IGHMBP2 is a ribosome-associated helicase inactive in the neuromuscular disorder distal SMA type 1 (DSMA1)

Guenther, Ulf-Peter; Handoko, Lusy; Laggerbauer, Bernhard; Jablonka, Sibylle; Chari, Ashwin; Alzheimer, Mona; Ohmer, Jürgen; Plöttner, Oliver; Gehring, Niels H.; Sickmann, Albert; Au, Katja von; Schuelke, Markus; Fischer, Utz

doi:10.1093/hmg/ddp028

Cited by 91 publications

(117 citation statements)

References 39 publications

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“…127,128 Senataxin is a large protein of 2700 aa that is ubiquitously expressed. 127,128 It contains a C-terminal DNA/RNA helicase module with strong homology to Upf1, a SF1 helicase involved in nonsense-mediated decay, 129 to IGHMBP2 (immunoglobulin Mu binding protein 2), an ATP-dependent DNA/RNA helicase, 130 and to the splicing endonuclease Sen1p, a nuclear helicase involved in tRNA, mRNA and snRNA processing essential for growth. 131 SETX mutations lead to increased sensitivity to hydrogen peroxide, camptothecin and mitomycin C, suggesting a role in DNA repair.…”

Section: Neurological Disordersmentioning

confidence: 99%

RNA helicases in infection and disease

Steimer

Klostermeier

2012

RNA Biology

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Section: Neurological Disordersmentioning

confidence: 99%

RNA helicases in infection and disease

Steimer

Klostermeier

2012

RNA Biology

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“…2,4,5 IGHMBP2 is a ubiquitously expressed helicase that colocalizes with factors controlling RNA splicing in the cytosol and nucleus. 6 A role for IGHMBP2 in translation has been proposed based on colocalization in the cytoplasm with ribosomal proteins and ribosomal RNA (rRNA). 6,7 As in many other disorders with motor neuron involvement, it is unclear why mutations in IGHMBP2 have a disproportionate effect on motor neurons.…”

mentioning

confidence: 99%

Congenital lethal motor neuron disease with a novel defect in ribosome biogenesis

et al. 2014

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Objective: We describe a novel congenital motor neuron disease with early demise due to respiratory insufficiency with clinical overlap with spinal muscular atrophy with respiratory distress (SMARD) type 1 but lacking a mutation in the IGHMBP2 gene.Methods: Exome sequencing was used to identify a de novo mutation in the LAS1L gene in the proband. Pathogenicity of the mutation was validated using a zebrafish model by morpholinomediated knockdown of las1l.Results: We identified a de novo mutation in the X-linked LAS1L gene in the proband (p.S477N).The mutation is in a highly conserved region of the LAS1L gene predicted to be deleterious by bioinformatic analysis. Morpholino-based knockdown of las1l, the orthologous gene in zebrafish, results in early lethality and disruption of muscle and peripheral nerve architecture. Coinjection of wild-type but not mutant human RNA results in partial rescue of the phenotype. Conclusion:We report a patient with a SMARD phenotype due to a mutation in LAS1L, a gene important in coordinating processing of the 45S pre-rRNA and maturation of the large 60S ribosomal subunit. Similarly, the IGHMB2 gene associated with SMARD type 1 has been suggested to have an important role in ribosomal biogenesis from its role in processing the 45S pre-rRNA. We propose that disruption of ribosomal maturation may be a common pathogenic mechanism linking SMARD phenotypes caused by both IGHMBP2 and LAS1L. Spinal muscular atrophy with respiratory distress (SMARD) is a rare autosomal recessive disorder of neonatal weakness and early respiratory failure (Online Mendelian Inheritance in Man [OMIM] #604320). 1 SMARD was first described in 1974 as a variant of WerdnigHoffmann disease (spinal muscular atrophy type I) but is distinguished by the prominence of early respiratory failure and distal muscle weakness or joint contractures.2 Since discovery of the IGHMBP2 gene as a cause for SMARD, 3 appreciation of the clinical and genetic heterogeneity has been increasing.2,4,5 IGHMBP2 is a ubiquitously expressed helicase that colocalizes with factors controlling RNA splicing in the cytosol and nucleus. 6 A role for IGHMBP2 in translation has been proposed based on colocalization in the cytoplasm with ribosomal proteins and ribosomal RNA (rRNA). 6,7 As in many other disorders with motor neuron involvement, it is unclear why mutations in IGHMBP2 have a disproportionate effect on motor neurons. 8Infants presenting with a SMARD phenotype but lacking mutations in IGHMBP2 are common, accounting for up to two-thirds of reported patients. 4,9 We describe an infant who presented with distal weakness and primary respiratory failure associated with diaphragm paralysis but lacking a

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“…encodes a helicase associated with ribosomes and is suggested to have additional roles in DNA damage repair [317,318,419,420]. Such a role would be consistent with the functions of high and moderate penetrance genes previously associated with breast cancer risk, the majority of which are components of the DNA damage repair pathways [2].…”

Section: Final Discussionsupporting

confidence: 61%

The long range regulation of breast cancer associated genes

Betts¹

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PrefacePage iBreast cancer is the most common non-cutaneous cancer of women and a major cause of mortality [1]. Genetic factors are the single biggest risk factor and 75% of the risk derives from common but low penetrance single nucleotide polymorphisms (SNPs) [2]. These are found using genome-wide association studies (GWAS) and the majority localize to non-coding regions of the genome [3] The identification of CCND1 as an interacting partner of PRE1 and PRE2 was done using a candidate gene approach with 3C (chromosome conformation capture) targeted confirmation of interaction. To detect other potential targets of PRE1 and PRE2 at the 11q13 locus using an agnostic approach, the 4Cseq and 5C techniques were used. These revealed a number of local interaction regions covering six gene promoters. A novel strategy using knockdown of enhancer RNA transcribed from PRE1 then identified the IGHMBP2 and CPT1A genes as likely additional targets of PRE1. Genome editing with transcription activator-like effector nucleases (TALENS) was also used, creating isogenic cell lines to clarify the effects of the SNPs in their native genomic context. Further functional work is required, however the range of techniques employed has substantially expanded our understanding of the 11q13 breast cancer risk locus and forms a template for future investigations of GWAS risk loci.To identify noncoding RNAs expressed at the 11q13 locus that may be interacting with PRE1 or PRE2 required the use of RNA Capture-seq. RNA Capture-seq involves a targeted enrichment step that greatly increases the sequencing depth at regions of interest and can reveal lowly expressed transcripts that may have not been found by traditional RNA-seq [7]. This identified one novel long non-coding RNA expressed from the (+) strand that was named CUPID1 and a second arising from the same locus on the (-) strand named CUPID2. They were located in the nucleus, oestrogen induced and both expressed relatively highly in ERα positive breast cancer cell lines but not in ERα The 11q13 locus is amplified in around 20% of breast cancers and is thought to contain a number of driver genes including CCND1 [8]. Given that CUPID1 and CUPID2 are widely over-expressed inERα positive breast cancer cell lines, it was hypothesized that they may also have a role in driving tumour growth. Publically available RNAseq data showed CUPID2 to be highly expressed in breast and renal cancer but not in normal tissue. Stable cell lines over-expressing the lncRNAs were then generated and subsequent oncogenic assays revealed that CUPID2 increased cellular proliferation and the efficiency of colony formation in breast cancer cells. A murine xenograft model confirmed these findings in vivo by demonstrating a marked increase in tumour size for the mice injected with cells over-expressing CUPID2. There is thus evidence that CUPID2 behaves as an oncogene and may be an additional driver of the 11q13 amplicon in ERα positive breast cancer.In summary, CPT1A and IGHMBP2 were identified as potential mediat...

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IGHMBP2 is a ribosome-associated helicase inactive in the neuromuscular disorder distal SMA type 1 (DSMA1)

Cited by 91 publications

References 39 publications

RNA helicases in infection and disease

RNA helicases in infection and disease

Congenital lethal motor neuron disease with a novel defect in ribosome biogenesis

The long range regulation of breast cancer associated genes

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