Clinical and Genetic Studies of Three Inherited Skeletal Disorders

......................................................................................................................8 ABBREVIATIONS............................................................................................................9 0BMEDICAL GENETICS ............................................................................................ 11 28BHuman genome................................................................................................................. 11 29BDNA structure................................................................................................................... 11 30BCharacteristics of Mendelian inheritance.......................................................................... 11 31BInter individual variations................................................................................................. 12 INTRODUCTION ...........................................................................................................14 15BThe Skeleton................................................................................................ 14 16BExtracellular matrix ...................................................................................... 14 17BCartilage....................................................................................................... 15 1BCOMPONENTS OF THE EXTRACELLULAR MATRIX NETWORK.................................... 16 18BThe large aggregating Proteoglycans.......................................................... 16 19BACAN-gene and Aggrecan .......................................................................... 16 32BMolecular gene structure, organization and function........................................................ 16 2BCHONDRODYSPLASIAS DUE TO AGGRECAN DEFECTS............................................. 18 3BCHONDRODYSPLASIAS DUE TO AGGRECAN DEFECTS ANIMAL MODELS ................. 19 33BCartilage matrix deficiency............................................................................................... 19 34BCartilage matrix deficiency-Bc ......................................................................................... 19 35BNanomelia......................................................................................................................... 19 36B ulldog dwarfism ............................................................................................................. 19 4BCHONDRODYSPLASIAS DUE TO AGGRECAN DEFECTS – HUMAN DISORDERS............ 20 37BSpondyloepiphyseal dysplasia type Kimberley (SEDK)................................................... 20 38BSpondyloepimetaphyseal dysplasia (SEMD-aggrecan-type) ............................................ 20 39BFamilial osteochondritis dissecans.................................................................................... 20 Disorders associated with defective sulfation of proteoglycans .................. 21 20BDegenerative diseases involving aggrecan ................................................. 21 40BVNTR-region of the ACAN-gene and OA ....................................................................... 21 41BAge-related changes of aggrecan ...................................................................................... 22 5BCOMPONENTS OF THE EXTRACELLULAR MATRIX NETWORK.................................... 22 42BThe Collagens ................................................................................................................... 22 CHONDRODYSPLASIA DUE TO DEFECTS IN ECM-PROTEINS ................................... 23 43BMultiple epiphyseal dysplasia........................................................................................... 23 SKELETONENESIS ............................................................................................... 23 22BThe Indian Hedgehog (IHH)-gene; an important gene for skeletal development................................................................................................. 24 44B rachydactyly type A1 ..................................................................................................... 25 AIMS OF THE THESIS .................................................................................................26