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  Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures

Knierim, E., Hirata, H., Wolf, N. I., Morales-Gonzalez, S., Schottmann, G., Tanaka, Y., et al. (2016). Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures. The American Journal of Human Genetics, 98, 1-17. doi:10.1016/j.ajhg.2016.01.006.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-CB04-4 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-CB05-2
Genre: Journal Article

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 Creators:
Knierim, Ellen, Author
Hirata, Hiromi , Author
Wolf, Nicole I. , Author
Morales-Gonzalez, Susanne , Author
Schottmann, Gudrun , Author
Tanaka, Yu, Author
Rudnik-Schöneborn, Sabine , Author
Orgeur, Mickael , Author
Zerres, Klaus, Author
Vogt, Stefanie, Author
van Riesen, Anne , Author
Gill, Esther, Author
Seifert, Franziska , Author
Zwirner, Angelika , Author
Kirschner, Janbernd , Author
Goebel, Hans Hilmar , Author
Hübner, Christoph , Author
Stricker, Sigmar1, Author              
Meierhofer, David2, Author              
Stenzel, Werner, Author
Schuelke, Markus, Author more..
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479669              

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Free keywords: TRIP4, ASCC1, spinal muscular atrophy, arthrogryposis multiplex congenita, respiratory distress, bone fractures, neuromuscular unit, exome sequencing, zebrafish model
 Abstract: 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.

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Language(s): eng - English
 Dates: 2016-01-052016-02-252016-03-03
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.ajhg.2016.01.006
 Degree: -

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Title: The American Journal of Human Genetics
  Other : Am. J. Hum. Genet.
Source Genre: Journal
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Publ. Info: American Society of Human Genetics
Pages: - Volume / Issue: 98 Sequence Number: - Start / End Page: 1 - 17 Identifier: ISSN: 0002-9297
CoNE: /journals/resource/954925377893_1