Concomitant partial exon skipping by a unique missense mutation of RPS6KA3 causes Coffin–Lowry syndrome

Labonne, Jonathan D J; Chung, Min Ji; Jones, Julie R.; Anand, Paras; Wenzel, Wolfgang; Iacoboni, Daniela; Layman, Lawrence C.; Kim, Hyung Goo

doi:10.1016/j.gene.2015.08.032

Cited by 8 publications

(5 citation statements)

References 22 publications

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“…Variants affecting canonical sequences are considered to have a major effect, where the relevant exon is skipped and even skipping of neighboring exons can be observed. In the presence of alternative splice sites in or outside of the exon, partial exon skipping or exon elongation also have been observed (Fadaie et al, 2019 ; Fang et al, 2001 ; Khan et al, 2020 ; Labonne et al, 2016 ; Ramalho et al, 2003 ; Sangermano et al, 2018 ; Symoens et al, 2011 ). Variants in the noncanonical splicing motifs are referred to as noncanonical splice site (NCSS) variants.…”

Section: Introductionmentioning

confidence: 99%

Benchmarking deep learning splice prediction tools using functional splice assays

et al. 2021

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Hereditary disorders are frequently caused by genetic variants that affect pre‐messenger RNA splicing. Though genetic variants in the canonical splice motifs are almost always disrupting splicing, the pathogenicity of variants in the noncanonical splice sites (NCSS) and deep intronic (DI) regions are difficult to predict. Multiple splice prediction tools have been developed for this purpose, with the latest tools employing deep learning algorithms. We benchmarked established and deep learning splice prediction tools on published gold standard sets of 71 NCSS and 81 DI variants in the ABCA4 gene and 61 NCSS variants in the MYBPC3 gene with functional assessment in midigene and minigene splice assays. The selection of splice prediction tools included CADD, DSSP, GeneSplicer, MaxEntScan, MMSplice, NNSPLICE, SPIDEX, SpliceAI, SpliceRover, and SpliceSiteFinder‐like. The best‐performing splice prediction tool for the different variants was SpliceRover for ABCA4 NCSS variants, SpliceAI for ABCA4 DI variants, and the Alamut 3/4 consensus approach (GeneSplicer, MaxEntScacn, NNSPLICE and SpliceSiteFinder‐like) for NCSS variants in MYBPC3 based on the area under the receiver operator curve. Overall, the performance in a real‐time clinical setting is much more modest than reported by the developers of the tools.

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Section: Introductionmentioning

confidence: 99%

Benchmarking deep learning splice prediction tools using functional splice assays

et al. 2021

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“…When CHEK2 mutation occurs, the coding kinase is inactivated and the damaged DNA cannot repair, following which abnormal DNA replicates uncontrollably, leading to the cancer (18,19). As primary forms of mutations in the malignant tumor, missense mutations and truncated mutants lead to a significant decrease or even the complete loss of CHEK2 kinase activity (20,21). For CHEK2, the four gene mutation sites, 1100delc, IVS2G>A, del5395 and 1157T, have been identified (22).…”

Section: Introductionmentioning

confidence: 99%

Associations between mutations of the cell cycle checkpoint kinase 2 gene and gastric carcinogenesis

Hong

Shi

Zhang

et al. 2017

Molecular Medicine Reports

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Gastric cancer is the most common malignant tumor of the digestive system. The etiology of gastric cancer is complex, and susceptibility at the genetic level remains to be fully elucidated in genetic investigations. In the present study, mutations of the cell cycle checkpoint kinase 2 (CHEK2) gene and its association with gastric cancer were examined. Reverse transcription‑quantitative polymerase chain reaction technology was used to detect the expression of CHEK2 and it was found that the expression of CHEK2 was low in gastric cancer. Using sequencing analysis, it was found that the low expression level of CHEK2 was associated with expression of its mutation. The present study also established a CHEK2‑overexpressing mutant and confirmed that CHEK2 promoted gastric cancer cell proliferation. Overexpression of the CHEK2 mutation was confirmed to promote cancer cell migration and invasion. Furthermore, western blot analysis results revealed that overexpression of the CHEK2 mutation downregulated E‑cadherin and upregulated vimentin expression, indicating the mechanism underlying the altered biological behavior. These results suggested that there was a correlation between mutation of the CHEK2 gene and gastric cancer, and provided an experimental basis for antitumor drug investigation and development according to its mutation target.

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“…In this assay, amplification of the AR gene both before and after digestion with the methylation-sensitive HpaII restriction enzyme was used to determine the methylation status of the maternal and paternal X chromosome. XCI degree threshold patterns are classified as random (XCI < 80 %), moderately skewed (80 % ≤ XCI ≤ 90 %), and highly skewed (>90 %) [ 26 ].…”

Section: Methodsmentioning

confidence: 99%

A microdeletion at Xq22.2 implicates a glycine receptor GLRA4 involved in intellectual disability, behavioral problems and craniofacial anomalies

et al. 2016

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BackgroundAmong the 21 annotated genes at Xq22.2, PLP1 is the only known gene involved in Xq22.2 microdeletion and microduplication syndromes with intellectual disability. Using an atypical microdeletion, which does not encompass PLP1, we implicate a novel gene GLRA4 involved in intellectual disability, behavioral problems and craniofacial anomalies.Case presentationWe report a female patient (DGDP084) with a de novo Xq22.2 microdeletion of at least 110 kb presenting with intellectual disability, motor delay, behavioral problems and craniofacial anomalies. While her phenotypic features such as cognitive impairment and motor delay show overlap with Pelizaeus-Merzbacher disease (PMD) caused by PLP1 mutations at Xq22.2, this gene is not included in our patient’s microdeletion and is not dysregulated by a position effect. Because the microdeletion encompasses only three genes, GLRA4, MORF4L2 and TCEAL1, we investigated their expression levels in various tissues by RT-qPCR and found that all three genes were highly expressed in whole human brain, fetal brain, cerebellum and hippocampus. When we examined the transcript levels of GLRA4, MORF4L2 as well as TCEAL1 in DGDP084′s family, however, only GLRA4 transcripts were reduced in the female patient compared to her healthy mother. This suggests that GLRA4 is the plausible candidate gene for cognitive impairment, behavioral problems and craniofacial anomalies observed in DGDP084. Importantly, glycine receptors mediate inhibitory synaptic transmission in the brain stem as well as the spinal cord, and are known to be involved in syndromic intellectual disability.ConclusionWe hypothesize that GLRA4 is involved in intellectual disability, behavioral problems and craniofacial anomalies as the second gene identified for X-linked syndromic intellectual disability at Xq22.2. Additional point mutations or intragenic deletions of GLRA4 as well as functional studies are needed to further validate our hypothesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0642-z) contains supplementary material, which is available to authorized users.

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Concomitant partial exon skipping by a unique missense mutation of RPS6KA3 causes Coffin–Lowry syndrome

Cited by 8 publications

References 22 publications

Benchmarking deep learning splice prediction tools using functional splice assays

Benchmarking deep learning splice prediction tools using functional splice assays

Associations between mutations of the cell cycle checkpoint kinase 2 gene and gastric carcinogenesis

A microdeletion at Xq22.2 implicates a glycine receptor GLRA4 involved in intellectual disability, behavioral problems and craniofacial anomalies

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