Molecular Genetics of Tibial Muscular Dystrophy (tmd) and a Novel Distal Myopathy

Academic Dissertation To be publicly discussed with permission of the Medical Faculty of the University of Helsinki, in the small lecture hall of the Haartman Institute, This thesis is based on the following original articles, which are referred to in the text by their Roman numerals. In addition, some unpublished data are presented. Secondary calpain3 deficiency in 2q-linked muscular dystrophy – Titin is the candidate gene. Neurology (2001) 56:869-77. dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. A distinct phenotype of distal myopathy in a large Finnish family. Neurology (2003) 61:87-92. Linkage to two separate loci in a family with a novel distal myopathy phenotype (MPD3). Submitted. ABBREVIATIONS AD autosomal dominant inheritance ANK1 ankyrin 1 gene AR autosomal recessive inheritance ATP adenosine triphosphate BAC bacterial artificial chromosome BLAST basic local alignment search tool bp base pair cDNA complementary DNA CK creatine kinase cM centiMorgan CT computed tomography DAB 3,3'-diaminobenzidine DCM dilated cardiomyopathy DGC dystrophin glycoprotein complex DMD Duchenne muscular dystrophy DMRV distal myopathy with rimmed vacuoles, Nonaka myopathy DNA deoxyribonucleic acid DRAL LIM-domain protein down-regulated in rhabdomyosarcoma EM electron microscopy EMG electromyography ENMG electroneuromyography EST expressed sequence tag FHL four and a half LIM-only protein FISH Fluorescence in situ hybridization FITC fluorescein isothiocyanate FN3 fibronectin type III HCM hypertrophic cardiomyopathy HGP Human Genome Project HIBM hereditary inclusion body myopathy (h-IBM) Ig immunoglobulin C2 IκBα inhibitory protein κBα kb kilobase kD kiloDalton LGMD limb-girdle muscular dystrophy LOD logarithm of odds LODM late-onset distal myopathy Mb megabase 9 MD megaDalton MDM muscular dystrophy with myositis in mouse MM Miyoshi myopathy MPD distal myopathy MLC1SA myosin light chain 1 slow-twitch muscle A MLCK myosin light chain kinase MRI magnetic resonance imaging mRNA messenger RNA MURF muscle-specific ring finger MyBP myosin-binding protein MYH7 β-cardiac myosin heavy chain NCBI National Center for Biotechnology Information NF-κB nuclear factor κB NM nemaline myopathy nNOS neuronal nitric oxide synthase OMIM Online Mendelian Inheritance in Man PAC P1 derived artificial chromosome PAGE polyacrylamide gel electrophoresis PCR polymerase chain reaction RH radiation hybrid RNA ribonucleic acid RT reverse transcription SG sarcoglycan SGC sarcoglycan complex s-IBM sporadic inclusion body myositis SNP single nucleotide polymorphism SSCP single strand conformational polymorphism STS sequence tagged site TA tibialis anterior TMD tibial muscular dystrophy TTN titin gene TUNEL deoxynucleotidyl transferase-mediated dUTP nick end labeling Θ recombination fraction WDM Welander distal myopathy YAC yeast artificial chromosome In …