1 UI - 433PU AU - Vaughan JR AU - Davis MB AU - Wood NW TI - Genetics of Parkinsonism: a review. LA - English RF - Review AD - Vaughan JR, Univ London, Dept Clin Neurol, Inst Neurol, Queen Sq, London WC1N 3BG, ENGLAND AB - Idiopathic Parkinson's disease (IPD), a progressive neurodegenerative disorder, is a common cause of disability. No current therapies modify disease progression. The pathological hallmarks are the presence of Levy bodies and massive losses of dopaminergic neurons in the pars compacta of the substantia nigra. Two genes (SNCA and parkin) as well as two gene loci have now been implicated in the pathogenesis of familial PD. These represent significant progress in our understanding of the disease, considering the rarity of large families, how heritability in the general population and genetic heterogeneity. Mutations in a further gene. UCHL1, have been described in familial Pd although the evidence for its role in PD is less clear. Knowledge of the genes described in PD to date should help to define molecular mechanisms of neurodegeneration in PD, as well as in other diseases where defects in protein handling may be a common feature. Nigral degeneration with Lewy body formation and the resulting clinical picture of PD may represent a final common pathway of a multifactorial disease process in which both environmental and genetic factors have a role. This review discusses the major advances in the field to date and genetic factors has now become firmly established. SO - Ann Hum Genet 2001 MAR;65:111-126 2 UI - 433PU AU - Hermon C AU - Alberman E AU - Beral V AU - Swerdlow AJ TI - Mortality and cancer incidence in persons with Down's syndrome, their parents and siblings. LA - English RF - Article AD - Hermon C, Univ Oxford, ICRF Canc Epidemiol Unit, Radcliffe Infirm, Gibson Bldg, Oxford OX2 6HE, ENGLAND AB - A cohort study of 1425 persons with Down's syndrome (DS), and of their parents (447 mothers, 435 fathers) and siblings (1176), was set up to investigate death rates from various causes and cancer incidence patterns. In individuals with DS the all-cause death rate was six times of the national population (SMR = 622; 95% CI 559 693), the excess being attributable to many different causes. These included: leukaemia (SMR = 1304 : 95% CI 651-2334): diabetes mellitus (SMR = 982:95% CI 267-2515); Alzheimer's disease (SMR = 22028 : 95% CI 7137-51326) ; epilepsy (SMR = 1727 : 95% CI 744-3403); and congenital anomalies (SMR = 4987 : 95% CI 4175-5955). The overall survival showed marked improvements for successive birth cohorts, particularly at young ages. For mothers and fathers of persons with DS, all-cause death rates were 20% lower than national rates and these were no significant excesses from any specific cause. For siblings, all-cause death rates were similar to national rates; the only condition with a a significantly raised ratio was colo-rectal cancer (SMR = 793 : 95% CI 216-2031), but this may well be a chance finding. SO - Ann Hum Genet 2001 MAR;65:167-176 3 UI - 433PU AU - Swerdlow AJ AU - Hermon C AU - Jacobs PA AU - Alberman E AU - Beral V AU - Daker M AU - Fordyce A AU - Youings S TI - Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study. LA - English RF - Article AD - Swerdlow AJ, Inst Canc Res, Epidemiol Sect, Block D, Cotswold Rd, Sutton SM2 5NG, Surrey, ENGLAND AB - Mortality and cancer incidence were assessed in a cohort of 1373 patients with numerical sex chromosome abnormalities diagnosed at three cytogenetics centres in Britain during 1959-90, and were compared with expectations from national rates. Four hundred patients with Turner's syndrome were followed , of whom 62 died, with a relative risk (RR) of death of 4.16 (95% confidence interval (CI) 3.22-5.39). Turner's syndrome patients had greatly raised risks of death from diseases of the nervous, cardiovascular, respiratory, digestive and genitourinary systems. One hundred and sixty three deaths occurred among 646 patients with Klinefelter's syndrome with a 47,XXY constitution, giving an RR of 1.63 (1.40- 1.91). Mortality in these patients was significantly raised from diabetes amd diseases of the cardiovascular, respiratory and digestive systems. These was also significantly increased mortality for patients with X polysomy (RR = 2.11 (1.43-3.02)) and Y polysomy (RR = 1.90 (1.20 2.85)), the former with significantly increased mortality from cardio-vascular disease and the latter form respiratory disease. The only significantly raised risks of cancer incidence or mortality in the cohort were for lung cancer and breast cancer in patients with Klinefelter's syndrome with a 47,XXY constitution, and non- Hodgkin's lymphoma in men with more than three sex chromosomes. SO - Ann Hum Genet 2001 MAR;65:177-188 4 UI - 433PU AU - Li H TI - A permutation procedure for the haplotype method for identification of disease-predisposing variants. LA - English RF - Article AD - Li H, Univ Calif Davis, Program Human Genet, Sch Med, Davis,CA 95616 USA AB - Once a genetic region involved in a complex disease has been localized through linkage or association studies, we need methods to help is identify the actual disease predisposing genetic variant(s) in the region. A large number of single nucleotide polymorphic (SNP) sites may exist in this region. It is important to identify genetic variants directly involved in disease from those in linkage disequilibrium, and thus associated with, the disease predisposing variant(s). A question of great interest is to test whether a SNP, or a combination of SNPs, that influence the trait under investigation have been identified. For many complex HLA-associated diseases, patterns of amino acid site variability raise the possibility that HLA-variation association with a disease may not be due to a given allele but rather one or more variable amino acid sites occurring on several alleles. Here the question is whether an amino acid variant or combination of amino variants involved in disease are identified. To address this question, this paper proposes a permutation procedure for the haplotype method, to test whether all the sites involved in the disease have been identified using the haplotypic data of patients and controls. The method is based on the amino acid sites involved in the disease process, the relative frequencies of amino acid variants at sites not involved in disease, but the linkage disequilibrium with the disease- predisposing sites, are expected to be the same in patients and controls. This procedure takes into account the non-independence of the sites sampled and is robust to mode of inheritance and penetrance of the disease and can definitely specify when all the disease predisposing sites have not been identified. Application to both simulated data and real data sets on type 1 diabetes and alcoholism indicates that the proposed procedure works well in testing the important null hypothesis all the predisposing sites are identified. SO - Ann Hum Genet 2001 MAR;65:189-196 5 UI - 433FZ AU - Miller W TI - Comparison of genomic DNA sequences: solved and unsolved problems. LA - English RF - Review AD - Miller W, Penn State Univ, Dept Comp Sci & Engn, University Pk,PA 16802 USA AB - Motivation: The DNA sequences of entire genomes are being determined at a rapid rate. Whereas initial genome sequencing efforts were for organisms chosen to be widely spaced in the tree of life, there is a growing emphasis on projects to sequence a species that is sufficiently similar to an already-sequenced species to allow direct comparison of those two DNA sequences. This and other changes in genome sequencing strategies have created a strong need for new methods to compare genomic sequences. Results: We sketch the current state of software for comparing genomic DNA sequences and outline research directions that we believe are likely to result in important advances in practice. SO - Bioinformatics 2001 MAY;17(5):391-397 6 UI - 433PE AU - Tajiri T AU - Tanaka S AU - Shono K AU - Kinoshita Y AU - Fujii Y AU - Suita S AU - Ihara K AU - Hara T TI - Quick quantitative analysis of gene dosages associated with prognosis in neuroblastoma. LA - English RF - Article AD - Tajiri T, Kyushu Univ, Grad Sch Med Sci, Dept Pediat Surg, Higashi Ku, 3 1 1 Maidashi, Fukuoka 8128582, JAPAN AB - The amplification of the N-myc gene and a gain of the chromosome 17q arm correlate with an unfavorable outcome in patients with neuroblastoma. In this study, we determined the gene dosage of the N-myc gene (located at 2p24) and Survivin gene (located at 17q25) using the p53 gene (located at 17p13) as the internal control gene by the TaqMan polymerase chain reaction (PCR)-based gene dosage analysis in 25 neuroblastoma samples. Based on the assumption that the gene dosages of each gene of a normal individual lymphocytes are 1.0, 11 of the 25 cases with a corrected gene dosage of N-myc (N-myc/p53) of more than 2.0 had a more unfavorable prognosis than the 14 cases with a N-myc gene dosage of less than 2.0 (5-year survival rate: 18 vs. 71%, P < 0.01). Ten of 25 cases with a corrected Survivin gene dosage (Survivin/p53) of more than 2.0 had a more unfavorable prognosis than the 15 cases with a Survivin gene dosage of less than 2.0 (5-year survival rate: 10 vs. 67%, P < 0.01). This quantitative PCR system is considered to be useful for quickly and accurately evaluating the degree of malignancy of neuroblastoma in order to select the optimal treatment. (C) 2001 Elsevier Science Inland Ltd. All rights reserved. SO - Cancer Lett 2001 MAY 10;166(1):89-94 7 UI - 434XG AU - Ohki I AU - Shimotake N AU - Fujita N AU - Jee JG AU - Ikegami T AU - Nakao M AU - Shirakawa M TI - Solution structure of the methyl-CpG binding domain of human MBD1 in complex with methylated DNA. LA - English RF - Article AD - Shirakawa M, Nara Inst Sci & Technol, Grad Sch Biol Sci, 8916 5 Takayama, Nara 6300101, JAPAN AB - In vertebrates, the biological consequences of DNA methylation are often mediated by protein factors containing conserved methyl-CpG binding domains (MBDs). Mutations in the MBD protein MeCP2 cause the neurodevelopmental disease Rett syndrome. We report here the solution structure of the MBD of the human methylation- dependent transcriptional regulator MBD1 bound to methylated BRA. DNA binding causes a loop in MBD1 to fold into a major and novel DNA binding interface. Recognition of the methyl groups and CG sequence at the methylation site is due to five highly conserved residues that form a hydrophobic patch. The structure indicates how MBD may access nucleosomal DNA without encountering steric interference from core histones, and provides a basis to interpret mutations linked to Rett syndrome in MeCP2. SO - Cell 2001 MAY 18;105(4):487-497 8 UI - 433GY AU - Venkitaraman AR TI - Chromosome stability, DNA recombination and the BRCA2 tumour suppressor. LA - English RF - Review AD - Venkitaraman AR, Univ Cambridge, CRC, Dept Oncol, Hills Rd, Cambridge CB2 2XY, ENGLAND AB - The BRCA2 tumour suppressor works in DNA recombination and repair pathways to preserve genome integrity. Recent progress provides fresh insights into its role as a regulator of the Rad51 recombination protein, underpinning a model in which BRCA2's involvement in chromosome stability and tumour suppression arises from its participation in recombinational processes essential for DNA replication. SO - Curr Opin Cell Biol 2001 JUN;13(3):338-343 9 UI - 422LU AU - Schutte BC AU - Carpten JD AU - Forus A AU - Gregory SG AU - Horii A AU - White PS TI - Report of the sixth international workshop on human chromosome 1 mapping 2000. LA - English RF - Editorial AD - Schutte BC, Univ Iowa, Dept Pediat, ML 3191, Iowa City,IA 52242 USA SO - Cytogenet Cell Genet 2001;92(1-2):24-40 10 UI - 422LU AU - Waters PD AU - Duffy B AU - Frost CJ AU - Delbridge ML AU - Graves JAM TI - The human Y chromosome derives largely from a single autosomal region added to the sex chromosomes 80-130 million years ago. LA - English RF - Article AD - Waters PD, La Trobe Univ, Dept Genet, Bundoora, Vic 3083, AUSTRALIA AB - Mapping of human X-borne genes in distantly related mammals has defined a conserved region shared by the X chromosome in all three extant mammalian groups, plus a region that was recently added to the eutherian X but is still autosomal in marsupials and monotremes. Using comparative mapping of human Y-borne genes, we now directly show that the eutherian Y is also composed of a conserved and an added region which contains most of the ubiquitously expressed Y-borne genes. Little of the ancient conserved region remains, and the human Y chromosome is largely derived from the added region. Copyright (C) 2001 S. Karger AG, Basel. SO - Cytogenet Cell Genet 2001;92(1-2):74-79 11 UI - 434DB AU - Moller P AU - Borg A AU - Heimdal K AU - Apold J AU - VallonChristersson J AU - Hovig E AU - Maehle L TI - The BRCA1 syndrome and other inherited breast or breast- ovarian cancers in a Norwegian prospective series. LA - English RF - Article AD - Moller P, Norwegian Radium Hosp, Unit Med Genet, N 0310 Oslo, NORWAY AB - Inherited breast cancer is a heterogenous group of diseases. We examined this heterogeneity in a prospective series of inherited breast and ovarian cancers. Previously demonstrated to include 84% of inherited cancers. Ninety- two tumours (65 breast and 97 ovarian) in 82 patients from 70 kindreds were prospectively diagnosed. Fifteen of the breast cancers were in situ, 50 were infiltrating. 40 (49%) of the 82 women carried a BRCA1 mutation. Whereas no mutation in BRCA2 was found. Approximately, two-thirds of the BRCA1 mutation carriers had one of the four most frequent Norwegian founder mutations. Ninety-five per cent of the epithelial ovarian cancers occurred in BRCA1 mutation carrying women versus 38% of infiltrating breast cancers and 7% of carcinoma in situ of the breast. The BRCA1 syndrome was phenotypically distinct with invasive. High grade, oestrogen receptor-negative breast cancers and epithelial ovarian cancers. Non-BRCA1/2 inherited breast cancers included carcinoma in situ and lobular carcinoma and were frequently bilateral. Non-BRCA1/2 inherited breast cancer is not associated with epithelial ovarian cancer and in breast cancers has distinct biological characteristics, indicating that the different subgroups of inherited breast cancer may need different healthcare services, (C) 2001 Elsevier Science Ltd. All rights reserved. SO - Eur J Cancer 2001 MAY;37(8):1027-1032 12 UI - 434DC AU - Paavola P AU - Helio T AU - Kiuru M AU - Halme L AU - Turunen U AU - Terwilliger J AU - Karvonen AL AU - Julkunen R AU - Niemela S AU - Nurmi H AU - Farkkila M AU - Kontula K TI - Genetic analysis in Finnish families with inflammatory bowel disease supports linkage to chromosome 3p21. LA - English RF - Article AD - Kontula K, Univ Helsinki, Dept Med, Haartmaninkatu 4, Pl 340, FIN 00290 Helsinki, FINLAND AB - In inflammatory bowel diseases (IBD), certain chromosomal candidate loci have been repeatedly identified by independent studies in different populations. To investigate the contribution of the loci on chromosomes 1, 3, 7, 12, 14, and 16 to the susceptibility of IBD in Finnish population, where the predominant feature is the excess of ulcerative colitis (UC) families compared to Crohn's disease (CD) families, we carried out linkage analyses using 93 Finnish, multiply-affected IBD families. We observed nominal evidence for linkage to chromosome 3p21, consistent with earlier reports. The lod scores peaked at D3S2432, with a maximum two-point lod score of 1.68 (p=0.0027). In addition, we studied whether risk of IBD is associated with functional variants of two positional candidate genes; the chemokine receptor CCR5 gene on chromosome 3p21 and the interleukin-4 receptor a- subunit gene (IL4RA) on chromosome 16. We did not find any significant correlation between a 32-bp deletion variant of CCR5 or a single nucleotide change A1902G (Gln576Arg) of IL RA, and IBD phenotypes, with the exception that in the UC group homozygosity for the G1902 allele of IL4RA was less frequent (0.019 vs 0.049, P=0.038). In conclusion, our study, carried out in a genetically homogenous population, suggests that chromosome 3 may contain a susceptibility gene for IBD. SO - Eur J Human Genet 2001 MAY;9(5):328-334 13 UI - 433RW AU - Chamberlain SJ AU - Brannan CI TI - The Prader-Willi syndrome imprinting center activates the paternally expressed murine Ube3a antisense transcript but represses paternal Ube3a. LA - English RF - Article AD - Brannan CI, Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Box 100266, Gainesville,FL 32610 USA AB - The imprinted UBE3A gene exhibits maternal-only expression in specific cell types in the brain, but exhibits biallelic expression in other cell types. UBE3A is located adjacent to a cluster of imprinted, paternally expressed genes that are known to be positively regulated by the Prader-Willi syndrome imprinting center (PWS-IC). Here, we examined the effect of the PWS-IC on the UBE3A locus. Using intersubspecific crosses, we found that deletion of the PWS-IC causes an upregulation of the paternal Ube3a allele. This indicates that unlike its positive effect on all the other paternally expressed transcripts in the region, the PWS-IC negatively regulates the levels of paternal UBE3A. Interestingly, we found that like the human UBE3A locus, the murine Ube3a locus includes an imprinted, paternally expressed antisense transcript. We show that this paternal antisense transcript is positively regulated by the PWS-IC. These results are consistent with a model in which the PWS-IC mediates activation and maintenance of paternal gene expression in the 15q11-q13 region, with repression of the paternal UBE3A gene occurring as an indirect result of expression of the antisense transcript, (C) 2001 Academic Press. SO - Genomics 2001 MAY 1;73(3):316-322 14 UI - 433RN AU - Adachi H AU - Kume A AU - Li M AU - Nakagomi Y AU - Niwa H AU - Do J AU - Sang C AU - Kobayashi Y AU - Doyu M AU - Sobue G TI - Transgenic mice with an expanded CAG repeat controlled by the human AR promoter show polyglutamine nuclear inclusions and neuronal dysfunction without neuronal cell death. LA - English RF - Article AD - Sobue G, Nagoya Univ, Sch Med, Dept Neurol, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, JAPAN AB - We generated transgenic mice that expressed a highly expanded 239 polyglutamine (polyQ) repeat under the control of the human androgen receptor promoter. These transgenic mice developed progressive neurological phenotypes of muscular weakness and ataxia, small body size and short life-span. PolyQ nuclear inclusions (Nls) were remarkable and widespread but found in selective regions of the central nervous system (CNS) such as the spinal cord, cerebrum and cerebellum as well as in selective peripheral visceral organs. This distribution pattern resembled that of spinal and bulbar muscular atrophy somewhat, but was more widespread. In neuronal tissues, Nls were present in astrocytes as well as neurons. Cytoplasmic and axonal inclusions were not observed, In the CNS regions with abundant Nls, neuronal populations were well-preserved, and neither neuronal cell death, reactive astrogliosis nor microglial invasions were detected. These findings suggest that polyQ alone can induce the neuronal dysfunction that precedes gross neuronal degeneration and provides a clue for investigating molecular mechanisms that underly the pathway to neuronal dysfunction from polyQ expansion. SO - Hum Mol Genet 2001 MAY 1;10(10):1039-1048 15 UI - 433RN AU - Jana NR AU - Zemskov EA AU - Wang GH AU - Nukina N TI - Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. LA - English RF - Article AD - Nukina N, RIKEN, Brain Sci Inst, Lab CAG Repeat Dis, 2 1 Hirosawa, Wako, Saitama 3510198, JAPAN AB - Expansion of CAG repeats within the coding region of target genes is the cause of several autosomal dominant neurodegenerative diseases including Huntington's disease (HD), A hallmark of HD is the proteolytic production of N- terminal fragments of huntingtin containing polyglutamine repeats that form ubiquitinated aggregates in the nucleus and cytoplasm of the affected neurons. In this study, we used an ecdysone-inducible stable mouse neuro2a cell line that expresses truncated N-terminal huntingtin (tNhtt) with different polyglutamine length, along with mice transgenic for HD exon 1, to demonstrate that the ubiquitin-proteasome pathway is involved in the pathogenesis of HD, Proteasomal 20S core catalytic component was redistributed to the polyglutamine aggregates in both the cellular and transgenic mouse models. Proteasome inhibitor dramatically increased the rate of aggregate formation caused by tNhtt protein with 60 glutamine (60Q) repeats, but had very little influence on aggregate formation by tNhtt protein with 150Q repeats. Both normal and polyglutamine-expanded tNhtt proteins were degraded by proteasome, but the rate of degradation was inversely proportional to the repeat length. The shift of the proteasomal components from the total cellular environment to the aggregates, as well as the comparatively slower degradation of tNhtt with longer polyglutamine, decreased the proteasome's availability for degrading other key target proteins, such as p53, This altered proteasomal function was associated with disrupted mitochondrial membrane potential, released cytochrome c from mitochondria into the cytosol and activated caspase-9- and caspase-9-like proteases These results suggest that the impaired proteasomal funaction plays an important role in polyglutamine protein-induced cell death. SO - Hum Mol Genet 2001 MAY 1;10(10):1049-1059 16 UI - 433RN AU - Wan MM AU - Zhao KJ AU - Lee SSJ AU - Francke U TI - MECP2 truncating mutations cause histone H4 hyperacetylation in Rett syndrome. LA - English RF - Article AD - Francke U, Stanford Univ, Sch Med, Dept Genet, Stanford,CA 94305 USA AB - Rett syndrome (RTT) is a mostly sporadic disorder of developmental regression, with loss of speech and purposeful hand use, microcephaly and seizures. It affects 1 in 10 000-15 000 females. RTT is caused by mutations in the MECP2 gene, which is located in Xq28 and subject to X inactivation. MECP2 encodes a methyl-CpG-binding protein that binds to 5-methyl-cytosine in DNA through its methyl- binding domain. Recruitment of a transcriptional silencing complex through MeCP2's transcriptional repression domain results in histone deacetylation and chromatin condensation. To study the effects of two common truncating RTT mutations (R168X and 803delG), we examined mutant MeCP2 expression and global histone acetylation levels in clonal cell cultures from a female RTT patient with the mutant R168X allele on the active X chromosome, as well as in cells from a male hemizygous for the frameshift mutation 803delG (V288X), Both mutant alleles generated stable RNA transcripts, but no intact MeCP2 protein was detected with an antibody against the C- terminal region of MeCP2, Western blots with antibodies against acetylated histones H3 and H4 revealed that H4, but not H3, was hyperacetylated. By using antibodies against individual acetylated lysine residues, the observed H4 hyperacetylation was attributed to increased acetylation of lysine 16. Therefore, expression of endogenous truncating MECP2 alleles, in the absence of wild-type MeCP2 protein, is specifically associated with an increase in the mono-acetylated histone isoform H4K16, This observed effect may result in over-expression of MeCP2 target genes and, thus, play a role in the pathogenesis of RTT. SO - Hum Mol Genet 2001 MAY 1;10(10):1085-1092 17 UI - 434JX AU - Dahl M AU - Nordestgaard BG AU - Lange P AU - TybjaergHansen A TI - Fifteen-year follow-up of pulmonary function in individuals heterozygous for the cystic fibrosis phenylalanine-508 deletion. LA - English RF - Article AD - Tybjaerg Hansen A, Univ Copenhagen Hosp, Rigshosp, Dept Clin Biochem KB 3011, Blegdamsvej 9, DK 2100 Copenhagen O, DENMARK AB - Background: In a cross-sectional study, we previously showed that cystic fibrosis phenylalanine-508 deletion (Delta F508) heterozygosity may be overrepresented among individuals with asthma. Objective: Using 15-year follow-up data from the Copenhagen City Heart Study, we now further explore this relationship. Methods: As part of 3 surveys in 1976 to 1978, 1981 to 1983, and 1991 to 1994, we measured pulmonary function and asked all participants about asthma and pulmonary risk factors. Results: There was no difference in annual decline in lung function between Delta F508 heterozygotes and noncarriers overall; however, among individuals with familial asthma, the annual declines in FEV1 and forced vital capacity (FVC) were 49 and 36 mt in Delta F508 heterozygotes versus 24 and 17 mt in noncarriers (P = .01 and P = .12, respectively). Cross-sectionally based on triple measurements, FEV1 and FVC in individuals aged 20 to 70 years were tower in heterozygous participants versus noncarriers (P = .02 and P = .004, respectively), The average reduction of FEV1 and FVC in Delta F508 heterozygotes versus noncarriers was 70 mt (P = .06) and 136 mt (P = .008). Finally, 10% of carriers reported asthma versus 7% of noncarriers (P = .02), resulting in an odds ratio of 2.0 (1.3-3.2) for asthma in Delta F508 heterozygotes, Conclusion: Cystic fibrosis Delta F508 heterozygotes may be overrepresented among individuals with asthma and may have poorer lung function than noncarriers. Furthermore, Delta F508 heterozygosity in context with familial predisposition to asthma may be associated with a greater annual FEV1 decline. SO - J Allerg Clin Immunol 2001 MAY;107(5):818-823 18 UI - 435FJ AU - Isaacs JS AU - Saito S AU - Neckers LM TI - Requirement for HDM2 activity in the rapid degradation of p53 in neuroblastoma. LA - English RF - Article AD - Neckers LM, NCI, Tumor Cell Biol Med Branch, NIH, KWC Ste 300, 9610 Med Ctr Dr, Rockville,MD 20850 USA AB - The wild type p53 tumor suppressor protein is rapidly degraded in normal cells by MDM2, the ubiquitin ligase that serves as the key regulator of p53 function by modulating protein stability. Cellular exposure to genotoxic stress triggers the stabilization of p53 by multiple pathways that converge upon interference with MDM2 function. In this study, we first investigated the ability of HDM2 (MDM2 human homologue) to degrade endogenous p53 in neuroblastoma (NB), Although the p53 protein in NE has been reported to be constitutively stabilized, we find that HDM2 in NE is functional and facilitates the rapid turnover of p53 in nonstressed cells via the proteasome pathway. Second, we examined the relationship between p53 and HDM2 in the adriamycin- mediated stabilization of p53 in NE. We demonstrate that while p53 stabilization depends neither upon the phosphorylation of specific N-terminal sites nor upon dissociation from HDM2, it requires inactivation of functional HDM2, In support of this notion, p53 stabilization following adriamycin resulted in an inhibition of both p53 ubiquitination and HDM2 ligase activity. Taken together, these data implicate a requirement for enzymatic inactivation of HDM2 as a novel mechanism for p53 stabilization in the DNA damage response pathway. SO - J Biol Chem 2001 MAY 25;276(21):18497-18506 19 UI - 434FF AU - Jyothy A AU - Kumar KSD AU - Rao GNM AU - Rao VB AU - Devi BU AU - Sujatha M AU - Reddy PP TI - Parental age and the origin of extra chromosome 21 in Down syndrome. LA - English RF - Article AD - Jyothy A, Osmania Univ, Inst Genet, Hyderabad 500016, Andhra Pradesh, INDIA AB - We present a report of the parental ages (n = 865) and parental origin of meiotic nondisjunction (n = 236) that are likely to show a predisposition in the etiology of Down syndrome (DS). Chromosomal analysis, performed over a 20-year period, on 1001 Down syndrome subjects, revealed pure trisomy 21 karyotype in 880 subjects (87.92%), mosaic trisomy karyotype in 77 (7.69%), and translocation karyotype in 44 (4.39%). The mean maternal age was found to be 30.34 years, and mean paternal age was 31.04 years. Nondisjunctional error was 79.24% maternal and 20.76% paternal. The findings of the study revealed the significant contribution of advanced parental age and increased maternal meiotic nondisjunctional error to the origin of trisomy 21 Down syndrome. SO - J Hum Genet 2001;46(6):347-350 20 UI - 433LR AU - Westphal V AU - Enns GM AU - McCracken MF AU - Freeze HH TI - Functional analysis of novel mutations in a congenital disorder of glycosylation Ia patient with mixed Asian ancestry. LA - English RF - Article AD - Freeze HH, Burnham Inst, 10901 N Torrey Pines Rd, La Jolla,CA 92037 USA AB - Congenital disorders of glycosylation (CDG) are caused by autosomal recessive mutations in genes affecting-N-glycan biosynthesis. Mutations in the PMM2 gene, which encodes the enzyme phosphomannomutase (mannose 6-phosphate <----> mannose 1-phosphate), give rise to the most common form: CDG-Ia. These patients typically present with dysmorphic features and neurological abnormalities, cerebellar hypoplasia, ataxia, hypotonia, and coagulopathy, in addition to feeding problems. However, the clinical symptoms vary greatly, The great majority of known CDG-Ia patients are of European descent where the most common mutant alleles originated. This ethnic bias can also be explained by lack of global awareness of the disorder. Here we report an Asian patient with prominent systemic features that we diagnosed with CDG-Ia resulting from two new mutations in the PMM2 gene (310C --> G resulting in L104V and an intronic mutation IVS1-1G --> A). The latter mutation seems to result in lower mRNA levels, and the L104V has been functionally analyzed in a yeast expression system together with known mutations, The Filipino and Cambodian origins of the parents show that CDG-Ia mutations occur in these ethnic groups as well as in Caucasians. (C) 2001 Academic Press. SO - Mol Genet Metab 2001 MAY;73(1):71-76 21 UI - 433LR AU - Westphal V AU - Kjaergaard S AU - Davis JA AU - Peterson SM AU - Skovby F AU - Freeze HH TI - Genetic and metabolic analysis of the first adult with congenital disorder of glycosylation type Ib: Long-term outcome and effects of mannose supplementation. LA - English RF - Article AD - Kjaergaard S, Univ Copenhagen Hosp, Rigshosp 4062, Dept Clin Genet, Blegdamsvej 9, DK 2100 Copenhagen, DENMARK AB - We report the diagnosis and follow-up of two sibs reported in 1980 with recurrent venous thromboses and protein- losing enteropathy; one sib with biopsy-proven hepatic fibrosis died at age 5. The combination of symptoms was suggestive of the recently characterized congenital disorder of glycosylation type Ib (CDG-Ib), which is caused by a deficiency of the enzyme phosphomannose isomerase (PMI). An abnormal serum transferrin isoelectric focusing (IEF) pattern and a reduced PMI activity confirmed the diagnosis of CDG-Ib. Furthermore, mutational analysis of the MPI gene revealed two missense mutations, 419 T --> C (I140T) and 636 G -->A (R219Q), a single base substitution in intron 5, 670 + 9G --> A, as well as a polymorphism 1131A --> C (V377V) in both sibs. The surviving 33-year-old sib has had no further symptoms following childhood. Short-term low-dose oral mannose supplementation improved her transferrin IEF pattern and normalized her antithrombin III activity, further substantiating the beneficial effect of mannose in CDG-Ib. When her mannose blood level was measured, she showed a lower steady-state level but a faster mannose clearance rate. These results suggest that the clinical manifestations of PMI deficiency, although serious in childhood, can improve with age, even without mannose therapy, and allow for a normal adult life. However, the long-term prognosis may vary from patient to patient. (C) 2001 Academic Press. SO - Mol Genet Metab 2001 MAY;73(1):77-85 22 UI - 437GE AU - Todd JA TI - Human genetics - Tackling common disease. LA - English RF - Editorial AD - Todd JA, Univ Cambridge, Inst Med Res, Juvenile Diabet Res Fdn, Wellcome Trust Lab, Wellcome Trust MRC Bldg, Hills Rd, Cambridge CB2 2XY, ENGLAND SO - Nature 2001 MAY 31;411(6837):537-539 23 UI - 437GE AU - Hugot JP AU - Chamaillard M AU - Zouali H AU - Lesage S AU - Cezard JP AU - Belaiche J AU - Almer S AU - Tysk C AU - OMorain CA AU - Gassull M AU - Binder V AU - Finkel Y AU - Cortot A AU - Modigliani R AU - LaurentPuig P AU - GowerRousseau C AU - Macry J AU - Colombel JF AU - Sahbatou M AU - Thomas G TI - Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. LA - English RF - Article AD - Thomas G, Fdn Jean Dausset CEPH, 27 Rue J Dodu, F 75010 Paris, FRANCE AB - Crohn's disease(1,2) and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped(3) to chromosome 16. Here we have used a positional- cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated. SO - Nature 2001 MAY 31;411(6837):599-603 24 UI - 437GE AU - Ogura Y AU - Bonen DK AU - Inohara N AU - Nicolae DL AU - Chen FF AU - Ramos R AU - Britton H AU - Moran T AU - Karaliuskas R AU - Duerr RH AU - Achkar JP AU - Brant SR AU - Bayless TM AU - Kirschner BS AU - Hanauer SB AU - Nunez G AU - Cho JH TI - A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. LA - English RF - Article AD - Nunez G, Univ Michigan, Sch Med, Dept Pathol, Ann Arbor,MI 48109 USA AB - Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to result from the effect of environmental factors in a genetically predisposed host. A gene location in the pericentromeric region of chromosome 16, IBD1, that contributes to susceptibility to Crohn's disease has been established through multiple linkage studies(1-6), but the specific gene(s) has not been identified. NOD2, a gene that encodes a protein with homology to plant disease resistance gene products is located in the peak region of linkage on chromosome 16 (ref. 7). Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease. Wild-type NOD2 activates nuclear factor NF-kappaB, making it responsive to bacterial lipopolysaccharides; however, this induction was deficient in mutant NOD2. These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial components and development of disease. SO - Nature 2001 MAY 31;411(6837):603-606 25 UI - 433MB AU - Carter AR AU - Segal RA TI - Rett syndrome model suggests MECP2 gives neurons the quiet they need to think. LA - English RF - News Item AD - Carter AR, Dana Farber Canc Inst, Dept Neurobiol & Pediat Oncol, Dana 620, 44 Binney St, Boston,MA 02115 USA AB - The neurodevelopmental disorder Rett syndrome Involves mutations in the transcriptional repressor MECP2. Two groups now show a role for MECP2 in postmitotic mouse neurons. SO - Nat Neurosci 2001 APR;4(4):342-343 26 UI - 432WY AU - Millard TH AU - Machesky LM TI - The Wiskott-Aldrich syndrome protein (WASP) family. LA - English RF - Editorial AD - Millard TH, Univ Birmingham, Sch Biosci, Div Mol Cell Biol, Birmingham B15 2TT, W Midlands, ENGLAND SO - Trends Biochem Sci 2001 MAR;26(3):198-199 27 UI - 432VM AU - McCarthy JJ TI - The true nature of pharmacogenomic associations?. LA - English RF - News Item SO - Trends Biotech 2001 FEB;19(2):40-41 28 UI - 432VM AU - Gilbert PX AU - Walter C TI - Patents and the human genome project - new claims for old?. LA - English RF - Article AD - Gilbert PX, Intellectual Property Dept Bristows, 3 Lincolns Inn Fields, London WC2A 3AA, ENGLAND AB - The development and application of genomics is set to revolutionize the life sciences. Commercial exploitation of this research will allow the development of novel therapies and diagnostic assays. However, some argue that a 'gold rush' is underway and conflicts have already arisen over the question of filing patents and sharing data. In this article we consider some of the issues that relate to patenting genomic inventions. SO - Trends Biotech 2001 FEB;19(2):49-52 29 UI - 432WA AU - Gottifredi V AU - Prives C TI - P53 and PML: new partners in tumor suppression. LA - English RF - Article AD - Gottifredi V, Columbia Univ, Dept Biol Sci, New York,NY 10027 USA AB - Whether cells die, differentiate or senesce depends on specific molecular programs. Although the full cast of players in each of these processes has not been identified, regulatory roles for the tumor suppressors p53 and the promyelocytic leukemia protein - PML - appear to be essential. The extent of cross-talk between these factors, however, remains to be determined. Recently, new discoveries link p53 and PML by showing that the latter is required for the efficient onset of both p53-dependent apoptosis and cell senescence induced by the oncogenic form of the ras protein. SO - Tr Cell Biol 2001 MAY;11(5):184-187 30 UI - 432VY AU - Aebi M AU - Hennet T TI - Congenital disorders of glycosylation: genetic model systems lead the way. LA - English RF - Review AD - Aebi M, ETH Zurich, Inst Mikrobiol, Schmelzbergstr 7, CH 8092 Zurich, SWITZERLAND AB - N-linked glycosylation is the most frequent modification of secretory proteins in eukaryotic cells. The highly conserved glycosylation process is initiated in the endoplasmic reticulum (ER), where the Glc(3)Man(9)GlcNAc(2) oligosaccharide is assembled on the lipid carrier dolichylpyrophosphate and then transferred to selected asparagine residues of polypeptide chains. In recent years, several inherited human diseases, congenital disorders of glycosylation (CDG), have been associated with deficiencies in this pathway. The ER-associated glycosylation pathway has been studied in the budding yeast Saccharomyces cerevisiae, and this model system has been invaluable in elucidating the molecular basis of novel types of CDG. SO - Tr Cell Biol 2001 MAR;11(3):136-141 31 UI - 432WG AU - Duret L TI - Why do genes have introns? Recombination might add a new piece to the puzzle. LA - English RF - Article AD - Duret L, Univ Lyon 1, Lab Biometrie & Biol Evolut, CNRS, UMR 5558, 43 Bd 11 Novembre 1918, F 69622 Villeurbanne, FRANCE AB - Much progress has been made recently regarding when and how spliceosomal introns invaded eukaryotic genomes. Although the 'intron early-intron late' debate seems to be settled, the original and essential question remains: why have introns at all-do they have a purpose? Analyses of the relationship between intron length and recombination in Drosophila shed new light on the forces that drive the evolution of introns. Comeron and Kreitman proposed recently that introns are advantageous because they enhance within-gene recombination and therefore increase selection efficacy (Hill-Robertson effects). However, their observations can also be explained by alternative neutralist models. SO - Trends Genet 2001 APR;17(4):172-175 32 UI - 432WG AU - Brookes AJ TI - HGBASE - a unified human SNP database. LA - English RF - Editorial AD - Brookes AJ, Karolinska Inst, Ctr Genom Res, S 17177 Stockholm, SWEDEN SO - Trends Genet 2001 APR;17(4):229 33 UI - 432WF AU - Petronis A TI - Human morbid genetics revisited: relevance of epigenetics. LA - English RF - Article AD - Petronis A, Ctr Addict & Mental Hlth, Neurogenet Sect, Rm 28, 250 Coll St, Toronto, ON M5T 1R8, CANADA AB - Identification of genes predisposing their carrier to complex diseases is a much more complicated task than finding genes involved in simple mendelian diseases. The slow progress in the genetic research of complex diseases could be due to limitations in the basic research strategy, which is almost exclusively orientated to the detection of disease-related DNA mutations or polymorphisms. I argue in this article that epigenetic misregulation of genes is more consistent with the features of complex diseases than is DNA sequence variation, and therefore that epigenetic factors could be important in understanding the origins of complex diseases. SO - Trends Genet 2001 MAR;17(3):142-146 34 UI - 432WF AU - Fortna A AU - Gardiner K TI - Genomic sequence analysis tools: a user's guide. LA - English RF - Software Review AD - Fortna A, Eleanor Roosevelt Inst Canc Res, 1899 Gaylord St, Denver,CO 80206 USA AB - The wealth of information from various genome sequencing projects provides the biologist with a new perspective from which to analyze, and design experiments with, mammalian systems. The complexity of the information, however, requires new software tools, and numerous such tools are now available. Which type and which specific system is most effective depends, in part, upon how much sequence is to be analyzed and with what level of experimental support. Here we survey a number of mammalian genomic sequence analysis systems with respect to the data they provide and the ease of their use. The hope is to aid the experimental biologist in choosing the most appropriate tool for their analyses. SO - Trends Genet 2001 MAR;17(3):158-164 35 UI - 432WD AU - Hurst LD AU - Pal C TI - Evidence for purifying selection acting on silent sites in BRCA1. LA - English RF - Editorial AD - Hurst LD, Univ Bath, Dept Biol & Biochem, Claverton Down, Bath BA2 7AY, Avon, ENGLAND AB - In mammals, it is usually assumed that selection cannot be strong enough to act on nucleotide mutations that do not cause a change at the protein level (i.e. 'silent' or 'synonymous' mutations). Here we report the results of a molecular evolutionary analysis of BRCA1. We find a repeatable pronounced peak in the ratio of nonsynonymous to synonymous substitutions between codons 200-300. Unusually,this peak is caused by a plummet in the silent- site rate of evolution. The most parsimonious interpretation of these data is that purifying selection is acting on silent sites. SO - Trends Genet 2001 FEB;17(2):62-65 36 UI - 432WD AU - Undlien DE AU - Lie BA AU - Thorsby E TI - HLA complex genes in type 1 diabetes and other autoimmune diseases. Which genes are involved?. LA - English RF - Review AD - Undlien DE, Natl Hosp, Inst Immunol, N 0027 Oslo, NORWAY AB - The predisposition to develop a majority of autoimmune diseases is associated with specific genes within the human leukocyte antigen (HLA) complex. However, it is frequently difficult to determine which of the many genes of the HLA complex are directly involved in the disease process. The main reasons for these difficulties are the complexity of associations where several HLA complex genes might be involved, and the strong linkage disequilibrium that exists between the genes in this complex. The latter phenomenon leads to secondary disease associations, or what has been called 'hitchhiking polymorphisms'. Here, we give an overview of the complexity of HLA associations in autoimmune disease, focusing on type 1 diabetes and trying to answer the question: how many and which HLA genes are directly involved? SO - Trends Genet 2001 FEB;17(2):93-100 37 UI - 433NK AU - Ingram DK TI - Vaccine development for Alzheimer's disease: a shot of good news. LA - English RF - Article AD - Ingram DK, NIA, Gerontol Res Ctr, Behav Neursci Sect, Lab Neurosci, NIH, 5600 Nathan Shock Lane Dr, Baltimore,MD 21224 USA AB - Studies in transgenic mouse models of Alzheimer's disease suggest the potential for vaccine development for this disease. Specifically, inoculation with A beta peptide reduces A beta plaque formation. However, this vaccination strategy has raised safety concerns. Recent studies have reduced these concerns by demonstrating that long-term A beta vaccination in transgenic mice does not produce detrimental behavioral effects and in fact appears to protect against age-related functional decline in spatial memory tasks. SO - Trends Neurosci 2001 JUN;24(6):305-307 38 UI - 433NG AU - Cattaneo E AU - Rigamonti D AU - Goffredo D AU - Zuccato C AU - Squitieri F AU - Sipione S TI - Loss of normal huntingtin function: new developments in Huntington's disease research. LA - English RF - Review AD - Cattaneo E, Univ Milan, Inst Pharmacol Sci, Via Balzaretti 9, I 20133 Milan, ITALY AB - Huntington's disease is characterized by a loss of brain striatal neurons that occurs as a consequence of an expansion of a CAG repeat in the huntingtin protein. The resulting extended polyglutamine stretch confers a deleterious gain-of-function to the protein. Analysis of the mutant protein has attracted most of the research activity in the field, however re-examination of earlier data and new results on the beneficial functions of normal huntingtin indicate that loss of the normal protein function might actually equally contribute to the pathology. Thus, complete elucidation of the physiological role(s) of huntingtin and its mode of action are essential and could lead to new therapeutic approaches. SO - Trends Neurosci 2001 MAR;24(3):182-188