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Molecular Genetics of Rare Puberty Disorders in Finland and Denmark

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Molecular Genetics of Rare Puberty Disorders in Finland and Denmark Doctoral Programme in Biomedicine Medicum/Physiology Faculty of Medicine University of Helsinki MOLECULAR GENETICS OF RARE PUBERTY DISORDERS IN FINLAND AND DENMARK Johanna Känsäkoski ACADEMIC DISSERTATION To be publicly discussed, with the permission of the Faculty of Medicine of the University of Helsinki, in Auditorium XIV, Main Building of the University of Helsinki, Unioninkatu 34, on August 18th 2017, at 12 o’clock noon Helsinki 2017 Supervised by Professor Taneli Raivio, MD, PhD Physiology, Faculty of Medicine University of Helsinki and Children's Hospital Helsinki University Hospital Helsinki, Finland and Docent Johanna Tommiska, PhD Physiology, Faculty of Medicine University of Helsinki and Children's Hospital Helsinki University Hospital Helsinki, Finland Reviewed by Docent Hannele Laivuori, MD, PhD Department of Medical and Clinical Genetics University of Helsinki and Helsinki University Hospital and Institute for Molecular Medicine Finland / HiLIFE University of Helsinki Helsinki, Finland and Docent Kirsti Näntö-Salonen, MD, PhD Department of Pediatrics Turku University Hospital and University of Turku Turku, Finland Official opponent Professor Helena Kääriäinen, MD, PhD National Institute for Health and Welfare and Department of Clinical Genetics Helsinki University Hospital Helsinki, Finland ISBN 978-951-51-3532-2 (paperback) ISBN 978-951-51-3533-9 (PDF) http://ethesis.helsinki.fi Unigrafia Oy Helsinki 2017 Table of Contents LIST OF ORIGINAL PUBLICATIONS ........................................................................ 7 ABBREVIATIONS AND DEFINITIONS ..................................................................... 8 ABSTRACT .................................................................................................................. 12 TIIVISTELMÄ .............................................................................................................. 14 1. INTRODUCTION ................................................................................................. 16 2. REVIEW OF THE LITERATURE ....................................................................... 19 2.1 Sex determination and sex differentiation....................................................... 19 2.1.1 Sex determination ....................................................................................... 19 2.1.2 Sex differentiation ...................................................................................... 21 2.2 Disorders of sex development ........................................................................... 23 2.2.1 46,XY and 46,XX disorders of sex development ...................................... 23 2.2.2 Androgen insensitivity syndrome (AIS) ................................................... 26 2.3 The hypothalamic-pituitary-gonadal axis ....................................................... 27 2.4 The development, migration and control of GnRH neurons ......................... 29 2.5 Current understanding on the factors controlling the onset of puberty ...... 32 2.6 Gonadotropin-dependent precocious puberty (GDPP) .................................. 34 2.6.1 Clinical manifestation of GDPP ................................................................ 34 2.6.2 Molecular genetics of GDPP ...................................................................... 35 2.7 Delayed puberty: congenital hypogonadotropic hypogonadism and Kallmann syndrome ................................................................................................ 38 2.7.1 Clinical presentation .................................................................................. 38 2.7.2 Molecular genetics of CHH ........................................................................ 40 2.7.3 Genetic defects underlying Kallmann syndrome ..................................... 48 2.7.4 Genetic defects underlying normosmic CHH .......................................... 52 2.7.5 Other genes implicated in CHH ................................................................ 53 2.7.6 Semaphorins ................................................................................................ 59 3. AIMS OF THE STUDY ........................................................................................ 65 4. SUBJECTS AND METHODS .................................................................................. 66 4.1 Subjects............................................................................................................... 66 4.1.1 Subjects with CAIS ..................................................................................... 66 4.1.2 Subjects with GDPP ................................................................................... 66 4.1.3 Danish subjects with KS or normosmic CHH .......................................... 67 4.1.4 Finnish subjects with KS or normosmic CHH ......................................... 67 4.1.5 Controls ....................................................................................................... 67 4.1.6 Ethical issues ............................................................................................... 68 4.2 Sanger-sequencing ............................................................................................. 68 4.3 Whole-genome resequencing ............................................................................ 69 4.4 Bioinformatic analysis of mutations ................................................................ 69 4.5 RNA extraction and cDNA synthesis ............................................................... 69 4.6 AR cDNA sequencing ........................................................................................ 69 4.7 RT-qPCR analysis ............................................................................................. 70 4.8 Cell culture ......................................................................................................... 70 4.9 Immunoprecipitation and western blotting .................................................... 71 4.10 Amplification of MKRN3 from a hypothalamic cDNA library ................... 72 5. RESULTS .............................................................................................................. 73 5.1 Deep intronic AR mutation leading to CAIS ................................................... 73 5.1.1 Genomic sequencing and cDNA analysis of AR ....................................... 73 5.1.2 In silico analysis with Human Splicing Finder ........................................ 74 5.1.3 Sequencing of the AR cDNA ...................................................................... 75 5.1.4 AR protein analysis and quantification of AR cDNA .............................. 75 5.2 MKRN3 .............................................................................................................. 79 5.2.1 Results of MKRN3 screening in Danish GDPP patients ......................... 79 5.2.2 Expression of MKRN3 in an adult human hypothalamic cDNA library ............................................................................................................................... 79 5.3 Phenotypic and genotypic features of Danish patients with CHH ................ 80 5.4 SEMA3A and SEMA7A mutations identified in Finnish CHH patients ....... 86 6. DISCUSSION ....................................................................................................... 89 6.1 New mechanisms underlying complete androgen insensitivity syndrome ... 89 6.2 MKRN3 mutations: a significant cause of GDPP in different populations ... 91 6.3 The genetic features of CHH in Denmark ....................................................... 94 6.4 Current knowledge on the involvement of SEMA3A and SEMA7A mutations in CHH pathogenesis ............................................................................................... 98 6.4.1 The role of SEMA3A mutations in CHH .................................................. 98 6.4.2 The role of SEMA7A mutations in CHH ................................................ 100 7. CONCLUSIONS AND FUTURE PERSPECTIVES .......................................... 102 8. ACKNOWLEDGEMENTS ................................................................................ 105 9. REFERENCES .................................................................................................... 107 LIST OF ORIGINAL PUBLICATIONS This thesis is based on the following publications, which are referred to in the text by the Roman numerals I-IV: I. Johanna Känsäkoski, Jarmo Jääskeläinen, Tiina Jääskeläinen, Johanna Tommiska, Lilli Saarinen, Rainer Lehtonen, Sampsa Hautaniemi, Mikko J. Frilander, Jorma J. Palvimo, Jorma Toppari, Taneli Raivio. Complete androgen insensitivity syndrome caused by a deep intronic pseudoexon-activating mutation in the androgen receptor gene. Sci Rep. 2016:6:32819. doi: 10.1038/srep32819. II. Johanna Känsäkoski, Taneli Raivio, Anders Juul, Johanna Tommiska. A missense mutation in MKRN3 in a Danish girl with central precocious puberty and her brother with early puberty. Pediatr Res. 2015:78:709-711. doi: 10.1038/pr.2015.159. III. Johanna Tommiska, Johanna Känsäkoski, Peter Christiansen, Niels Jørgensen, Jacob Lawaetz, Anders Juul, Taneli Raivio. Genetics of Congenital Hypogonadotropic Hypogonadism in Denmark. Eur J Med Genet. 2014:57:345-348. doi: 10.1016/j.ejmg.2014.04.002. IV. Johanna Känsäkoski, Rainer Fagerholm, Eeva-Maria Laitinen, Kirsi Vaaralahti, Peter Hackman, Nelly Pitteloud, Taneli Raivio, Johanna Tommiska. Mutation screening
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