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MOLECULAR GENETICS of the GRACILE SYNDROME (Growth Retardation, Aminoaciduria, Cholestasis, Iron Overload, Lactacidosis and Early Death)

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MOLECULAR GENETICS of the GRACILE SYNDROME (Growth Retardation, Aminoaciduria, Cholestasis, Iron Overload, Lactacidosis and Early Death) CORE Metadata, citation and similar papers at core.ac.uk Provided by Helsingin yliopiston digitaalinen arkisto MOLECULAR GENETICS OF THE GRACILE SYNDROME (Growth Retardation, Aminoaciduria, Cholestasis, Iron overload, Lactacidosis and Early death) Ilona Visapää Department of Molecular Medicine, National Public Health Institute and Department of Medical Genetics, University of Helsinki, Helsinki, Finland, and Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA, and Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, Finland. Academic Dissertation Helsinki University Biomedical Dissertations No. 19 Helsinki Biomedical Graduate School To be publicly discussed with permission of the Medical Faculty of the University of Helsinki, in auditorium 2 of the Biomedicum Helsinki, Haartmaninkatu 8, on December 5th, 2002, at 12 noon. Helsinki 2002 Supervised by Professor Leena Peltonen-Palotie National Public Health Institute and University of Helsinki, Helsinki, Finland and David Geffen School of Medicine at UCLA, Los Angeles, California, USA Reviewed by Professor Pertti Aula University of Helsinki Helsinki, Finland Docent Kirsi Huoponen University of Turku Turku, Finland Copyright National Public Health Institute Julkaisija – Utgivare – Publisher Kansanterveyslaitos Mannerheimintie 166 00300 Helsinki Puh. vaihde (09) 47441, telefax (09) 4744 8408 Folkhälsoinstitutet Mannerheimvägen 166 00300 Helsingfors Tel. växel (09) 47441, telefax (09) 4744 8408 National Public Health Institute Mannerheimintie 166 FIN-00300 Helsinki, Finland Telephone +358 9 47441, telefax +358 9 4744 8408 Publications of the National Public Health Institute, KTL A28/2002 ISBN 951-740-323-2 (Paperback) ISBN 951-740-324-0 (PDF) ISSN 0359-3584 (printed versions) ISSN 1458-6290 (electronic versions) Helsinki University Biomedical Dissertations No. 19 ISSN 1457-8433 Cosmoprint Oy Helsinki 2002 CONTENTS LIST OF ORIGINAL PUBLICATIONS ............................................................. 7 ABBREVIATIONS ................................................................................................ 8 SUMMARY........................................................................................................... 10 REVIEW OF THE LITERATURE.................................................................... 12 The GRACILE Syndrome............................................................................... 12 Clinical Features ........................................................................................... 12 Histopathological findings............................................................................. 13 Iron metabolism............................................................................................. 13 Mitochondrial investigations......................................................................... 14 Non-Finnish patients ..................................................................................... 14 The Human Genome Project .......................................................................... 15 Identification of human disease genes............................................................ 18 The Finnish disease heritage ........................................................................... 21 Founder effect................................................................................................ 21 Genealogy of the GRACILE syndrome .......................................................... 23 Ancestral haplotypes and linkage disequilibrium.......................................... 23 Molecular genetics of the Finnish disease heritage ...................................... 25 Nuclear gene defects resulting in mitochondrial disease .............................. 29 Mitochondrial functions .................................................................................. 32 Oxidative phosphorylation............................................................................. 32 Complex III of the respiratory chain and BCS1L .......................................... 34 Formation of FeS clusters ............................................................................. 35 ABCB7 and ABCB6, the human orthologs of yeast Atm1p............................ 36 Other diseases with abnormalities of mitochondrial iron metabolism.......... 37 AIMS OF THE STUDY ....................................................................................... 38 SUBJECTS AND METHODS............................................................................. 39 GRACILE families and patient samples........................................................ 39 Control samples................................................................................................ 39 DNA and RNA extraction................................................................................ 39 Genotyping........................................................................................................ 39 Linkage and LD analyses ................................................................................ 40 Radiation hybrid mapping .............................................................................. 41 Bioinformatics .................................................................................................. 41 5 Sequencing and mutation screening............................................................... 42 Northern blot analysis ..................................................................................... 43 Expression plasmid construction, cell culture, and transfections................ 43 Immunofluorescence microscopy ................................................................... 43 Western blot analysis....................................................................................... 43 Pulse chase analysis.......................................................................................... 44 Yeast complementation studies....................................................................... 44 Activity measurements of mitochondrial enzyme complexes....................... 44 RESULTS AND DISCUSSION........................................................................... 46 Assignment of the GRACILE locus to chromosome 2 (I)............................. 46 Genome screen and linkage analysis............................................................. 46 LD analyses and RH mapping of the critical region ..................................... 47 Haplotype analysis......................................................................................... 49 The mapping strategy and the importance of LD .......................................... 50 Analysis of the positional candidate genes ABCB6 and BCS1L (III, IV) .... 51 Genes in the critical GRACILE region.......................................................... 51 Sequence analysis of ABCB6 and BCS1L...................................................... 52 Northern blot analysis of ABCB6 and BCS1L............................................... 54 Positional exclusion of ABCB6...................................................................... 54 BCS1L sequence analysis in the British patients........................................... 54 Genomic structure of BCS1L (IV) .................................................................. 55 Functional consequences of the S78G mutation on BCS1L (IV) ................. 56 Expression, targeting, and stability of the mutant BCS1L............................. 56 Yeast complementation studies...................................................................... 58 Activity measurements of complex III in the Finnish GRACILE patients...... 58 Pathogenicity of the identified BCS1L mutations (IV) ................................. 61 Phenotype heterogeneity of the BCS1L mutations (IV)................................ 63 DNA diagnostics of the GRACILE syndrome (I, II, IV) .............................. 67 CONCLUDING REMARKS............................................................................... 68 ACKNOWLEDGEMENTS................................................................................. 70 ELECTRONIC DATABASE INFORMATION................................................ 73 REFERENCES ..................................................................................................... 74 6 LIST OF ORIGINAL PUBLICATIONS This thesis is based on the following original articles, which are referred to in the text by their Roman numerals. I Visapää I, Fellman V, Varilo T, Palotie A, Raivio KO, Peltonen L (1998) Assignment of the locus for a new lethal neonatal metabolic syndrome to 2q33-37. American Journal of Human Genetics 63:1396-1403 II Fellman V, Visapää I, Vujic M, Wennerholm UB, Peltonen L (2002) Antenatal diagnosis of hereditary fetal growth retardation with aminoaciduria, cholestasis, iron overload, and lactic acidosis in the newborn infant. Acta Obstetricia et Gynecologica Scandinavica 81:398- 402 III Visapää I, Fellman V, Lanyi L, Peltonen L (2002) ABCB6 (MTABC3) excluded as the causative gene for the growth retardation syndrome with aminoaciduria, cholestasis, iron overload, and lactacidosis. American Journal of Medical Genetics 109:202-205 IV Visapää I, Fellman V, Vesa J, Dasvarma A, Hutton JL, Kumar V, Payne GS, Makarow M, Van Coster R, Taylor RW, Turnbull DM, Suomalainen A, Peltonen L (2002) GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. American
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