p15, which results in maternal loss of heterozygosity. These results, together with the data from previous reports, suggest that WT1 may function in gonadogenesis, nephrogenesis, and Wilms' tumor tumorigenesis.

Chromosomes, Human, Pair 11↗
PubMed2000

A novel imprinted gene, KCNQ1DN, within the WT2 critical region of human chromosome 11p15.5 and its reduced expression in Wilms' tumors.

WT2 is defined by a maternal-specific loss of heterozygosity on human chromosome 11p15.5 in Wilms' and other embryonal tumors. Therefore, the imprinted genes in this region are candidates for involvement in Wilms' tumorigenesis. We now report a novel imprinted gene, KCNQ1DN (KCNQ1 downstream neighbor). This gene is located between p57(KIP2) and KvLQT1 (KCNQ1) of 11p15.5 within the WT2 critical region. KCNQ1DN is imprinted and expressed from the maternal allele. We examined the expression of KCNQ1DN in Wilms' tumors. Seven of eighteen (39%) samples showed no expression. In contrast, other maternal imprinted genes in this region, including p57(KIP2), IMPT1, and IPL exhibited almost normal expression in these samples, although some samples expressed IGF2 biallelically. These results suggest that KCNQ1DN existing far from the H19/IGF2 region may play some role in Wilms' tumorigenesis along with IGF2.

Chromosome Mapping↗
PubMed2000

[Wilms' tumors and malformation complexes].

Wilms' tumor is an embryonal tumor which is derived from metanephric metanephric blastema. The occurrence of both sporadic and hereditary forms, along with various congenital abnormalities of Wilms' tumor suggest that the tumors develop when a predisposing germ line mutation is accompanied by a second mutation. The existence of both gross chromosomal abnormalities has led to the genetic characterization of a number of loci involved in the development of Wilms' tumor. A tumor suppressor gene for Wilms' tumor, WT1, has been isolated from the 11p13 region. The product of this gene is a transcription factor with four zinc fingers. Because of expression of WT1 is limited to the developing glomeruli of the kidneys and the genital ridge, it is thought to have a functional role in renal and gonadal organogesis. Thus dysfunction of WT1 causes loss of normal regulation of proliferation and leads to tumor formation and occurrence of Wilms' tumor anomaly complexes. The role of the imprinting genes, H19 and IGF2 in oncogenesis of Wilms' tumors are also discussed.

Chromosome Aberrations↗
PubMed1999

Digynic triploid infant surviving for 46 days.

We report on a triploid infant who survived for 46 days. She had severe intrauterine growth retardation, relative macrocephaly, and a small, noncystic placenta, which are manifestations compatible with type II phenotype. Cultured amniotic fluid cells, skin fibroblasts, cord blood, and peripheral blood lymphocytes all showed a nonmosaic 69,XXX karyotype. Analysis of chromosomal heteromorphisms and microsatellite DNA polymorphisms in the infant and her parents indicated that the extra haploid set in the infant resulted from nondisjunction at maternal second meiosis. Postzygotic, mitotic nondisjunction was ruled out because of the presence of both homozygous and heterozygous markers of maternal origin. A search of the literature demonstrated five triploid infants, including the girl we described, who survived 4 weeks or more, and the parental origin of whose triploidy was studied: four were digynic and one was diandric. These findings support the notion that type II triploids are digynic in parental origin and that they survive longer than type I, diandric triploids.

Abnormalities, Multiple↗
PubMed1999

High frequency of inactivation of the imprinted H19 gene in "sporadic" hepatoblastoma.

Embryonal tumors such as Wilms' tumor (WT), embryonal rhabdomyosarcoma (eRMS) and hepatoblastoma have been thought to have a common pathogenetic mechanism. H19 was found to be inactivated in WT and eRMS either by loss of heterozygosity or by hypermethylation of the maternal allele. We show here that the expression of the H19 gene is inactivated by maternal allelic loss or hypermethylation in 7 out of 8 "sporadic" hepatoblastomas. Furthermore, we analyzed expression of the IGF2 gene. Loss of imprinting of the IGF2 gene was detected and linked to inactivation of the H19 gene in 2 hepatoblastomas. However, 2 sporadic cases demonstrated monoallelic expression of the IGF2 gene with inactivation of the H19 gene. Our results suggest that H19 may play a role as a common imprinted tumor suppressor gene in "sporadic" hepatoblastomas but may at times work independently of IGF2 expression.

Child↗
PubMed1998

Variability of platyspondylic lethal chondrodysplasia: another case report.

We report the radiological and histological findings of another case of platyspondylic lethal chondrodysplasia. The patient was a girl, who died of respiratory failure at 18 days of age. The radiological changes comprised moderate platyspondyly with ovoid-shaped vertebral bodies, broad and short ilia, rhizomelic shortening and mild bowing of the long bones (particularly of the humeri), relatively long short tubular bones, and retarded epiphyseal ossification and ragged metaphyses, which were most similar to those of a mild variant of this entity, the Luton type. However, the histological findings of cartilage, including hypercellularity of the reserve zone with round resting chondrocytes, relatively normal column formation of the proliferative and hypertrophic zones, and incorporation of hypertrophic cartilage with a columnar arrangement into metaphyseal bony trabeculae, resemble those of a severe variant of this entity, the Torrance type. Our observation provides an insight into the phenotypic variabilities of platyspondylic lethal chondrodysplasia.

Fatal Outcome↗
PubMed1998

Do intronic mutations affecting splicing of WT1 exon 9 cause Frasier syndrome?

The WT1 gene, one of the genes responsible for Wilms tumour, is thought to play a crucial role in the development of the kidneys and gonads. This gene encodes four protein isoforms resulting from two alternative splicing sites, one of which involves inclusion or exclusion of lysine, threonine, and serine (KTS) between the third and fourth zinc finger domains. WT1 is virtually always mutationally inactivated in patients with Denys-Drash syndrome. We analysed WT1 in eight patients who had been diagnosed as having this syndrome, and identified five previously unknown mutations affecting splicing donor sites of intron 9. These mutations affect alternative splicing. The isoforms retaining KTS are not produced. The clinical features of the patients with these intronic mutations were consistent with those of Frasier syndrome, characterised by a more slowly progressive nephropathy than Denys-Drash syndrome, associated streak gonads, and no Wilms tumour development. Our results indicate that WT1 isoforms, including/excluding KTS, have different functions in tumorigenesis and organogenesis of the kidneys and gonads.

Adolescent↗
PubMedDate not supplied

Nesidioblastosis and mixed hamartoma of the liver in Beckwith-Wiedemann syndrome: case study including analysis of H19 methylation and insulin-like growth factor 2 genotyping and imprinting.

An infant with persistent hyperinsulinemic hypoglycemia, diffuse nesidioblastosis, and mixed hamartoma of the liver (MHL), in addition to demonstrating clinical, pathologic, and molecular manifestations of Beckwith-Wiedemann syndrome (BWS), is the subject of this report. H19 methylation assay and allelic expression analysis for insulin-like growth factor 2 (IGF2) indicated that the patient was mosaic for paternal isodisomic cells and normal cells in lung tissue, nontumoral liver tissue, tissue from the MHL, and pancreatic tissue. We propose that abundant IGF2 expression during development due to paternal isodisomy resulted in hepatomegaly and islet cell hyperplasia, which led to nesidioblastosis. MHL, by contrast, may have resulted from a decrease in disomic cells, compared with nontumoral liver tissue, which showed an increase in disomic cells. Thus, somatic mosaicism may result in unbalanced tissue growth, which may contribute to the formation of MHL in BWS.

Allelic Imbalance↗
PubMedDate not supplied

Long-term peritoneal dialysis is a risk factor of sclerosing encapsulating peritonitis for children.

OBJECTIVE: Sclerosing encapsulating peritonitis (SEP) is a clinical syndrome with a high mortality rate and is a serious complication of peritoneal dialysis (PD). Peritoneal sclerosis (PS) is a histological diagnosis. PS is usually observed in the peritoneal specimens of patients with SEP. Avoiding SEP is considered to be extremely important for pediatric patients who may require long-term PD. In this study, the characteristics of patients with PS were investigated to determine when to perform peritoneal biopsies and how long PD can be performed safely. DESIGN: A retrospective single-center study. SETTING: Tokyo Metropolitan Kiyose Children's Hospital. PATIENTS: A total of 109 children younger than 16 years have received chronic PD in our unit since 1981. Among these children, 16 patients had been on PD for more than 5 years (mean 7.4+/-2.5 years) from May 1992 to March 1999. Peritoneal biopsies were performed in 14 of the 16 patients, who were divided into two groups based on the histological diagnoses: a PS and a peritoneal fibrosis (PF) group. RESULTS: The 14 patients were on PD for a mean of 7.8+/-2.5 years. There were 8 patients with PS and 6 patients with PF. SEP was observed in 2 patients in the PS group. The risk of PS increased with the duration of PD: 57% (8/14) > 5 years, 80% (4/5) > 8 years, and 100% (3/3) > 10 years. All patients in the PS group showed both peritoneal calcifications on abdominal CT scan and poor ultrafiltration at the time of diagnoses. CONCLUSION: Long-term PD was the important risk factor of SEP. If both peritoneal calcification on abdominal CT scan and poor ultrafiltration are observed in a patient on PD more than 5 years, a peritoneal biopsy should be performed. If PS is detected, PD should be discontinued.

Adolescent↗