Cryptic splicing: common pathological mechanisms involved in male infertility and neuronal diseases

Aldalaqan, Saad; Dalgliesh, Caroline; Luzzi, Sara; Siachisumo, Chileleko; Reynard, Louise N.; Ehrmann, Ingrid; Elliott, David

doi:10.1080/15384101.2021.2015672

Cited by 12 publications

(16 citation statements)

References 66 publications

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“…We identified a deleterious duplication in the RBMXL2 candidate gene, which created a premature stop codon. RBMXL2 belongs to a family of hnRNPs that bind to nuclear RNAs during transcription and regulates their splicing patterns (Ehrmann et al, 2019; Aldalaqan et al, 2021). It was previously shown that in the mouse, knock‐out of the testis‐specific gene coding for Rbmxl2 causes germ cell apoptosis during the meiotic diplotene stage and thus abrogates sperm production (Ehrmann et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

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Cryptic splice site poisoning and meiotic arrest caused by a homozygous frameshift mutation in RBMXL2 : A case report

et al. 2022

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Gene expression in meiotic cells in the testis is characterized by intense transcriptional activity and alternative splicing. These processes are mainly controlled by RNA‐binding proteins expressed strongly in germ cells. Functional impairments in any of these proteins' functions can lead to defects in meiosis and thus severe male infertility. Here, we have identified a homozygous frameshift mutation (NM_014469.4:c.301dup; p.Ser101LysfsTer29) in the RNA‐binding motif protein, X‐linked like 2 (RBMXL2) gene in a man with an azoospermia due to meiotic arrest. As RBMXL2 is known to be crucial for safeguarding the meiotic transcriptome in mice testes, we hypothesized that this variant leads to cryptic splice site poisoning. To determine the variant's impact on spermatogenesis, we confirmed the absence of RBMXL2 protein in the patient's testis tissue and then evidenced abnormal expression of several spermatogenesis proteins (e.g. meiosis‐specific with coiled‐coil domain) known to be altered in rbmxl2 knock‐out mice with meiotic arrest. Our results indicate that RBMXL2's function in spermatogenesis is conserved in mammals. We hypothesize that deleterious variant in the RBMXL2 gene can result in male infertility and complete meiotic arrest, due to the disruption of gene expression by cryptic splice site poisoning.

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Section: Discussionmentioning

confidence: 99%

“…In the mouse, Rbmxl2 is required to suppress cryptic splice sites – especially during meiotic events. Many studies have shown that spliceosome defects and cryptic splicing can lead to NOA and thus male infertility (Wu et al, 2016) (Aldalaqan et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Cryptic splice site poisoning and meiotic arrest caused by a homozygous frameshift mutation in RBMXL2 : A case report

et al. 2022

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“…This especially affects a subcategory of exon skipping, in which ssASOs are employed to correct so-called cryptic splicing. Cryptic splicing is a naturally occurring process by which the splicing apparatus uses splice sites (cryptic splice sites) outside of the canonical splice sites, creating transcripts that can incorporate parts of introns (then called cryptic exons) or removing parts of canonical exons [74,96,97]. Certain pathogenic variants can strengthen or create new cryptic splice sites, resulting in increased usage of these sites for the generation of mRNA transcripts.…”

Section: Exon Skippingmentioning

confidence: 99%

Treatability of the KMT2-Associated Neurodevelopmental Disorders Using Antisense Oligonucleotide-Based Treatments

Zardetto,

van Roon-Mom,

Aartsma-Rus

et al. 2024

Human Mutation

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Neurodevelopmental disorders (NDDs) of genetic origin are a group of early-onset neurological diseases with highly heterogeneous etiology and a symptomatic spectrum that includes intellectual disability, autism spectrum disorder, and learning and language disorders. One group of rare NDDs is associated with dysregulation of the KMT2 protein family. Members of this family share a common methyl transferase function and are involved in the etiology of rare haploinsufficiency disorders. For each of the KMT2 genes, at least one distinct disorder has been reported, yet clinical manifestations often overlap for multiple of these individually very rare disorders. Clinical care is currently focused on the management of symptoms with no targeted treatments available, illustrating a high unmet medical need and the urgency of developing disease-modifying therapeutic strategies. Antisense oligonucleotides (ASOs) are one option to treat some of these rare genetic disorders. ASOs are RNA-based treatments that can be employed to modulate gene expression through various mechanisms. In this work, we discuss the phenotypic features across the KMT2-associated NDDs and which ASO approaches are most suited for the treatment of each associated disorder. We hereby address variant-specific strategies as well as options applicable to larger groups of patients.

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“…Canonical mRNAs are generated using canonical splice sites whereas variant transcripts are frequently produced using cryptic splice sites located within exonic and intronic sequences (Aldalaqan et al, 2022;Baralle and Baralle, 2005;Keegan et al, 2021;Lee and Rio, 2015).…”

Section: Introductionmentioning

confidence: 99%

Activation of Cryptic Donor Splice Sites within the UDP-Glucuronosyltransferase (UGT)1A First-Exon Region Generates Variant Transcripts That Encode UGT1A Proteins with Truncated Aglycone-Binding Domains

Hu,

Marri,

Hulin

et al. 2024

Drug Metab Dispos

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The human UDP-glucuronosyltransferases (UGTs) have crucial roles in metabolizing and clearing numerous small lipophilic compounds. The UGT1A locus generates nine UGT1A mRNAs, 65 spliced transcripts and 34 circular RNAs. In this study, our analysis of published UGT-CaptureSeq datasets identified novel splice junctions that predict 24 variant UGT1A transcripts derived from ligation of exon 2 to unique sequences within the UGT1A first-exon region using cryptic donor splice sites. Of these variants, seven (1A1_n1, 1A3_n3, 1A4_n4, 1A5_n1, 1A8_n2, 1A9_n2v, 1A10_n7) are predicted to encode UGT1A proteins with truncated aglycone-binding domains. We assessed their expression profiles and deregulation in cancer using four RNA-seq datasets of paired normal and cancerous drug-metabolizing tissues from large patient cohorts. Variants were generally co-expressed with their canonical counterparts with a higher relative abundance in tumor than in normal tissues. Variants showed tissuespecific expression with high interindividual variability but overall low abundance. However, 1A8_n2 showed high abundance in normal and cancerous colorectal tissues with levels that approached or surpassed canonical 1A8 mRNA levels in many samples. We cloned 1A8_n2 and showed expression of the predicted protein (1A8_i3) in HEK293T cells. Glucuronidation assays with 4-MU showed that 1A8_i3 had no activity and was unable to inhibit the activity of 1A8_i1 protein. In summary, the activation of cryptic donor splice sites within the UGT1A first-exon region expands the UGT1A transcriptome and proteome. The 1A8_n2 cryptic donor splice site is highly active in colorectal tissues, representing an important cis-regulatory element that negatively regulates the function of the UGT1A8 gene through pre-mRNA splicing.

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Cryptic splicing: common pathological mechanisms involved in male infertility and neuronal diseases

Cited by 12 publications

References 66 publications

Cryptic splice site poisoning and meiotic arrest caused by a homozygous frameshift mutation in RBMXL2 : A case report

Cryptic splice site poisoning and meiotic arrest caused by a homozygous frameshift mutation in RBMXL2 : A case report

Treatability of the KMT2-Associated Neurodevelopmental Disorders Using Antisense Oligonucleotide-Based Treatments

Activation of Cryptic Donor Splice Sites within the UDP-Glucuronosyltransferase (UGT)1A First-Exon Region Generates Variant Transcripts That Encode UGT1A Proteins with Truncated Aglycone-Binding Domains

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