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Biomedical subjects

N Niikawa

Publications and source records attributed to N Niikawa.

At least 55 records · Page 3Linked to original sources
PubMed2000

Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III.

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Three subtypes have been described: TRPS I, caused by mutations in the TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses. To investigate whether TRPS III is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, we performed extensive mutation analysis and evaluated the height and degree of brachydactyly in patients with TRPS I or TRPS III. We found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicates that TRPS1 is the major locus for TRPS I and TRPS III. We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the five missense mutations alter the GATA DNA-binding zinc finger, and six of the seven unrelated patients with these mutations may be classified as having TRPS III. Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene.

Adolescent↗
PubMed2000

Standard growth curves for Japanese patients with Prader-Willi syndrome.

We constructed the standard growth (length/height and weight) curves for Japanese individuals with Prader-Willi syndrome (PWS). Crude height and weight data were collected from 153 males and 99 females with the syndrome, and the collected data were arranged by a mathematical method to construct the curves. Height growth patterns were quite different between PWS and normal children. Mean height of individuals with the syndrome by puberty is -2 SD for normal children, and it drops off far below -2 SD value after puberty. Final mean height is 141.2 +/- 4.8 cm for females (n = 13) and 147.7 +/- 7.7 cm for males (n = 17), showing 15.8 and 21.9 cm below the average height for normal Japanese girls and boys, respectively. Thus, the degree of shortness is more pronounced in male than in female patients. There was no difference in height between those with chromosome 15q deletion and those without. Mean weight at birth of girls (n = 88) and boys (n = 131) were 2.70 +/- 0.45 Kg and 2.62 +/- 0.47 Kg, respectively. These values were smaller than those for normal neonates (P < 0.05, t-test). The weight of PWS children was under the mean value for normal infants by age 2 years, but gradually increase above the mean values for normal children around ages 2-4 years. Overweight in both males and females becomes obvious during prepuberty. Growth patterns are not different between Japanese and Caucasian children with the syndrome. Short stature is more prominent in boys of both ethnic groups, whereas the degree of overweight appears much more severe in Caucasians.

Adolescent↗
PubMed2000

Bardet-Biedl syndrome type 3 in an Iranian family: clinical study and confirmation of disease localization.

Bardet-Biedl syndrome (BBS) is a group of autosomal recessive MCA/MR syndromes characterized by pigmentary retinopathy, postaxial polydactyly, hypogenitalism, obesity, and mental retardation. Five BBS loci have been identified; among them, BBS type 1 (BBS1) and type 3 (BBS3) are most common and most rare, respectively. We encountered an Iranian family that had seven affected members. All patients had a history of mild to severe obesity, but it was reversible in some patients by caloric restriction and exercise. All patients had pigmentary retinopathy, beginning as night blindness in early childhood and progressing toward severe impairment of vision by the end of the second decade. Polydactyly varied in limb distribution, ranging from four-limb involvement to random involvement or even to nonaffectedness. Six of the seven patients were not mentally retarded. Although kidney anomaly or an adrenal mass was pres- ent in two patients, the fact that one patient had seven children rules out reproductive dysfunction. Linkage analysis with microsatellite markers showed that the disease in the family was assigned to a region around marker loci at 3p13-p12 (maximum LOD score = 4.15 and recombination fraction straight theta = 0, at D3S1603 microsatellite marker), to which the BBS3 locus has been mapped. Haplotype analysis did not reduce the extent of the previously reported critical region of BBS3. A comparison of clinical manifestations of our patients with those of previously reported BBS3 patients did not support any type-specific phenotypes, though manifestations in our patients are similar to those in BBS3 patients of a family in Newfoundland.

Adolescent↗
PubMed2000

The novel gene, gamma2-COP (COPG2), in the 7q32 imprinted domain escapes genomic imprinting.

The gene MEST (or PEG1) on chromosome 7q32 is paternally expressed in human fetal tissues as a result of genomic imprinting. Since some imprinted genes are clustered, we speculated that an imprinted gene cluster might exist at 7q32. We have sought to isolate additional human genes close to MEST and to characterize their allelic expression patterns. Here, we report the biallelic expression of the gene, gamma2-COP (coatomer protein complex, subunit gamma 2, HUGO-approved symbol COPG2), and monoallelic expression of the transcript, CIT1, which is located in intron 20 of gamma2-COP. Recently, gamma2-COP was reported to be a novel imprinted gene that overlaps the 3'-untranslated region (3'-UTR) of MEST in a tail-to-tail orientation. However, our results revealed biallelic expression in all fetal tissues and adult blood lymphocytes. On the other hand, CIT1 was an antisense transcript of gamma2-COP intron 20 and was expressed from the paternal allele in all fetal tissues examined. Adult blood lymphocytes showed biallelic expression. We identified additional MEST 3'-UTR sequence, which overlaps the last four exons and introns of gamma2-COP. This additional MEST 3'-UTR may complicate analysis of gamma2-COP imprinting. Our data indicate that the region containing MEST at 7q32 is an imprinted domain, but gamma2-COP adjacent to MEST escapes genomic imprinting.

3' Untranslated Regions↗
PubMed2000

Construction of a physical and transcript map flanking the imprinted MEST/PEG1 region at 7q32.

MEST/PEG1, a gene expressed paternally in mesodermal derivatives in early embryonic stages, is the first imprinted gene mapped to chromosome 7q32. Since imprinted genes are clustered in general at a chromosomal region, we speculated that a similar imprinted-gene cluster may exist at chromosome region 7q32 and that the functions of some such genes may contribute to the phenotype of Silver-Russell syndrome including maternal uniparental disomy for chromosome 7 (maternal UPD7). As an initial step toward the isolation of imprinted genes at 7q32, we adopted an integrated approach involving the construction of a PAC contig and ESTs mapping in the vicinity of MEST. Here, we have constructed a complete contig of PAC and BAC clones and a transcript map spanning the entire approximately 1-Mb region between D7S530 and D7S649. We developed 60 novel STSs and precisely mapped 47 genes/ESTs. This map contains a putative autistic disorder locus that has been suggested to be localized near markers D7S530 and D7S684. This integrated physical and transcript map provides a valuable resource for identification of an imprinted gene(s) in this region as well as a candidate gene(s) for autistic disorder.

Base Sequence↗
PubMed2000

Genetically distinct autosomal dominant posterior polar cataract in a four-generation Japanese family.

PURPOSE: To describe the clinical findings of a form of posterior polar cataract in a large Japanese family and to determine whether the posterior polar cataract is causally related to other autosomal dominant cataracts with known genes, chromosomal locations, or both. METHODS: Systemic and ocular histories were obtained and comprehensive ophthalmic examinations were performed in 15 of 37 members of the Japanese family. The posterior polar cataract was transmitted in an autosomal dominant manner through four generations. Although there is some variation in the degree of opacification, the posterior polar cataract in this family is characterized by progressive disk-shaped posterior subcapsular opacities. Genetic linkage analysis was performed with 41 polymorphic microsatellite markers located in chromosomal regions known for linkage to cataracts. Genomic DNA extracted from the 15 individuals was amplified by polymerase chain reaction, the genotype at the marker loci was determined in each family member, and the lod score was calculated at each locus. RESULTS: Significant linkage of the posterior polar cataract was ruled out from the following 10 loci or chromosomal regions: 16q22 and 1p36, to which two forms of autosomal dominant posterior polar cataract have been assigned: 1q21-q25, 2q33-q35, 13cen, 17p13, 17q11-q12, 17q24, 21q22, and 22q, which are the regions responsible for other autosomal dominant congenital cataracts. CONCLUSIONS: This study confirms the genetic heterogeneity of autosomal dominant posterior polar cataracts and demonstrates that the posterior polar cataract in this Japanese family is phenotypically and genetically distinct from previously mapped cataracts.

Adolescent↗
PubMed2000

Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease.

Camurati-Engelmann disease (CED, MIM 131300) is an autosomal dominant, progressive diaphyseal dysplasia characterized by hyperosteosis and sclerosis of the diaphyses of long bones. We recently assigned the CED locus to an interval between D19S422 and D19S606 at chromosome 19q13.1-q13.3, which two other groups confirmed. As the human transforming growth factor-1 gene (TGFB1) is located within this interval, we considered it a candidate gene for CED.

Base Sequence↗
PubMed2000

An autosomal dominant posterior polar cataract locus maps to human chromosome 20p12-q12.

We assigned the locus for a previously reported new type of autosomal dominant posterior polar cataract (CPP3) to 20p12-q12 by a genome-wide two-point linkage analysis with microsatellite markers. CPP3 is characterized by progressive, disc-shaped, posterior subcapsular opacity. The disease was seen in 10 members of a Japanese family and transmitted in an autosomal dominant fashion through four generations. We obtained a maximum lod score (Zmax) of 3.61 with a recombination fraction (theta) of 0.00 for markers D20S917, D20S885 and D20S874. Haplotype analysis gave the disease gene localization at a 15.7-cM interval between D20S851 and D20S96 loci on chromosome 20p12-q12. Since the BFSP1 that encodes the lens-specific beaded filament structural protein 1 (filensin) has been mapped around the CPP3 region, we performed sequence analysis on its entire coding region. However, no base substitution or deletion was detected in the CPP3 patients. The mapping of the CPP3 locus to 20p12-q12 not only expands our understanding of the genetic heterogeneity in autosomal dominant posterior polar cataracts but also is a clue for the positional cloning of the disease gene.

Base Sequence↗
PubMed2000

Cancer-associated alternative usage of multiple promoters of human GalCer sulfotransferase gene.

The galactosylceramide sulfotransferase (cerebroside sulfotransferase, CST) (EC 2.8.2.11) gene is highly expressed in human renal cancer cells. To elucidate the regulatory mechanism of its gene expression, we have determined the genomic organization of the human CST gene. The gene comprises at least four exons and spans about 20 kb. The coding region is located in exons 3 and 4. To determine the transcription initiation sites, 5'-rapid amplification of cDNA ends analysis was performed using mRNA obtained from four human renal cancer cell lines, SMKT-R1-R4, and normal human renal proximal tubular cells. We found four transcription initiation sites and alternative usage of six exons corresponding to the 5'-untranslated region in cancer cells. On the other hand, the only transcript beginning at exon 1a was observed in normal cells. Using reverse transcriptase-PCR analysis, we confirmed that all of the exons 1a-d, especially exons 1c and 1d, are used as a transcription initiation site in cancer cells, whereas only exons 1a and 1b, mostly 1a, are utilized in normal cells. Analyzing the protein production from the mRNA variants with different 5'-UTRs, we found that all the transcripts examined produced the identical proteins. These observations suggest that the aberrant usage of transcription initiation sites flanked with promoters/enhancers is involved in the cancer-associated expression of the CST gene. Furthermore, this gene was assigned to human chromosome 22q12 by means of fluorescence in situ hybridization.

Base Sequence↗
PubMed2000

Genetic mapping of the Camurati-Engelmann disease locus to chromosome 19q13.1-q13.3.

Camurati-Engelmann disease (CED [MIM 131300]), or progressive diaphyseal dysplasia, is an autosomal dominant sclerosing bone dysplasia characterized by progressive bone formation along the periosteal and endosteal surfaces at the diaphyseal and metaphyseal regions of long bones and cranial hyperostosis, particularly at the skull base. The gene for CED, or its chromosomal localization, has not yet been identified. We performed a genomewide linkage analysis of two unrelated Japanese families with CED, in which a total of 27 members were available for this study; 16 of them were affected with the disease. Two-point linkage analysis revealed a maximum LOD score of 7.41 (recombination fraction.00; penetrance 1.00) for the D19S918 microsatellite marker locus. Haplotype analysis revealed that all the affected individuals shared a common haplotype observed, in each family, between D19S881 and D19S606, at chromosome 19q13.1-q13.3. These findings, together with a genetic distance among the marker loci, indicate that the CED locus can be assigned to a 15.1-cM segment between D19S881 and D19S606.

Camurati-Engelmann Syndrome↗
PubMed2000

Colocalization of doublecortin with the microtubules: an ex vivo colocalization study of mutant doublecortin.

Doublecortin (DCX) plays an important role in neuronal migration and development, and the participation of DCX in neuronal migration has been demonstrated by intensive mutational analysis for patients with X-linked or sporadic lissencephaly, and/or subcortical laminar heterotopia. Although a previous search for protein similarity showed that DCX has a region homologous to the putative Ca(2+)/calmodulin-dependent protein kinase, the function of the DCX gene (DCX) has remained unknown. We show here that mouse DCX colocalizes with the microtubules and provide evidence that its conformational structure is important for its subcellular localization by means of mutant doublecortin expression study. The results of our study may suggest that the cytoskeleton involving DCX mediates the neuronal migration during brain development.

Animals↗
PubMed2000

[Beckwith-Wiedemann syndrome].

Beckwith-Wiedemann syndrome(BWS) is one of the most common overgrowth syndrome and is believed that imprinted genes contribute to the phenotypes of syndrome. Embryonic tumors are observed in 7.5%-10.0% of BWS, so BWS could be classified in one of the familial cancer syndrome. We describe here the causative mechanisms of BWS, mechanisms of tumorigenesis related to the BWS, and what to be uncovered in the next step.

Beckwith-Wiedemann Syndrome↗