Combining full-length gene assay and SpliceAI to interpret the splicing impact of all possible SPINK1 coding variants

Human Genomics, Год журнала: 2024, Номер 18(1)

Опубликована: Фев. 27, 2024

Single-nucleotide variants (SNVs) within gene coding sequences can significantly impact pre-mRNA splicing, bearing profound implications for pathogenic mechanisms and precision medicine. In this study, we aim to harness the well-established full-length splicing assay (FLGSA) in conjunction with SpliceAI prospectively interpret effects of all potential SNVs four-exon SPINK1 gene, a associated chronic pancreatitis.

Язык: Английский

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Genetics and clinical implications of SPINK1 in the pancreatitis continuum and pancreatic cancer

Human Genomics, Год журнала: 2025, Номер 19(1)

Опубликована: Март 26, 2025

Serine peptidase inhibitor, Kazal type 1 (SPINK1), a 56-amino-acid protein in its mature form, was among the first pancreatic enzymes to be extensively characterized biochemically and functionally. Synthesized primarily acinar cells traditionally known as secretory trypsin SPINK1 protects pancreas by inhibiting prematurely activated trypsin. Since 2000, interest has resurged following discovery of genetic variants linked chronic pancreatitis (CP). This review provides historical overview SPINK1's discovery, function, gene structure before examining key findings. We highlight three with well-characterized pathogenic mechanisms: c.-4141G > T, causative enhancer variant studied p.Asn34Ser (c.101A G), which disrupts PTF1L-binding site within an evolutionarily conserved HNF1A-PTF1L cis-regulatory module; c.194 + 2T C, canonical 5′ splice GT GC that retains 10% wild-type transcript production; Alu insertion 3′-untranslated region, causes complete loss function forming extended double-stranded RNA structures pre-existing elements deep intronic regions. emphasize integration full-length splicing assay (FLGSA) SpliceAI's predictive capabilities, establishing disease for impact all possible coding prospectively determined. Findings from both mouse models association studies support sentinel acute event (SAPE) model, explains progression CP. Additionally, may contribute increased risk ductal adenocarcinoma (PDAC). Finally, we discuss therapeutic potential SPINK1, particularly through adeno-associated virus 8 (AAV8)-mediated overexpression strategy treating preventing pancreatitis, areas future research.

Язык: Английский

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Emerging roles of ADAM6 and PRSS1 as novel diagnostic/prognostic biomarkers for acute lymphoblastic and myeloid leukemia in adults

BMC Cancer, Год журнала: 2025, Номер 25(1)

Опубликована: Май 17, 2025

Acute leukemia is an aggressive, highly heterogeneous hematological malignancy. A Disintegrin And Metalloproteinase Domain-6 (ADAM6), a member of ADAMs family, has emerged recently as potential novel player in pediatric acute lymphoblastic (ALL), and its function remains largely elusive. Serine Protease-1 (PRSS1) another emerging molecular mediator cancer development. However, role not been adequately studied. Interestingly, ADAM6 PRSS1 were identified among the genes with highest percentage chromosomal changes profiled B-cell precursor ALL patients. Both are mediators extracellular matrix (ECM) remodeling. Thus, this study was designed to investigate roles myeloid (AML) adults. Adult patients de novo (n = 36), AML 40), healthy control subjects 55) enrolled study. Circulating serum levels measured by ELISA technique. Serum significantly higher compared (208.7(178.3-337.3), 186.4(155.3-479.6), 78.6(55.8-101.8) pg/ml, p < 0.0001), respectively. Whereas, found be lower controls (175.1(153.7-232.2), 177.9(145.3-206.4), 247.5(204.3-375.3) ng/ml, exhibited very good diagnostic ROC analyses. varied between CD22+/CD22- CD45+/CD45-, while HLA-DR+/HLA-DR- patients, suggesting their prognostic implications. Also, correlated each other. The results current portray new diagnostic/prognostic biomarkers therapeutic targets adult shed light on interrelated possibly implicated tumor micro-environment

Язык: Английский

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Frequency of de novoPRSS1pathogenic variants in a French cohort of idiopathic pancreatitis

Gut, Год журнала: 2024, Номер unknown, С. gutjnl - 333908

Опубликована: Дек. 31, 2024

Язык: Английский

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Identification of protease-sensitive but not misfolding PNLIP variants in familial and hereditary pancreatitis

Pancreatology, Год журнала: 2023, Номер 23(5), С. 507 - 511

Опубликована: Май 27, 2023

Язык: Английский

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Frameshift coding sequence variants in the LPL gene: identification of two novel events and exploration of the genotype–phenotype relationship for variants reported to date

Lipids in Health and Disease, Год журнала: 2023, Номер 22(1)

Опубликована: Авг. 11, 2023

Lipoprotein lipase (LPL) is the rate-limiting enzyme for triglyceride hydrolysis. Homozygous or compound heterozygous LPL variants cause autosomal recessive familial chylomicronemia syndrome (FCS), whereas simple are associated with hypertriglyceridemia (HTG) and HTG-related disorders. frameshift coding sequence usually complete functional loss of affected allele, thereby allowing exploration impact different levels function in human disease.All exons flanking intronic regions were Sanger sequenced patients acute pancreatitis (HTG-AP) HTG-AP pregnancy. Previously reported collated from Human Gene Mutation Database through PubMed keyword searching. Original reports manually evaluated following information: zygosity status variant, plasma activity variant carrier, disease referred genetic analysis, patient's age at history. SpliceAI was employed to predict potential on splicing.Two novel rare identified, 53 known collated. Of 51 informative zygosity, 30 heterozygotes, 12 homozygotes, 9 heterozygotes. Careful evaluation 55 respect their clinical data generated several interesting findings. First, we conclude that 6-7% residual could significantly delay onset FCS reduce prevalence FCS-associated syndromes. Second, a large majority completely disrupt gene "frameshift" nature, small fraction these may act wholly partly as "in-frame" variants, leading generation protein products some function. Third, identified two candidate retain based genotype-phenotype correlation SpliceAI-predicted data.This study yielded new insights into relationship it pertains variants.

Язык: Английский

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Combining full-length gene assay and SpliceAI to interpret the splicing impact of all possibleSPINK1coding variants

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Ноя. 14, 2023

Abstract Background Single-nucleotide variants (SNVs) within gene coding sequences can significantly impact pre-mRNA splicing, bearing profound implications for pathogenic mechanisms and precision medicine. However, reliable splicing analysis often faces practical limitations, especially when the relevant tissues are challenging to access. While in silico predictions valuable, they alone do not meet clinical classification standards. In this study, we aim harness well-established full-length assay (FLGSA) conjunction with SpliceAI prospectively interpret effects of all potential SNVs four-exon SPINK1 gene, a associated chronic pancreatitis. Results We initiated study retrospective correlation (involving 27 previously FLGSA-analyzed SNVs), progressed prospective (incorporating 35 newly FLGSA-tested followed by data extrapolation, ended further validation. total, analyzed 67 SNVs, representing 9.3% 720 possible affecting 19.2% 240 nucleotides. Among these 12 were found splicing. Through extensive cross-correlation FLGSA-obtained SpliceAI-predicted data, reasonably extrapolated that none unanalyzed 653 likely exert significant effect on Out splice-altering events, nine produced both wild-type aberrant transcripts, while remaining three exclusively generated transcripts. These predominantly concentrated exons 1 2, particularly first and/or last nucleotide each exon. 11 missense variants, constituting 2.17% 506 one was synonymous, accounting 0.61% 164 synonymous variants. Conclusions Integrating FLGSA SpliceAI, conclude less than 2% (1.67%) have discernible influence outcomes. Our findings underscore importance performing broader genomic sequence context highlight inherent uncertainties intermediate scores (i.e., those ranging from 0.20 0.80), general shift “retrospective” “prospective” terms variant classification.

Язык: Английский

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Study on the Complex Electrical Response Characteristics of Loaded Coal and the Control Mechanism of the Main Fracture System Structure

ACS Omega, Год журнала: 2024, Номер 9(8), С. 9686 - 9701

Опубликована: Фев. 15, 2024

The structure of coal seam fractures is the main physical property coalbed methane reservoir evaluation, and complex resistivity method a potential geophysical evaluation for fractures. In this study, cylindrical samples with axial directions perpendicular to bedding, face cleat, butt cleat were prepared. electrical parameters loaded specimens tested test frequencies ranging from 1 Hz 10 kHz. response characteristics are summarized, control mechanism fracture system analyzed. results indicated that (1) as loading pressure increased, resistance R absolute values reactance X(|X|) gradually decreased, especially in frequency band where slowly decreased characteristic X, amplitude was more significant, cutoff X all increased. (2) properties show obvious anisotropic characteristics. Both |X| sequentially according direction cleat; increased sequentially. (3) dispersion phenomenon attributed induced polarization; elevated stress enhances polarization effects molecular-induced moments skeleton, difference due difficulty degree transport charged particles by structural differences system. (4) R3 capacitance Xc selected electrically sensitive orthogonal structures. A logarithmic inversion model reflecting constructed. This provides certain theoretical basis efficient exploration

Язык: Английский

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The link between trypsinogen and chymotrypsinogen in gastrointestinal cancer

Elsevier eBooks, Год журнала: 2024, Номер unknown, С. 423 - 434

Опубликована: Ноя. 1, 2024

Язык: Английский

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