(33/1138) Profound obesity associated with a balanced translocation that disrupts the SIM1 gene.

Studies of mice and humans have revealed a number of genes that when mutated result in severe obesity. We have studied a unique girl with early-onset obesity and a de novo balanced translocation between chromosomes 1p22.1 and 6q16.2. Her weight gain is most likely due to excessive food intake, since measured energy expenditure was normal. We cloned and sequenced both translocation breakpoints. The translocation does not appear to affect any transcription unit on 1p, but it disrupts the SIM1 gene on 6q. SIM1 encodes a human homolog of Drosophila Sim (Single-minded), a transcription factor involved in midline neurogenesis, and is a prototypical member of the bHLH-PAS (basic helix-loop-helix + period, aryl hydrocarbon receptor, Single-minded) gene family. Our subject's trans- location separates the 5' promoter region and bHLH domain from the 3' PAS and putative transcriptional regulation domains. The transcriptional targets of SIM1 are not known. Mouse Sim1 is expressed in the developing kidney and central nervous system, and is essential for formation of the supraoptic and paraventricular (PVN) nuclei of the hypothalamus. Previous neuroanatomical and pharmacological studies have implicated the PVN in the regulation of body weight: PVN neurons express the melanocortin 4 receptor and appear to be physiological targets of alpha-melanocyte-stimulating hormone, which inhibits food intake. We hypothesize that haploinsufficiency of SIM1, possibly acting upstream or downstream of the melanocortin 4 receptor in the PVN, is responsible for severe obesity in our subject.  (+info)

(34/1138) Five novel immunogenic antigens in meningioma: cloning, expression analysis, and chromosomal mapping.

Tumorigenesis of meningioma has been associated with chromosome 22, most notably the NF2 gene, but additional genes have been implicated in meningioma development. Here, we report the identification of five novel immunogenic antigens expressed in meningioma. An expression library was generated from a meningioma that retained both copies of chromosome 22. Screening with autologous patient serum identified seven cDNA clones that were indicated by antigen-antibody complexes. The clones were sequenced, and sequence comparison revealed that the seven clones represent five different genes, providing evidence that meningiomas express a spectrum of immunoreactive antigens, which were termed meningioma expressed antigens (MGEAs). One gene was identical with the connective tissue growth factor, one gene was in part homologous to an Alzheimer disease-associated gene, and a third gene was in part identical to Homo sapiens molybdenum cofactor biosynthesis proteins A and C mRNA. One gene was partially homologous to previously reported cDNA sequences of unknown function, and the fifth gene showed no significant homologies to sequences deposited in databases. Using somatic hybrid mapping, three genes were localized on chromosome 6, and two genes were localized on chromosomes 3 and 17, respectively. To distinguish the MGEAs from the so-called natural autoantigenes, we also screened the library with 12 sera from individuals without obvious disease. The clones identified by reactivity with normal sera were completely different from the clones identified by screening the same meningioma expression library with serum from the patient bearing the tumor. These data suggest that the newly identified MGEA genes may be useful for diagnosis and possibly therapy of meningioma.  (+info)

(35/1138) Androgen receptor gene alterations and chromosomal gains and losses in prostate carcinomas appearing during finasteride treatment for benign prostatic hyperplasia.

Finasteride is commonly used for the treatment of benign prostatic hyperplasia and has been suggested to prevent prostate cancer development. To gain insight to the molecular effects of finasteride on prostate cancer development, we studied six prostate cancers diagnosed during finasteride treatment for benign prostatic hyperplasia. Comparative genomic hybridization detected genetic alterations in four tumors (1-5 changes/tumor). Xq gains and 6q losses were the most common alterations. The recurrent Xq gains motivated us to study the involvement of the androgen receptor (AR) gene. One tumor with Xq gain had a 3-fold amplification of the AR gene, suggesting that tumor development in finasteride-treated patients may require increased AR copy number and expression, as has previously been shown for prostate cancers recurring during hormonal therapy. Furthermore, in another tumor, an Arg726Leu mutation of the AR gene was found. This mutation was also present in the germ-line DNA of the patient. Arg726Leu mutation has previously been reported to affect the transactivational properties of the AR. In summary, prostate cancers developing during finasteride therapy may have distinct biological properties, such as a low number of chromosomal alterations and frequent involvement of the AR gene. Further studies are needed to explore the role of germ-line AR mutations in these patients.  (+info)

(36/1138) The importance of genetic influences in asthma.

Asthma is a complex genetic disorder in which the mode of inheritance is not known. Many segregation studies suggest that a major gene could be involved in asthma, but until now different genetic models have been obtained. Twin studies, too, have shown evidence for genetic influences in asthma, but have also revealed substantial evidence for environmental influences, in which nonshared environmental influences appeared to be important. Linkage, association studies and genome-wide screening suggest that multiple genes are involved in the pathogenesis of asthma. At least four regions of the human genome, chromosomes 5q31-33, 6p21.3, 11q13 and 12q14.3-24.1, contain genes consistently found to be associated with asthma and associated phenotypes. Not only genes associated with asthma but also genes which are involved in the development and outcome of asthma will be found in the future. This will probably provide greater insight into the identification of individuals at risk of asthma and early prevention and greater understanding for guiding therapeutic intervention in asthma. Exchange of information between researchers involved in the genetics of asthma is important because of mandatory agreement on phenotypes and analytical approaches. Genetics will contribute to the a better understanding and management of asthma in the future.  (+info)

(37/1138) Recombinant balanced and unbalanced translocations as a consequence of a balanced complex chromosomal rearrangement involving eight breakpoints in four chromosomes.

We report on a family with a balanced complex chromosomal rearrangement (CCR) involving eight breakpoints between chromosomes 6, 7, 18, and 21 in the father. All three sons inherited one derivative chromosome from the father and in addition each inherited a different recombinant chromosome resulting in a partial trisomy 6q in the first, an apparently balanced karyotype in the second, and a partial trisomy 7q in the third son. Fluorescence in situ hybridisation (FISH) and microsatellite analysis were essential for the identification of the breakpoints. In addition, the results were confirmed by a 24-colour FISH experiment using the spectral karyotyping (SKYtrade mark) system. Paternal origin of the de novo CCR in the father was demonstrated for the first time by haplotype analysis. This is the second report of a CCR leading to simpler but unbalanced translocations in offspring as a consequence of recombination during gametogenesis, and the first report of a family case of CCR exhibiting as many as eight breakpoints in the transmitting carrier. The initial prediction that viable offspring would be quite unlikely had to be revised after the birth of three children. Genetic counselling of carriers of balanced complex rearrangements has to consider a higher probability for unbalanced recombinations than has been so far commonly assumed.  (+info)

(38/1138) Refinement of the 6q chromosomal region implicated in transient neonatal diabetes.

Transient neonatal diabetes mellitus (TNDM) is estimated to occur in approximately 1 in 500,000 births and represents 50-60% of cases of neonatal diabetes. The pattern of inheritance of TNDM and its association with chromosome 6 uniparental disomy is consistent with the presence on chromosome 6 of an imprinted gene involved in pancreatic beta-cell development. Systematic screening for chromosome 6 abnormalities in nine families with 13 individuals affected by TNDM revealed paternal isodisomy of chromosome 6 in one child and paternally derived trisomy of the chromosomal region 6q in six children from three unrelated families. To delineate more accurately the region suspected of harboring the gene of interest, precise mapping of the duplicated area was performed in children exhibiting partial 6q trisomy by using microsatellite markers. The smallest region of duplication observed in our patients was flanked by markers D6S308 and D6S1010, which are separated by <1 cM. These findings confirm that TNDM may result from the overexpression of a gene located on chromosome 6q that is exclusively expressed from the paternal allele at least during some periods of life and further refine the localization of this gene.  (+info)

(39/1138) North Carolina macular dystrophy (MCDR1) locus: a fine resolution genetic map and haplotype analysis.

PURPOSE: We previously reported linkage of North Carolina macular dystrophy in a single isolated family to a broad region on chromosome 6q16. In order to refine the localization of the MCDR1 gene (North Carolina macular dystrophy), additional families with this disease and new markers were studied. METHODS: We ascertained 10 families with the North Carolina macular dystrophy phenotype (MCDR1). These families were of various ethnic and geographic origins such as Caucasian, Mayan Indian, African-American, French, British, German, and American of European decent. Two hundred thirty-two individuals in these families underwent comprehensive ophthalmic examinations and blood was collected for genotyping. One hundred seventeen were found to be affected. Linkage simulation studies were performed. Two-point linkage, haplotype analysis, and multipoint linkage was performed using VITESSE and FASTLINK. HOMOG was used to test for genetic heterogeneity. RESULTS: The clinical features were consistent with the diagnosis of North Carolina macular dystrophy in all families. Multipoint linkage analysis indicates that the MCDR1 gene is in the interval between D6D249 and D6S1671 with a maximum LOD score of 41.52. There was no evidence of genetic heterogeneity among the families studied. Families 765, 768, 772, 1193, and 1292 shared the same chromosomal haplotype in this region. CONCLUSIONS: This is the largest single data set of families with the MCDR1 phenotype. The single large family from North Carolina continues to be informative for the closest flanking markers and alone supports the minimal candidate region as suggested by previous studies. There remains no evidence of genetic heterogeneity in this disease. Most of the American families appear to have descended from the same ancestral mutation. The remaining families could each represent independent origins of the mutation in the MCDR1 gene.  (+info)

(40/1138) Cloning and characterization of a novel human dual flavin reductase.

Flavoprotein reductases play a key role in electron transfer in many physiological processes. We have isolated a cDNA with strong sequence similarities to cytochrome P-450 reductase and nitric-oxide synthase. The cDNA encodes a protein of 597 amino acid residues with a predicted molecular mass of 67 kDa. Northern blot analysis identified a predicted transcript of 3.0 kilobase pairs as well as a larger transcript at 6.0 kilobase pairs, and the gene was mapped to chromosome 9q34.3 by fluorescence in situ hybridization analysis. The amino acid sequence of the protein contained distinct FMN-, FAD-, and NADPH-binding domains, and in order to establish whether the protein contained these cofactors, the coding sequence was expressed in insect cells and purified. Recombinant protein bound FMN, FAD, and NADPH cofactors and exhibited a UV-visible spectrum with absorbance maxima at 380, 460, and 626 nm. The purified enzyme reduced cytochrome c, with apparent K(m) and k(cat) values of 21 microM and 1.3 s(-1), respectively, and metabolized the one-electron acceptors doxorubicin, menadione, and potassium ferricyanide. Immunoblot analysis of fractionated MCF7 cells with antibodies to recombinant NR1 showed that the enzyme is cytoplasmic and highly expressed in a panel of human cancer cell lines, thus indicating that this novel reductase may play a role in the metabolic activation of bioreductive anticancer drugs and other chemicals activated by one-electron reduction.  (+info)