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

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.

A new case of SMABF2 diagnosed in stillbirth expands the prenatal presentation and mutational spectrum of ASCC1

“…Microarray analysis (180 K; Agilent Technologies, Walldbronn, Germany) was performed on DNA extracted from umbilical cord, according to the manufacturer's protocol (v7.3; Agilent Technologies; Waldbronn, Germany), and microarray data were analyzed by CytoGenomics software (v3.0.6.6; Agilent, ADM‐2 algoritm, release hg19). This analysis identified a microdeletion of about 64 Kb (chr10:73873192_73936691) within the 10q22.1 chromosome band, only encompassing exons 7–10 of the ASCC1 gene (MIM: 614215; NM_001198799.2), or exons 6‐9a based on exon count proposed by Knierim et al (). Starting from now the latter nomenclature will be used in the current manuscript.…”

“…(c) Sequencing performed by TruSightOne panel (Illumina, Inc.) displaying the nucleotide variant [NM_001198799.2 c.1027C>T; (p.Arg343 *)] within ASCC1 apparently in homozygous state (green). (d) ASCC1 exon structure of the isoform NM_001198799.2 with the location of the present (red) and the previously described nucleotide variants (black) (1) and ASCC1 exon nomenclature proposed by Knierim et al, , based on the genomic sequence ENSG00000138303 (2); below (3): the scheme of the expected consequences of the microdeletion on ASCC1, whose domains were predicted according to the most abundant transcript ENST00000317168 (Knierim et al, ) ( https://www.ebi.ac.uk/interpro/ IPR009210; Accessed data 07/10/2019). In gray color the alternatively spliced exons of the main isoforms [Color figure can be viewed at wileyonlinelibrary.com]…”

Genetics of neuromuscular fetal akinesia in the genomics era

“…One TRIP4 patient showed apoptotic alpha-motoneurons, while sural nerve biopsy of two ASCC1 patients showed unmyelinated axon loss. All patients died of respiratory distress before the age of 2 23. In 2017, a second ASCC1 case was described, supporting this as a human disease gene 25…”

“…The tetrameric ASC-1 transcriptional cointegrator complex comprised four subunits: subunit 1 ( ASCC1 ; MIM 614215), subunit 2 ( ASCC2 ; MIM 614216), subunit 3 ( ASCC3 ; MIM 614217) and thyroid hormone receptor interactor 4 ( TRIP4 ; MIM 604501) 23. This complex may act in neuromuscular unit development via myogenic differentiation and growth regulation 23 24.…”

Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy

“…Together, these disorders are exceptionally rare, with autosomal recessive or X-linked recessive ( UBA1 ) inheritance and descriptions confined to case reports [34–39]. …”