25, 1996, Sapporo, Japan
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Abstracts of the 41st Annual Meeting of THE JAPAN SOCIETY OF HUMAN GENETICS October 23-25, 1996, Sapporo, Japan President." Kiyotaro KONDO, M.D., D.M.Sc. (Professor, Department of Public Health, Hokkaido University School of Medicine, Sapporo) List of invited papers and symposium Plenary Lectures PL-2 DNA Repair Defects in Mutagenesis and Carcinogenesis .......... M. Sekiguchi 27 PL-3 Human Genetics--Past, Present, and Future ........................ T. Yanase 27 PL-4 Molecular Pathogenesis of Nonketotic Hyperglycinemia ................ S. Kure 28 PL-5 Molecular Basis of Zellweger Syndrome, fl-Ketothiolase Deficiency and Mucopoty- saccharidoses ...................................................... T. Orii 28 Luncheon Seminars LS-I Apoptosis of Hepatocytes in Genetic Diseases ................... "..... F. Endo 29 LS-2 Molecular Genetics of Essential Hypertension ......................... I. Inoue 29 LS-3 Ethical, Legal and Social Issues in Human Genetics ................. H. Takebe 30 LS-4 Intra-body Evolution of Pathogenic Viruses with Special References to HIV and HCV ......................................................... T. Gojobori 30 LS-5 Developmental and Morphological Plans of Mammalian Viscerocranium ...................................... S. Kuratani, I. Matsuo and S. Aizawa 31 LS-6 A New Technology for Cancer Diagnosis--Telomerase-- .............................. K. Ohyashiki, J.H. Ohyashiki and M. Oshimura 31 Symposium S-I-I Fluorescence In Situ Hybridization: Application on Genome Mapping and the Cytomolecular Genetics of Cancer ................................ J. Inazawa 32 S-I-2 Genomic Imprinting and Its Relevance to Genetic Diseases .......... N. Niikawa 32 S-I-3 Behavior of the Human XIST Gene in Mouse Cells... I. Yoshida and N. Takagi 33 S-I-4 Cellular Senescence and Telomerase ............................. M. Oshimura 33 S-II-I Genetic Alterations and Diagnosis in Human Breast Cancer ........................................ M. Emi, Y. Miki and Y. Nakamura 34 S-II-2 Hyperlipidemia and Coronary Heart Disease ............................... H. Hamaguchi, K. Kobayashi and T. Arinami 34 S-II-3 Genetic Studies of Alcoholism................... T. Muramatsu and S. Higuchi 35 S-II-4 A Prospect of Early Prevention of Pregnancy-induced Hypertension Using Genetic and Environmental Risk Factors ................................. G. Kobashi 35 Abstracts of 41st Annual Meeting 27 Plenary Lectures PL-2 DNA REPAIR DEFECTS IN MUTAGENESIS AND CAgCINOGENESIS. Mutsuo SEKIGUCHI (Dept. Biol., Fukuoka Dental College, Fukuoka) There is a special class of mutations that increases the frequency of spontaneous mutation. These are collectively termed mutators and are useful tools for elucidating cellular mechanisms related to the high fidelity of DNA replication. Once a mutant with a mutator phenotype is isolated, it can be used to clone the gene responsible and the gene product can be identified. This in turn paves the way for determination of the biochemical nature of the gene product and further elucidation of its role in the entire process of replication. These proteins may be responsible for genomic stability and defects in the genes would cause an increased frequercy of occurrence of cancers. PL-3 HUMAN GENETICS-- PAST, PRESENT, AND FUTURE Toshiyuki YANASE (Prof. Emeritus, Univ. Kyushu, Fukuoka) This is aspecial lecture commemorating the 40th anniversary of the founding of the Japan Society of Human Genetics. The following items are covered: Human genetics in the earlier days and four pioneering studies in Japan/Establishment of the Japan Society of Human Genetics (1956)/Monumentary studies at the dawn of a new age- those in human population genetics, cytogenetics, and biochemical genetics/Genetic epidemiology and statistical genetics particularly involving analysis of family data and genetic linkage/Inborn errors of metabolism discovered in Japan/Studies on biological effects of inbreeding and genetic load (1960-1970)/Some indications of new current-discoveries of major histocompatibility antigens (HLA), Philadelphia chromosome, somatic cell fusion, two hit theory in carcinogenesis, etc. (1955-1970)/Introduction of technologies of gene manipulation into medical biology/New knowledges of interactions between allelic or non-allelic genes/Heterogeneity at the DNA level of mutation and molecular pathology of single gene disorders/Classification of single gene disorders based upon new genetic concepts/Genomic rearrangement-programmed and unprogrammed rearrangement/ Approaches to the analysis of molecular basis of common polygenic diseases/A mile stone of gene mapping- assignment of genetic locus responsible for Huntington's disease by RFLP linkage/Human genome project- present and future directions/Gene diagnosis and therapy/ Estimation of genetic risks and informed consent in the recombinant DNA era/Ecogenetic and xenogenetic problems in the recent past, present, and future, with special reference to genomic chanaes in microbes and man. Vol, 42, No. 1, 1997 28 Abstracts of 41st Annual Meeting PL-4 Molecular pathogenesis of nonketotic hyperglycinemia. Shigeo Kure (Dept. Biochem. Genet., Tohoku Univ. School of Medicine, Sendai) Nonketotic hyperglycinemia (NKH) is a metabolic disorder with autosomal recessive inheritance, causing severe neurological symptoms. The metabolic lesion of NKH resides in the glycine cleavage system (GCS)r a complex enzyme system with four components; P-,T-, H-, and L-protein. The enzymatic analysis revealed that more than 80% of the patients with NKH are deficient of P-protein activity° We cloned the P-protein cDNA and its genomic counterparts. P-protein gene spanned more than 130 kbp and had 25 exonso Several mutations were identified: One missence mutation accounts for 70% of the mutant alleles in Finland, where the incidence of NKH is unusually high. To elucidate the neuropathogenesis of NKH we examined structure and expression of the GCS in rat brain and primary cultured neurons and astrocytes. Those studies supports the hypothesis that the neurological disturbance in NKH is caused by excitoneurotoxicity through the NMDA receptor, which is allosterically activated by high concentration of glycineo PL-5 MOLECULAR BASIS OF ZELLWEGER SYNDROME,/3 -KETOTHIOLASE DEFICIENCY AND MUCOPOLYSACCHARIDOSES. Tadao ORII (Chubu Women's College, Seki) Zellweger syndrome is a fatal autosomal recessive disease,with clinical evidence of severe neurologic abnormalities, dysmorphic features, hepatomegaly, and multiple renal cysts. We isolated three different types of peroxisome-deficient mutant Chinese- hamster-ovary cells--Z24, Z65, and ZP92--as models for human groups E, F, and C, respectively, and clarified that mutation in PAF-1 is the primary defect in the group F patient. We recently cloned human PAF-2 cDNA that restores peroxisomes of group C Zellweger fibroblasts and identified two pathogenic mutations in the PAF-2 gene in two patients with group C Zellweger syndrome. /3 -Ketothiolase deficiency is a deficiency in mitochondrial acetoacetyl-CoA thiolase (T2). Seventeen mutations were identified in 13 T2-deficient patients. We have identified the first different exonic mutations causing /3 -glucuronidase deficiency in three unrelated Japanese familiies with mucopolysaccharidosis VII, and the first two kinds of exonic mutations causing GalNAc6S sulfatase deficiency : one is the two base pair deletion which causes a flame shift (1342delCA) found in a classical Morquio patient and the other is a point mutation (N204K)which destroys one of the two asparagine-linked glycosylation sites, as detected in two mildly affected siblings with mucopolysaccharidosis IVA. Jpn J Human Genet Abstracts of 41st Annual Meeting 29 Luncheon Seminars LS-I APOPTOSIS OF HEPATOCYTES IN GENETIC DISEASES Fumio Endo (Deparrtment of Pediatrics Kumamoto University School of Medicine, Honjo 1-1-I 860 Japan) Many genetic disorders involve inpairment of metabolic activities in hepatocytes. Some of these cause hepatocytes injury, typically seen in diseases such as galactosemia, furctose intolerance, Wilson disease, a-1 anti-trypsin deficiency. The hepaticytes in the patients with these diseases seem to undergo premature death due to chemical sustances formed in the hepatocyets. However precise mechanisms of hepatocyte death under such conditions have not been elucidated. Among these, hereditary tyrosinemia I(HT1) is characterized by progressive liver damage from infancy and by a high risk for hepatocellular carcinomas. HT1 is caused by the mutations in the fumarylacetoacetate hydrolase gene FAH, encoding the .last enzyme in the tyrosine catabolic pathway. To investigate the hepatocytes injury in HT1 we developed a mouse model which carried inactivating mutations in both FAH gene and HPD gene, in which the later mutation rescues the perinatal death due to FAH defect. The double mutant FAH- /- HPD-/- mice appeared normal, at least until age 18 months and with no evidence of liver disease. The hepatocytes of FAH-/- undergo rapid apoptosis by retrieval of HPD function and acute death follows. Apoptosis of hepetocyes in HI1 has implications in treatment and mechanism for liver pathology of genetic liver diseases. LS-2 MOLECULAR GENETICS OF ESSENTIAL HYPERTENSION. Ituro INOUE (Human Genetics, University of Utah) Human hypertension is a very common, heterogeneous disorder. In the recent study, angiotensinogen (AGT) gene has been implicated in human essential hypertension (EH) through both genetic linkage and allehc association. In particular, the substitution