FRG2, an FSHD candidate gene, is transcriptionally upregulated in differentiating primary myoblast cultures of FSHD patients
| Autor: | S.M. van der Maarel, Jane E. Hewitt, R.J.L.F. Lemmers, George W. Padberg, Giancarlo Deidda, R.R. Frants, S. van Koningsbruggen, Tonnie Rijkers, M. van Geel, D. Figlewicz, J.C.T. van Deutekom |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Transcriptional Activation musculoskeletal diseases congenital hereditary and neonatal diseases and abnormalities Candidate gene Myoblasts Skeletal Molecular Sequence Data Chromosomal rearrangement Biology Muscle Development Genetics medicine Humans Gene family Facioscapulohumeral muscular dystrophy Genetic Predisposition to Disease Amino Acid Sequence Promoter Regions Genetic Gene Cells Cultured Genetics (clinical) Base Sequence Chromosomes Human Pair 10 Myogenesis Nuclear Proteins Proteins Cell Differentiation Promoter medicine.disease Molecular biology Neuromuscular development and genetic disorders [UMCN 3.1] Muscular Dystrophy Facioscapulohumeral Up-Regulation Chromosome 4 Female Original Article Chromosomes Human Pair 4 |
| Zdroj: | Journal of Medical Genetics, 41, 826-36 Journal of Medical Genetics, 41, 11, pp. 826-36 |
| ISSN: | 1468-6244 0022-2593 |
| DOI: | 10.1136/jmg.2004.019364 |
| Popis: | Contains fulltext : 58455.pdf (Publisher’s version ) (Closed access) BACKGROUND: Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is associated with partial deletion of the subtelomeric D4Z4 repeat array on chromosome 4qter. This chromosomal rearrangement may result in regional chromatin relaxation and transcriptional deregulation of genes nearby. METHODS AND RESULTS: Here we describe the isolation and characterisation of FRG2, a member of a chromosomally dispersed gene family, mapping only 37 kb proximal to the D4Z4 repeat array. Homology and motif searches yielded no clues to the function of the predicted protein. FRG2 expression is undetectable in all tissues tested except for differentiating myoblasts of FSHD patients, which display low, yet distinct levels of FRG2 expression, partly from chromosome 4 but predominantly originating from its homologue on chromosome 10. However, in non-FSHD myopathy patients only distantly related FRG2 homologues are transcribed, while differentiating myoblasts from healthy controls fail to express any member of this gene family. Moreover, fibroblasts of FSHD patients and control individuals undergoing forced Ad5-MyoD mediated myogenesis show expression of FRG2 mainly originating from chromosome 10. Luciferase reporter assays show that the FRG2 promoter region can direct high levels of expression but is inhibited by increasing numbers of D4Z4 repeat units. Transient transfection experiments with FRG2 fusion-protein constructs reveal nuclear localisation and apparently FRG2 overexpression causes a wide range of morphological changes. CONCLUSION: The localisation of FRG2 genes close to the D4Z4 repeats on chromosome 4 and 10, their transcriptional upregulation specifically in FSHD myoblast cultures, potential involvement in myogenesis, and promoter properties qualify FRG2 as an attractive candidate for FSHD pathogenesis. |
| Databáze: | OpenAIRE |
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