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Biomedical subjects

N Niikawa

Publications and source records attributed to N Niikawa.

At least 91 records · Page 5Linked to original sources
PubMed1999

47,XX,UPD(7)mat,+r(7)pat/46,XX,UPD(7)mat mosaicism in a girl with Silver-Russell syndrome (SRS): possible exclusion of the putative SRS gene from a 7p13-q11 region.

Maternal uniparental disomy for chromosome 7 (UPD7) may present with a characteristic phenotype reminiscent of Silver-Russell syndrome (SRS). Previous studies have suggested that approximately 10% of SRS patients have maternal UPD7. We describe a girl with a mos47,XX,+mar/46,XX karyotype associated with the features of SRS. Chromosome painting using a chromosome 7 specific probe pool showed that the small marker was a ring chromosome 7 (r(7)). PCR based microsatellite marker analysis of the patient detected only one maternal allele at each of 16 telomeric loci examined on chromosome 7, but showed both paternal and maternal alleles at four centromeric loci. Considering her mosaic karyotype composed ofdiploid cells and cells with partial trisomy for 7p13-q11, the allele types obtained at the telomeric loci may reflect the transmission of one maternal allele in duplicate, that is, maternal UPD7 (complete isodisomy or homodisomy 7), whereas those at the centromeric loci were consistent with biparental contribution to the trisomic region. It is most likely that the patient originated in a 46,XX,r(7) zygote, followed by duplication of the maternally derived whole chromosome 7 in an early mitosis, and subsequent loss of the paternally derived ring chromosome 7 in a subset of somatic cells. The cell with 46,XX,r(7) did not survive thereafter because of the monosomy for most of chromosome 7. If the putative SRS gene is imprinted, it can be ruled out from the 7p11-q11 region, because biparental alleles contribute to the region in our patient.

Chromosomes, Human, Pair 7↗
PubMed1998

Identification, characterization and mapping of the human ZIS (zinc-finger, splicing) gene.

From a human fetal brain cDNA library, we isolated two transcripts (ZIS-1 and ZIS-2) corresponding to the human ZIS gene, an ortholog of the rat Zis (zinc finger, splicing). A comparison of base sequences of the cDNA and its corresponding genomic DNA (a P1-derived artificial chromosome clone) revealed that both transcripts have an ORF of 1011bp and encodes 337 amino acids, but ZIS-1 has 10 exons and ZIS-2 contains 11 exons. Although both transcripts share the first nine exons, exon 10 of ZIS-2 is lacking in ZIS-1, and instead, exon 11 (10th exon) of ZIS-1 is larger in size, leading to the longer 3'-UTR. Thus, the two transcripts result from differential splicing. A Northern blot analysis on various adult and fetal tissues revealed that 5.2- and 3.2-kb transcripts were ubiquitously expressed, and 3.9- and 1.9-kb transcripts were highly expressed in the fetal brain and kidney, respectively. There were several other transcripts that may be alternatively processed forms of the human ZIS. Considering the ZIS gene size, the 3.2-kb transcripts most likely corresponds to ZIS-1 and may act as a major transcript of ZIS. The human ZIS has a high homology to the rat Zis for the coding DNA sequence with 91% identity and for the amino acid sequence with 87% identity. ZIS and Zis contain the same numbers of exons and introns. Both genes have unusually long 3'-UTR, and their encoding proteins contain similar components, i.e. a zinc finger domain, a nuclear localization signal, an Asp-Glu region, and a Ser-Arg-rich region. Furthermore, the expression patterns of the two genes in tissues are similar each other. Thus, the human ZIS may act as a transcriptional factor to regulate transcription and/or splicing, as does the rat Zis.

Amino Acid Sequence↗
PubMed1998

Frequent loss of imprinting of the H19 and IGF-II genes in ovarian tumors.

Several human imprinted genes have been identified and are implicated in genetic diseases and tumorigenesis. We studied alterations of two imprinted genes, the paternally imprinted H19 and maternally imprinted IGF2, in 15 ovarian tumors with various cell types. To know allele-specific expression of the two genes, we analyzed restriction fragment length polymorphisms (RFLPs) at the 3'-untranslated region (UTR) in their cDNA, compared with those in the respective genomic DNA. As a result, biallelic H19 and IGF2 expression was observed in 8 (62%) of 13 informative (heterozygous) ovarian cancers and in 6 of 11 informative cases, respectively. H19 loss of imprinting (LOI) was most frequently observed in malignant serous cystadenocarcinoma (in four of six cases), whereas IGF2 LOI was not common in malignant epithelial cancers because three of six such LOI events occurred in benign mucinous cystadenomas and non-cancerous endometriotic cyst. Our data suggest that the alteration of H19 and IGF2 imprinting plays differential roles in tumorigenesis and progression of ovarian tumors, depending on the tissue type as well as the developmental stage. Our data may argue against tumor suppressor activity of H19 in ovarian cancers.

Alleles↗
PubMed1998

Translocation t(X;21)(q13.3; p11.1) in a girl with Menkes disease.

A girl with a 46,X,t(X;21) (q13.3;p11.1) karyotype presented with skin redundancy, especially in the neck, prominent occiput and micrognathia, and later developed hypotonia, hypopigmentation, sparse scalp hair, and profound mental retardation characteristic of Menkes disease. Her serum copper (14 microg/dl) and ceruloplasmin (9 mg/dl) levels were extremely low. Fluorescent in situ hybridization analysis with a 100-kb P1-derived artificial chromosome probe containing the Menkes disease gene demonstrated three twin-signals, one on the normal X chromosome and one each on derivative chromosomes X and 21, indicating that the Xq13.3 breakpoint was located within the gene. Replication pattern analysis showed that the normal X chromosome was late replicating, whereas the derivative X chromosome was selectively early replicating. These results indicated that Menkes disease in our patient resulted from a de novo translocation that disrupts the disease gene.

Adenosine Triphosphatases↗
PubMed1998

Three new cases of spondylocarpotarsal synostosis syndrome: clinical and radiographic studies.

Spondylocarpotarsal synostosis syndrome (SSS) or congenital synspondylism is a recently delineated clinical entity. At least 15 patients have been reported. We present 3 new patients, 2 of whom were sibs born to first-cousin parents. All of our patients had multiple synostoses involving cervical, thoracic and/or lumbar vertebral bodies and carpal/tarsal bones, scoliosis/lordosis, and short stature. Sensorineural deafness was found in 2 of the 3 patients. Analysis of clinical manifestations suggests clinical variability and genetic heterogeneity in SSS. Of a total of 18 SSS patients, 10 were five pairs of sibs from five families, with first-cousin consanguinity of parents in 3, indicating that at least one type of SS is an autosomal-recessive disorder.

Abnormalities, Multiple↗
PubMed1998

Origin and mechanism of formation of 45,X/47,XX,+21 mosaicism in a fetus.

Chromosome analysis of amniotic fluid cells from a 17-week-old fetus with a nuchal cystic hygroma showed a 45,X/47,XX,+21 karyotype. Analyses of cord blood lymphocytes, skin fibroblasts, amniotic membrane, and chorionic villi demonstrated both cell lines in various proportions. We studied the origin and mechanism of formation of the double mosaic aneuploid using Q-banded chromosomal heteromorphisms, and one RFLP, two VNTRs, one tetranucleotide repeat, 28 CA repeat markers, mapped to every member of chromosomes. The heteromorphic markers examined showed no discordant patterns in parent-to-child transmission or between the two cell lines except for those in chromosomes 21 and X. Fetal DNA was extracted from its established monoclonal fibroblast cell lines with 45,X or 47,XX,+21 karyotypes. Genotyping with the DNA markers showed that each cell line was identical at every locus, except for chromosome 21 or X loci, indicating that the fetus was not a chimera but a mosaic. The 21-trisomic cells had one paternal allele and two maternal heterozygous alleles at the D21S270 locus, and the 45,X (21-disomic) cells had two biparental alleles. Alleles at two X chromosomal loci, DXS991 and DXS8057, were biparental in the 47,XX,+21 cells, whereas only the paternal allele was retained in the 45,X cells. Based on these findings, we concluded that the fetus started as a 47,XX,+21 zygote that had resulted from nondisjunction at the maternal first meiotic division and that one each of the maternally derived chromosomes 21 and X was lost during an early mitotic division, leading to the mosaicism.

Alleles↗
PubMed1998

Visible integration of the adenosine deaminase (ADA) gene into the recipient genome after gene therapy.

Gene therapy for patients with adenosine deaminase (ADA) deficiency has become practical in the 1990s, and the exogenous gene has been reported to survive for several years in the recipient genome. To evaluate the integration efficiency of the ADA gene (ADA) into peripheral blood lymphocytes (PBL) of a patient with ADA deficiency who is receiving gene therapy, we performed two-color interphase fluorescence in situ hybridization (FISH) analysis by using digoxigenin-labeled ADA-cDNA and the biotin-labeled lambda-genomic ADA clone as probes. After each of 9 sequential series of gene therapy, interphase nuclei of 100 mononuclear cells from the patient were analyzed, and those of a LASN-producing cell line were used as a control. FISH signals were detected with rhodamine and FITC for the cDNA and the genomic DNA, respectively. The number of PBL giving a transgene signal grew after the sequential gene therapies, and the proportion of signal-positive cells reached about 10%. Our results indicate that the two-color FISH system can be used as a potential aid to monitor the efficiency of the ADA gene therapy.

3T3 Cells↗
PubMed1998

Promoter-specific insulin-like growth factor 2 gene imprinting in human fetal liver and hepatoblastoma.

Insulin-like growth factor 2 (IGF2) gene imprinting has been demonstrated to be promoter-specific, in that expression from the P1 promoter is biallelic whereas that from the P2-P4 promoters is monoallelic. In the present study, in order to investigate IGF2 gene imprinting status at the cellular level, allelic analysis was performed of IGF2 gene expression transcribed from the P1 and P3 promoters, using reverse transcription polymerase chain reaction (RT-PCR) on human fetal liver and hepatoblastoma. In situ hybridization was also undertaken, to obtain information about the cellular localization of transcripts expressed from the P1 and P3 promoters. The results indicated that transcripts expressed from the P1 and P3 promoters co-localized in the same fetal or neoplastic hepatocytes. These data should provide information regarding the molecular basis of genomic imprinting, suggesting that an imprint recognized for the differential expression may be strictly local and localized downstream of the IGF2 P1 promoter.

Alleles↗
PubMed1998

The gene for mesomelic dysplasia Kantaputra type is mapped to chromosome 2q24-q32.

Mesomelic dysplasia Kantaputra type (MDK) (MIM *156232) is a new autosomal dominant skeletal dysplasia characterized by dwarfism, shortening of the forearms/lower-legs, carpal/tarsal synostosis, and dorsolateral foot deviation. We studied a Thai family in which 15 members in 3 generations were affected with MDK. With reference to the breakpoints of a balanced translocation [t(2;8)(q31;p21)] in patients from a previously reported Italian family with a skeletal dysplasia that appears similar to MDK, a linkage analysis was performed in the Thai family using 50 CA-repeat markers mapped to nearby regions (2q22-q34 and 8p24-p21) of the translocation breakpoints. The results clearly ruled out a linkage of MDK to marker loci at the 8p24-p21 region, whereas all nine affected members available for the study shared a haplotype at four loci (D2S2284, D2S326, D2S2188, and D2S2314) spanning about 22.7 cM in the 2q24-q32 region. The computer-assisted two-point linkage analysis revealed maximum logarithm of odds (lod) scores of 4.82, 4.21, 4.82, and 4.21 (theta = 0) at these loci, respectively. These data indicated that the MDK locus is in the vicinity of D2S2284 and D2S2188 loci that are most likely mapped to 2q24-q32.

Chromosome Mapping↗
PubMed1998

A SacII polymorphism in the human ASCL2 (HASH2) gene region.

The mouse achaete-scute homolog-2 gene (Ascl2 or Mash2) encodes a transcription factor playing a role in the development of the trophoblast. The Ascl2 gene is paternally imprinted in the mouse, but whether this applies to its human homolog is unknown. In the present study, we found a SacII polymorphism in the possible 3' untranslated region (UTR) of the gene. It would be very useful to determine definitively whether the gene is imprinted, as well as to analyze the allelic methylation status of the gene.

Alleles↗
PubMed1998

Maternal uniparental disomy for chromosome 14 in a boy with intrauterine growth retardation.

Maternal uniparental disomy (UPD) for chromosome 14 [upd(14)mat] may cause a characteristic phenotype with growth and developmental deficiency and precocious puberty. We report the case of a Japanese infant with an isochromosome 14 [i(14q)] and intrauterine growth retardation (IUGR). The infant is one of triplets comprising a boy (the patient) and two karyotypically normal girls. We analyzed parent-child transmission modes of alleles on the i(14q) at 17 CA-repeat marker loci along the entire length of chromosome 14. Genotypes at 4 proximal and 5 distal loci on the i(14q) were consistent with maternal isodisomy, whereas those at an intervening region indicated maternal heterodisomy. Thus, the derivative chromosome 14 had arisen through a translocation between maternal homologous chromosomes 14 [t(14;14)(p10;q10)] after at least two crossing-over events at the first meiosis. This result also suggests that there must be maternally imprinted gene(s) on 14q, and that loss of the functionally active, paternally derived allele in the same locus may lead to IUGR. Alternatively, IUGR may be an autosomal recessive trait. In the latter case, the mother would be a heterozygote and the putative disease locus would be either at the most proximal or most distal region of 14q.

Abnormalities, Multiple↗
PubMed1998

A HhaI/BstUI polymorphism in a novel gene at human chromosome 11p15.5.

We found a HhaI/BstUI polymorphism in the 3' untranslated region of a novel gene which was localized to 11p15.5. This region is one of prominent imprinting domains and contains multiple imprinted genes, such as H19, IGF2, KVLQT1, and p57KIP2, which suggests that regional factors might contribute to the imprinting. This polymorphism will be useful in the allelic analysis of expression and methylation of the novel gene.

Alleles↗
PubMed1998

No parental origin bias for the rearranged chromosomes in myeloid leukemias associated with t(9;22), t(8;21) and t(15;17).

We investigated parental origin of rearranged chromosomes 9 and 22 (9q + and 22q -) in five patients with Ph-positive chronic myeloid leukemia (CML) using the C-banding and silver-staining methods of nucleolus organizer regions, respectively; of rearranged chromosome 21 (21q +) in seven patients with t(8;21)-positive acute myeloid leukemia (AML); and of rearranged chromosome 15 (15q +) in six patients with t(15;17)-positive AML. It was found that these rearranged chromosomes can be of either paternal or maternal origin. Although the number of patients examined was small, these results indicate that the genes rearranged as a result of these chromosome translocations (ABL, BCR, AML-1 and PML) are not genomically imprinted.

Adolescent↗
PubMed1998

Genomic discordance between monozygotic twins discordant for schizophrenia.

OBJECTIVE: Genomic DNA of monozygotic twins discordant for schizophrenia was analyzed to determine whether their genomes were truly identical. METHOD: The subjects were monozygotic male twins, one of whom had DSM-III-R schizophrenia, undifferentiated type. Genomic DNA was extracted from leukocytes and was applied to restriction landmark genome scanning analysis, which was developed for a high-speed survey of restriction sites throughout a genome and measurement of their copy number in each locus. RESULTS: After comparisons of patterns with approximately 2,000 spots, the authors detected at least two spots with autoradiographic intensities that obviously differed in the two twins. CONCLUSIONS: The discrepancies likely were generated either by differences in the methylation status at NotI sites between the twins or by submicroscopic changes occurring at NotI-flanking sites in one twin after (or simultaneous with) twinning. In either case, the difference may influence the transcription level of one or more genes.

Adult↗
PubMed1998

Comparative reverse transcription-polymerase chain reaction and in situ hybridization analyses of human imprinted p57KIP2 and insulin-like growth factor 2 gene transcripts in fetal kidney and Wilms' tumors using archival tissue.

p57KIP2 (KIP2) is a cyclin-dependent kinase inhibitor that arrests cells in G1 and an imprinted gene mapped on chromosome 11p15.5. To investigate the role of KIP2 in Wilms' tumor (WT), DNA and RNA were extracted from archival tissue sections of WT. KIP2 expression was investigated by reverse transcription-polymerase chain reaction and in situ mRNA hybridization. Thirteen of 39 WT were informative for length polymorphism of KIP2 and subjected to reverse transcription-polymerase chain reaction. KIP2 was expressed predominantly from one allele, although a low level of expression was also detected from the other. Three WT with loss of heterozygosity at the KIP2 locus demonstrated that the remaining KIP2 allele was still active, which was also confirmed by in situ hybridization. Furthermore, among 13 KIP2-informative WT, 2 were heterozygous for insulin-like growth factor II (IGF2). Allele-specific analysis demonstrated that one showed monoallelic IGF2 expression, whereas the other showed biallelic expression. In situ hybridization of fetal kidney showed that KIP2 transcripts were detected in a variety of cell types, among which differentiated epithelial structures showed higher expression than undifferentiated mesenchyme, whereas IGF2 was expressed predominantly in undifferentiated mesenchyme and renal vesicles of an early phase. WT demonstrated KIP2 and IGF2 hybridization patterns similar to fetal kidney in that KIP2 transcripts were detected in epithelial structures and blastema, whereas IGF2 transcripts were seen in blastema and immature epithelial structures. Hybridization results indicated that KIP2 expression in WT did not appear to be significantly reduced compared with that in fetal kidney and that WT demonstrated a significant amount of KIP2 transcripts regardless of retention or loss of heterozygosity at the KIP2 locus. These data suggest that although KIP2 may play a role in differentiation of the fetal kidney, it is not likely as a tumor suppressor gene, which is implicated as the cause of the development of a majority of WT.

Alleles↗
PubMed1998

[Identification of aneuploids in uncultured amniotic fluid cells by interphase fluorescence in situ hybridization].

We report the diagnosis of aneuploids in uncultured amniotic fluid cells by the use of interphase fluorescence in situ hybridization (FISH). About a dozen of cases was studied to detect chromosome aneuploids (trisomies 13, 18 and 21, and monosomy X), especially those in the perinatal period. Results of FISH experiments in each specimen were compared with those of conventional chromosome analysis, and showed no discrepancy between them in most cases. FISH analysis revealed that four 18-trisomies had two different cells, one of which showed two fluorescence signals and the other three signals, the result indicating a maternal cell contamination. Thus, special attention should be paid when FISH analysis is adopted to the diagnosis in uncultured amniotic fluid cells in order to avoid misdiagnosis that may originate in maternal cell contamination.

Amniotic Fluid↗
PubMed1997

A 1.2-megabase BAC/PAC contig spanning the 14q13 breakpoint of t(2; 14) in a mirror-image polydactyly patient.

We previously assigned a 14q13 breakpoint of t(2; 14) in a patient with mirror-image polydactyly to a segment between two loci, AFM200ZH4 and D14S306, within a genetic distance of 0.6 cM. In the present study, we constructed a 1.2-Mb high-resolution physical map with a contig composed of 16 bacterial artificial chromosomes (BACs) and 6 P1-derived artificial chromosomes (PACs) at a region around the breakpoint, extending from D14S75 to D14S728 loci. Thirty-four novel sequence-tagged sites (STSs) were also characterized at this region. Of nine ESTs that had been mapped between D14S75 and D14S288, T99065 was confirmed to be in two BAC clones, B102 and B319. This BAC/PAC contig with STSs is useful for further genomic sequencing, for construction of a transcription map, and for the isolation of the putative gene for mirror-image polydactyly.

Chromosome Mapping↗