Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures
| Autor: | Susanne Morales-Gonzalez, Janbernd Kirschner, Klaus Zerres, Mickael Orgeur, Gudrun Schottmann, Esther Gill, Werner Stenzel, Ellen Knierim, Nicole I. Wolf, Hiromi Hirata, Angelika Zwirner, Yu Tanaka, Anne van Riesen, Stefanie Vogt, Markus Schuelke, Franziska Seifert, David Meierhofer, Sigmar Stricker, Sabine Rudnik-Schöneborn, Christoph Hübner, Hans H. Goebel |
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| Přispěvatelé: | Pediatric surgery, Amsterdam Neuroscience - Cellular & Molecular Mechanisms |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Activating signal cointegrator 1 complex Fractures Bone Mice 0302 clinical medicine arthrogryposis multiplex congenita Genetics(clinical) Zebrafish Genetics (clinical) ASCC1 Cells Cultured spinal muscular atrophy Genetics Arthrogryposis Gene knockdown biology Homozygote bone fractures Gene Expression Regulation Developmental Nuclear Proteins LIM Domain Proteins Cell biology Pedigree Phenotype Molecular Sequence Data Article Frameshift mutation Muscular Atrophy Spinal 03 medical and health sciences respiratory distress medicine Animals Humans Amino Acid Sequence Transcription factor Spinal Cord Regeneration Gene Expression Profiling neuromuscular unit SEMA3A Spinal muscular atrophy Fibroblasts Zebrafish Proteins medicine.disease biology.organism_classification 030104 developmental biology TRIP4 Mutation Carrier Proteins exome sequencing 030217 neurology & neurosurgery zebrafish model Transcription Factors |
| Zdroj: | Knierim, E, Hirata, H, Wolf, N I, Morales-Gonzalez, S, Schottmann, G, Tanaka, Y, Rudnik-Schoeneborn, S, Orgeur, M, Zerres, K, Vogt, S, van Riesen, A, Gill, E, Seifert, F, Zwirner, A, Kirschner, J, Goebel, H H, Huebner, C, Stricker, S, Meierhofer, D, Stenzel, W & Schuelke, M 2016, ' Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures ', American journal of human genetics, vol. 98, no. 3, pp. 473-489 . https://doi.org/10.1016/j.ajhg.2016.01.006 American journal of human genetics, 98(3), 473-489. Cell Press The American Journal of Human Genetics |
| ISSN: | 0002-9297 |
| Popis: | Transcriptional signal cointegrators associate with transcription factors or nuclear receptors and coregulate tissue-specific gene transcription. We report on recessive loss-of-function mutations in two genes ( TRIP4 and ASCC1 ) that encode subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex. We used autozygosity mapping and whole-exome sequencing to search for pathogenic mutations in four families. Affected individuals presented with prenatal-onset spinal muscular atrophy (SMA), multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. We identified homozygous and compound-heterozygous nonsense and frameshift TRIP4 and ASCC1 mutations that led to a truncation or the entire absence of the respective proteins and cosegregated with the disease phenotype. Trip4 and Ascc1 have identical expression patterns in 17.5-day-old mouse embryos with high expression levels in the spinal cord, brain, paraspinal ganglia, thyroid, and submandibular glands. Antisense morpholino-mediated knockdown of either trip4 or ascc1 in zebrafish disrupted the highly patterned and coordinated process of α-motoneuron outgrowth and formation of myotomes and neuromuscular junctions and led to a swimming defect in the larvae. Immunoprecipitation of the ASC-1 complex consistently copurified cysteine and glycine rich protein 1 (CSRP1), a transcriptional cofactor, which is known to be involved in spinal cord regeneration upon injury in adult zebrafish. ASCC1 mutant fibroblasts downregulated genes associated with neurogenesis, neuronal migration, and pathfinding ( SERPINF1, DAB1, SEMA3D, SEMA3A ), as well as with bone development ( TNFRSF11B, RASSF2, STC1 ). Our findings indicate that the dysfunction of a transcriptional coactivator complex can result in a clinical syndrome affecting the neuromuscular system. |
| Databáze: | OpenAIRE |
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