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Mapping Genes for X-Linked Disorders

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Mapping Genes for X-Linked Disorders r6's'êf1 [l MAPPING GENES FOR X.LINKED DISORDERS by Ági Kyra Gedeon B.Sc.(Hons.) This thesis is submitted as the complete requirement for the degree of Doctor of Philosophy within the Department of Genetics, Faculty of Science, at The University of Adelaide, South Australia. September 1996 Declaration This thesis contains no material that has been accepted for the award of any other degree or diploma in any University or other tertiary institution, nor to the best of the candidate's knowledge any material previously published or written by another person, except where due reference is made in the text. Throughout this volume any reference to 'the candidate' signifies the author Agi Kyra Gedeon. The work described in this thesis has been performed by the candidate or under the candidate's supervision, except where duly acknowledged in the text. NAME: A.q4 ..K.,,..6.ç.ù.çp-M.'...." couRSE: F¿. Þ.,..ßçi.c.r.c*) v in the university Libraries' being available I give consent to this copy of my thesis, when deposited for photocoPying and loan. 2..ï..: !9.:1.ú SIGNATURE: ... DArE: Table of Contents Declaration Table of Contents 1l Abbreviations iii Acknowledgments v Summary vii Note regarding Publications ix CHAPTER 1 : Gene Mapping: Review of the literature and Objectives 1 CHAPTER 2 : Materials and Methods JJ CHAPTER 3 : Evolution of the Background Map of the X Chromosome 62 CHAPTER 4 : Non-specific X-linked Mental Retardation (MRX) 92 CHAPTER 5 : Syndromal X-linked Mental Retardation (XLMR) r46 CHAPTER 6 : Other X-linked Disorders 167 CHAPTER 7 : Submicroscopic Deletions of the X Chromosome Associated With Mental Impairment 180 CHAPTER 8 : Conclusion 192 References t97 Appendix I : Publications from Chapter 3 Appendix II : Publications from Chapter 4 Appendix III: Publications from Chapter 5 Appendix IV : Publications from Chapter 6 Appendix V : Publications from Chapter 7 ll Abbreviations 5'UTR 5' untranslated region ofa gene (AC)" a dinucleotide repeat sequence comprised of the bases AC repeated n times (ccc)" a trinucleotide repeat sequence comprised of the bases CCG repeated n times A,C,G,T the four nitrogenous organic bases; adenine, cytosine, guanine and thymine ANGIS Australian National Genomic Information Service bp basepairs; deoxyribonucleoside pairs BFLS Börjeson-Forssman-Lehmann syndrome; a syndromal XLMR (Chapter 5) BTHS Barth syndrome; X-linked cardiomyopathy (Chapter 6) cDNA complementary DNA or copy DNA; reverse transcribed in vitro from mRNA CEPH Centre d'Étude du Potymorphisme Humain in France cM centimorgan; the unit of genetic distance CVS chorionic villus sample DMD Duchenne muscular dystrophy DNA deoxyribonucleic acid DXS... standardised D alphanumeric locus symbol representing a unique segment of the X chromosome identified by a cloned DNA sequence EST expressed sequence tag; partial sequence of a cDNA clone corresponding to an mRNA. FISH fl uorescent i n-s itu hybridisation FMRI gene symbolfor Fragile X mental retardation I gene at FRAXA FMR2 gene symbolfor Fragile X mentalretardation 2 gene at FRAXE FraX fragile X syndrome at the FRAXA fragile site FRAXA folate sensitive fragile site atXq27.3 FRAXE folate sensitive fragile site in Xq28 FRAXF folate sensitive fragile site in Xq28 GDB Genome Data Base (GT)" complementary strand to an (AC) n sequence HGP Human Genome Project IQ intelligence quotient; a standardised measure of intellectual functioning kb kilobase; 1000 basepairs of DNA M Morgan; 1000 centiMorgans mA milliampere; unit of electrical current Mb megabase; 1000 kilobases of DNA MIM Mendelian Inheritance in Man; a listing and numeric code for human disease genes mRNA messenger RNA; transcript of a gene and serves as a template for translation MRX mental retardation, X-linked; used for non-specific forms only (Chapter 4) MRXS mental retardation, X-linked, syndrome; lnterim symbol used for syndromal forms only (Chapter 5) oDzoo optical density at a wavelength of 260nm oDooo optical density at a wavelength of 600nm OMIM on-line version of the Mendelian Inheritance in Man (MIM) database PAGE polyacrylamide gel electrophoresis PAR pseudoautosomal region of the X chromosome PC personal computer PCR polymerase chain reaction; an in vifro process for DNA amplification PDR X-linked reticulate pigmentary disorder (Chapter 6) PFGE pulsed-fi eld gel electrophoresis PIC polymorphic information content POWCH Prince of 'Wales Children's Hospital, Sydney, New South Wales PRTS Partington syndrome; XLMR with dystonic movements of the hands (Chapter s) RTLP restriction fragment length polymorphism RNA ribonucleic acid SHS Sutherland-Haan syndrome; XLMR with spastic diplegia (Chapter 5) SSCA single stranded conformational analysis SSCP single stranded conformational po lymorphism STR simple tandem repeat STS sequence tagged site; a short, unique DNA sequence VNTR variable number of tandem repeats volume per volume weight per volume WCH Women's and Children's Hospital, Adelaide, South Australia WTS Wilson-Turner syndrome; XLMR with gynaecomastia and obesity (Chapter s) XCW X chromosome workshop XLMR X-linked mental retardation; general term XS X-linked Lutheran suppressor gene (Chapter 6) YAC yeast artificial chromosome; used for cloning large DNA fragments IV Acknowledgments This project was carried out in the Department of C¡ogenetics and Molecular Genetics at the Women's and Children's Hospital in Adelaide, South Australia. The work was done on a part-time basis alongside the full+ime diagnostic commitment to families with fragile X syndrome, myotonic dystrophy, fascio-scapulo-humeral dystrophy and miscellaneous other rare genetic disorders including those described in this thesis. I gratefully acknowledge the pafticipation of the families and their clinicians in the study. It is particularly gratifoing that many of the results in this thesis have already, or are being, put to use in the genetic counselling of the family members. I wish to express appreciation to Professor Grant R. Sutherland, my supervisor and head of the department, for the opportunity to complete this study under his guidance. Many thanks also to Dr. Rory Hope, my supervisor, Deparlment of Genetics, University of Adelaide and Dr. John Mulley, GM unit section head, who participated in many useful discussions and gave helpful advice on several aspects ofthis project. Several clinicians entered into this study by contributing families. I am indebted to them all, but outstandingly to Drs. Gillian Turner and Bronwyn Kerr then of the Prince of Wales Children's Hospital, as well as Drs. Lesley Ades and Meredith Wilson then of Camperdown Children's Hospital. Hazel Robinson, Sam Wake and the Sydney team, have been reliably helpful and pleasant associates. I have great respect for Dr. Michael Partington, Dr. Gillian Turner and Dr. Eric Haan and am honoured to have worked with each of them on some of the families presented here. The contributions of specialised skills and extra hands to this work by my colleagues Elizabeth Baker, Andrew Donnelly, Helen Kozman and Jozef Gecz are gratefully acknowledged. The opportunity to work together with colleagues toward a common goal have been most valuable and insightful. My thanks to my supportive family who hold me up from all corners of the globe, especially my husband, Dietmar Blanke, who I lean on the heaviest. My thanks also to my baby daughter, Dominique, who peacefully gestated whilst I was in the throes of writing-up, and continued to be a model baby until thesis submission. I dedicate this effort to the fond memory of my grandfather - Töled jön az erö folytatni s befejezni. Nektek tartozok mindennel, irtoan szeretlek Benneteket. I am grateful to all for their immense patience with me and their unfailing support and encouragement when the going got rough. Apart from my family, my team of moral supporters included Lesley Ades, Bryone Kuss, Jozef Gecz, Sinoula Apostolou, Kathy Friend and numerous others who periodically boosted my flagging energJ towards the end. v A Salient Quote "1f......IQ is due to sex-linked genes, it is of more importance that a boy should have a clever mother than a clever father," Hogben, 1932 (quoted in Lehrke, 1974) vt Summary The human genome project aims to sequence the genome, identifli genes and thus the causes of inherited disease. The research presented in this thesis reports contributions to the development of the evolving map of the X chromosome, and the localisation and genetic delineation of rare X-linked monogenic neuropsychiatric diseases and other X-linked disorders, culminating in the identification of two new genes. New polymorphic PCR-based markers were characterised from probes of known location (DXSl02,DXS237, DXS294 and DXS300). Three were physically mapped between somatic cell hybrid breakpoints and on a YAC contig of Xq25-27. Development of a regional genetic map contributed to the integration of maps in Xq26.40 CEPH reference families were genotyped for these markers and another, DXS538, and added to a comprehensive genetic map constructed from the CEPH database (ver 5.0). Additional PCR-based markers gathered from the literature, were ordered by comparisons with other genetic and physical maps, to create a composite background map spanning the entire X chromosome to facilitate localisation of disease genes by linkage. The disproportionate excess of retarded males in the population may be accounted for by a number of X-linked disorders with mental retardation as a feature. The fragile X syndrome is responsible for less than half of these. To determine the number and distribution of other genes involved in XLMR, frfteen non-FRAXA families segregating mental retardation were collected into two distinct classes: i) MRX, where the mental retardation was the sole and major feature in otherwise clinically apparently normal individuals and ii) MRXS, with associated clinically distinct features. The disease gene in each family was localised by demonstration of significant linkage to markers in an interval flanked by recombinant events. These linkage studies identified 7 distinct regions of the X chromosome involved in MRX and confirmed the genetic heterogeneity of MRX.
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