PP88. SPECTRUM OF MUTATIONS IN THE LMNA GENE, CAUSING MUSCULAR DYSTROPHY WITH CONDUCTION SYSTEM DISEASE (EDMD-AD OR LGMD1B)
TIHOMIR TODOROV 1, A. Todorova 1, 2, B. Halliger-Keller 2, W. Kress 2, I. Tournev 3, M-C. Dabauvalle 4, I. Kremensky 1, C.R. Mueller 2 1. National Genetic Laboratory, Laboratory of Molecular Pathology, University Hospital of Obstetrics and Gynecology, Sofia Medical University, Sofia, Bulgaria 2. Department of Human Genetics, Biozentrum, University of Wuerzburg, Wuerzburg, Germany 3. Clinic of Neurology, Alexandrovska Hospital, Sofia Medical University, Sofia, Bulgaria 4. Department of Cell and Developmental Biology, Biozentrum, University of Wuerzburg, Wuerzburg, Germany e-mail: todorova@medfac.acad.bg
*Corresponding Author:
page: 87

Abstract

Laminopathies are clinically extremely heterogeneous group of inherited disorders, caused by mutations in the same gene - lamin A/C (LMNA) gene. Lamins A and C are nuclear envelope proteins, representing alternatively spliced forms of the LMNA gene. It was identified that mutations in the LMNA gene cause inherited neuromuscular disorders and/or cardiac conduction disturbances, lipodystrophies, peripheral neuropathy and progeroid syndromes. Independent of the phenotype, the vast majority of LMNA mutations are homo- or heterozygous missense mutations. A few splice-site mutations some of which caused by silent codon changes resulting in a cryptic splice-site activation have been reported. In addition, single cases of nonsense mutations or in-frame and frame-shifting small nucleotide deletions and insertions are on record. Here we report on 8 different (5 novel) mutations in the LMNA gene, detected in a group of EDMD/LGMD1B patients by direct sequencing of the whole gene. A nonsense substitution, a splice-site change; a synonymous codon change, activating a cryptic splice-site and five missense substitutions were detected in our sample. Genotype-phenotype correlation was investigated in unrelated cases sharing the same mutation in the LMNA gene, as well as within a single family. We believe that the present results on this chameleonic gene might help to a better understanding of the pathophysiological mechanisms involved in the appearance of these tissue-specific diseases as a result of mutations in a gene expressed all over.




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