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

Am J Hum Genet. 2016 Mar 3;98(3):473-489. doi: 10.1016/j.ajhg.2016.01.006.

Ellen Knierim ¹, Hiromi Hirata ², Nicole I Wolf ³, Susanne Morales-Gonzalez ¹, Gudrun Schottmann ¹, Yu Tanaka ⁴, Sabine Rudnik-Schöneborn ⁵, Mickael Orgeur ⁶, Klaus Zerres ⁷, Stefanie Vogt ⁸, Anne van Riesen ⁹, Esther Gill ¹, Franziska Seifert ¹, Angelika Zwirner ¹, Janbernd Kirschner ¹⁰, Hans Hilmar Goebel ¹¹, Christoph Hübner ⁹, Sigmar Stricker ⁶, David Meierhofer ¹², Werner Stenzel ¹¹, Markus Schuelke ¹³

Affiliations

1 Department of Neuropediatrics, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany; NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
2 Department of Chemistry and Biological Science, College of Science and Engineering, Aoyama Gakuin University, Sagamihara 252-5258, Japan; Center for Frontier Research, National Institute of Genetics, Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Mishima 411-8540, Japan. Electronic address: hihirata@chem.aoyama.ac.jp.
3 Department of Child Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
4 Department of Chemistry and Biological Science, College of Science and Engineering, Aoyama Gakuin University, Sagamihara 252-5258, Japan.
5 Institute of Human Genetics and University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany; Division of Human Genetics, Medical University Innsbruck, 6020 Innsbruck, Austria.
6 Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; Free University Berlin, Institute for Chemistry and Biochemistry, 14195 Berlin, Germany.
7 Institute of Human Genetics and University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.
8 Medizinisches Versorgungszentrum Dr. Eberhard & Partner, 44137 Dortmund, Germany.
9 Department of Neuropediatrics, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
10 Department of Neuropediatrics and Muscle Disorders, University Medical Center Freiburg, 79106 Freiburg, Germany.
11 Department of Neuropathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
12 Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
13 Department of Neuropediatrics, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany; NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany. Electronic address: markus.schuelke@charite.de.

PMID: 26924529 DOI: 10.1016/j.ajhg.2016.01.006

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.

Keywords

ASCC1; TRIP4; arthrogryposis multiplex congenita; bone fractures; exome sequencing; neuromuscular unit; respiratory distress; spinal muscular atrophy; zebrafish model.

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