A Frameshift RBM10 Variant Associated With TARP Syndrome

Daicheng, Han; Xia, Shiwen; Zhang, Jingxuan; Hu, Junbo; Wang, Bo

doi:10.3389/fgene.2022.922048

Cited by 7 publications

(5 citation statements)

References 16 publications

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“…In recent research from the UK NHS Genomic Medicine Centre, a heterozygous GDF2 variant lead to vascular malformation such as hereditary hemorrhagic telangiectasia (HHT), and it might be one of the genetic mutations for coronary-pulmonary fistula (6). Mutations in the RBM10 gene are a cause of ASD, and might be responsible for PA fistula, according to a molecular study by Han and his colleague (7). To deeply understand this complex case, we analyzed the patient's hemodynamic results, the moderate left-to-right ASD shunt overload, and abraded the tricuspid valve.…”

Section: Discussionmentioning

confidence: 99%

Case report: Conquer a complex variant: Coronary-pulmonary artery fistulas, atrial septal defect and bicuspid pulmonary valve, under beating heart surgery

Zhou

Liu²,

Zhang³

2022

Front. Cardiovasc. Med.

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Coronary artery to pulmonary artery fistula (CPAF) is a congenital or acquired abnormal channel between arteries, with a left-to-right cardiac shunting, which may lead to myocardial ischemia, arrhythmia, thrombotic complications, and heart failure. CPAF is usually detected by coronary angiography but few reports have used beating-heart surgery as a detection method. The patient in this case report is a 39-year-old male diagnosed with atrial septal defect (ASD), bicuspid pulmonary valve, and moderate tricuspid regurgitation (TR). He is asymptomatic. In preoperative evaluation, significant CPAF was suspected using echocardiography. The patient refused coronary angiography due to allergic history. Therefore, the cardiac team designed and performed on-pump beating-heart surgery (OPBHS) to detect and repair these disorders, and suggested OPBHS as a myocardial protection strategy for the patient at low surgical risk. A rare and complex cardiovascular case with CPAFs from two branches of the left anterior descending coronary (LAD) artery to the main pulmonary artery (MPA) with ASD, bicuspid pulmonary valve, and moderate TR has not yet been reported in the literature, and its embryological hypothesis has been further analyzed in this report.

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Section: Discussionmentioning

confidence: 99%

Case report: Conquer a complex variant: Coronary-pulmonary artery fistulas, atrial septal defect and bicuspid pulmonary valve, under beating heart surgery

Zhou

Liu²,

Zhang³

2022

Front. Cardiovasc. Med.

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“…One very attractive and yet unexplored therapeutic target is the RNA-binding protein, RBM10. RBM10 is mapped to the X chromosome 18 , and its mutations cause TARP syndrome, an Xlinked disorder that leads to pre-and postnatal lethality in affected males [19][20][21][22][23][24][25] . RBM10 is a key regulator of alternative splicing that mainly promotes exon skipping of its target genes [26][27][28][29][30][31][32] .…”

Section: Introductionmentioning

confidence: 99%

Harnessing DNA replication stress to target RBM10 deficiency in lung adenocarcinoma

Machour

Abu‐Zhayia

Kamar

et al. 2023

Preprint

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Lung adenocarcinoma (LUAD) is a leading cause of cancer-related deaths worldwide. The splicing factor RBM10 is commonly mutated in various cancer types and is strikingly one of the most mutated genes in LUAD (~9-25%). Most RBM10 cancer mutations are loss-of-function that correlate with increased tumorigenesis and poor survival, and limit the efficacy of targeted therapies in EGFR-mutated lung cancer. Notably, exploiting RBM10 deficiency for targeted cancer therapy has not yet been explored, highlighting the urgency of identifying genetic vulnerabilities to RBM10 loss. Prompted by this, we performed a genome-wide CRISPR-Cas9 synthetic lethal (SL) screen in isogenic LUAD cell line harboring RBM10 cancer mutation and identified 262 high-scoring RBM10 SL genes, including Aurora A and WEE1 kinases. We show that pharmacological inhibition of WEE1 selectively sensitizes RBM10-deficient LUAD cells, including patient-derived cells harboring RBM10 cancer mutations, in vitro and in mouse xenograft model. Moreover, the sensitivity of RBM10-deficient cells to WEE1 inhibition is further exacerbated by combined treatment with Aurora kinase A inhibitor. Mechanistically, we demonstrate that the sensitivity to WEE1 inhibition is irrespective of RBM10 splicing activity, and potentiated by DNA damage accumulation, replication stress, and premature mitotic entry. Interestingly, we also reveal an unexpected role of RBM10 in promoting replication fork progression and stress response, at least in part, through its association with replication fork components. Collectively, our data identify DNA replication stress as an SL pathway with RBM10 loss, and provide a repertoire of targets that can be harnessed therapeutically to eradicate RBM10-deficient tumors.

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“…Two regulators studied both for their biology and the mechanism by which they alter splicing are the proteins RBM5 and RBM10, which are implicated in cancer development, where they alter apoptotic regulation and cell proliferation 8–12 . RBM10 is also seen to be mutated in the multisystem genetic disorder TARP syndrome 13,14 . RBM5 and RBM10 share domain structures 11,15,16 , and both proteins interact with several U2 snRNP-specific or U2-associated proteins 15,17–20 , and were detected in A- and B-complex spliceosomes 21 .…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The apoptotic splicing regulators RBM5 and RBM10 are subunits of the U2 snRNP engaged with intron branch sites on chromatin

Damianov,

Lin,

Huang

et al. 2023

Preprint

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Understanding the mechanisms of pre-mRNA splicing and spliceosome assembly is limited by technical challenges to examining spliceosomes in vivo. Here we report the isolation of RNP complexes derived from precatalytic A or B-like spliceosomes solubilized from the chromatin pellet of lysed nuclei. We found that these complexes contain U2 snRNP proteins and a portion of the U2 snRNA, bound with intronic branch sites prior to the first catalytic step of splicing. Sequencing these pre-mRNA fragments allowed the transcriptome-wide mapping of branch sites with high sensitivity. In addition to known U2 snRNP proteins, these complexes contained the proteins RBM5 and RBM10. RBM5 and RBM10 are alternative splicing regulators that control exons affecting apoptosis and cell proliferation in cancer, but were not previously shown to associate with the U2 snRNP or to play roles in branch site selection. We delineate a common segment of RBM5 and RBM10, separate from their known functional domains, that is required for their interaction with the U2 snRNP. We identify a large set of splicing events regulated by RBM5 and RBM10 and find that they predominantly act as splicing silencers. Disruption of their U2 interaction renders the proteins inactive for repression of many alternative exons. We further find that these proteins assemble on branch sites of nearly all exons across the transcriptome, including those whose splicing is not altered by them. We propose a model where RBM5 and RBM10 act as components of the U2 snRNP complex. From within this complex, they sense structural features of branchpoint recognition to either allow progression to functional spliceosome or rejection of the complex to inhibit splicing.

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A Frameshift RBM10 Variant Associated With TARP Syndrome

Cited by 7 publications

References 16 publications

Case report: Conquer a complex variant: Coronary-pulmonary artery fistulas, atrial septal defect and bicuspid pulmonary valve, under beating heart surgery

Case report: Conquer a complex variant: Coronary-pulmonary artery fistulas, atrial septal defect and bicuspid pulmonary valve, under beating heart surgery

Harnessing DNA replication stress to target RBM10 deficiency in lung adenocarcinoma

The apoptotic splicing regulators RBM5 and RBM10 are subunits of the U2 snRNP engaged with intron branch sites on chromatin

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