Common calcium-sensing receptor (CASR) gene variants do not modify risk for chronic pancreatitis in a Hungarian cohort

Takáts, A.; Berke, Gergő; Szentesi, Andrea; Farkas, Gyula; Izbéki, Ferenc; Erőss, Bálint; Czakó, László; Vincze, Áron; Hegyi, Péter; Sahin–Tóth, Miklós; Hegyi, E

doi:10.1016/j.pan.2021.08.012

Cited by 7 publications

(3 citation statements)

References 34 publications

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“…This variant is found to be common in different populations ( Table 2 ), and increased Ca 2+ levels in cells in response to lower concentrations of extracellular calcium in comparison with wild type CASR ( Vezzoli et al, 2007 ). However, both loss and gain-of-function mutations of the CASR gene have been associated with pancreatitis ( Hasan et al, 2018 ), and recent studies even suggest that variants do not modify the risk for chronic pancreatitis ( Takats et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

A novel frameshift mutation in TRPV6 is associated with hereditary pancreatitis

Shah

Prasad²,

Banerjee³

et al. 2023

Front. Genet.

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Introduction: Hereditary pancreatitis (HP) is a rare debilitating disease with incompletely understood etio-pathophysiology. The reduced penetrance of genes such as PRSS1 associated with hereditary pancreatitis indicates a role for novel inherited factors.Methods: We performed whole-exome sequencing of three affected members of an Indian family (Father, Son, and Daughter) with chronic pancreatitis and compared variants with those seen in the unaffected mother.Results: We identified a novel frameshift mutation in exon 11 of TRPV6 (c.1474_1475delGT; p.V492Tfs*136), a calcium channel, in the patients. Functional characterization of this mutant TRPV6 following heterologous expression revealed that it was defective in calcium uptake. Induction of pancreatitis in mice induced Trpv6 expression, indicating that higher expression levels of the mutant protein and consequent dysregulation of calcium levels in patients with chronic pancreatitis could aggravate the disease.Discussion: We report a novel frameshift mutation in TRPV6 in an Indian family with HP that renders the mutant protein inactive. Our results emphasize the need to expand the list of genes used currently for evaluating patients with hereditary pancreatitis.

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Section: Resultsmentioning

confidence: 99%

A novel frameshift mutation in TRPV6 is associated with hereditary pancreatitis

Shah

Prasad²,

Banerjee³

et al. 2023

Front. Genet.

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“…Similar to CFTR mutations, the exact contribution of CaSR variants to pancreatitis risk remains controversial, although it has been demonstrated that these variants may impair calcium sensing and promote higher ductal Ca 2+ levels [ 22 ]. Recent studies in the literature reported that common CaSR variants do not alter the risk of CP and should not be considered as responsible for genetic risk in subjects suffering from pancreatitis [ 23 , 24 ]. Instead, our patient shows p.Phe790Ser, a de novo CaSR variant, classified as probably pathogenic, and its interaction with the other two described variants, p.Leu997Phe ( CFTR ) and p.Ile73Phe ( SPINK1 ), is strongly suggestive of the pancreatic phenotype.…”

Section: Discussionmentioning

confidence: 99%

A De Novo CaSR Missense Variant in Combination with Two Inherited Missense Variants in CFTR and SPINK1 Detected in a Patient with Chronic Pancreatitis

Bontempo,

Surace,

Menale

et al. 2024

Biomedicines

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Chronic pancreatitis is often secondary to alcohol abuse, but pancreatitis with no other aetiology is frequently associated with variants in genes encoding proteins related to zymogen granule activation. Our goal was to identify genomic variants in a patient by analyzing an extended panel of genes associated with the intra-pancreatic activation of the trypsin pathway. A 23-year-old woman was addressed at our institution because of chronic pancreatitis of unknown aetiology presenting recurrent episodes since she was the age of four. Next Generation Sequencing was performed to analyze a panel of nine genes associated with pancreatitis (CaSR, CFTR, CPA1, CTRC, CTSB, KRT8, PRSS1, PRSS2, and SPINK1). Three missense variants were found: p.Leu997Phe, maternally inherited, in the CFTR gene; p.Ile73Phe, paternally inherited, in the SPINK1 gene; and p.Phe790Ser, a de novo variant, in the CaSR gene. They were classified, respectively as probably benign, a Variant of Uncertain Significance, and the last one, which has never been described in the literature, as likely being pathogenic following American College of Medical Genetics and Genomics standard guidelines. Extensive intra-pancreatic activation of trypsin pathway gene sequencing detected rare variants that were not found with other gene screening and showed that variants in different genes may interact in contributing to the onset of the pancreatitis phenotype.

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“…In a more recently published French study, rare CASR variants were overrepresented in idiopathic CP and a significant association between CASR alterations and CP was identified for the A986S variant, but only in homozygous carriers [85]. Controversially, the most recent study investigating the role of different CASR variants in a Hungarian cohort of 337 patients with alcoholic and non-alcoholic CP did not identify any association between CASR variants and CP risk modification [86]. Taken together, there is no clear evidence to consider CASR variants as risk genes for the development of pancreatitis so far.…”

Section: Calcium-sensing Receptor (Casr)mentioning

confidence: 98%

Genetic Testing in Acute and Chronic Pancreatitis

Piseddu

Vielhauer

Mayerle

2022

Curr Treat Options Gastro

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Purpose of review Premature intracellular activation of pancreatic zymogens leads to the initiation of pancreatitis, which in up to 25% leads to chronic tissue destruction, exocrine and endocrine organ failure, and a moderate increased risk of pancreatic cancer development. Whereas in many cases, the trigger of organ damage is identified, diagnostic workup in a significant number of patients does not reveal the underlying etiology of pancreatic inflammation. In these cases, alterations in different pancreatic susceptibility genes have been described to be directly or indirectly involved in disease development. In this review, we want to give an update on the most important pancreatitis risk genes and their impact on clinical diagnostics and risk stratification as well as possible treatment options. Recent findings Genetic testing is not routinely implemented in the diagnostic workup of acute or chronic pancreatitis, as most genetic variations are not considered causative for pancreatitis development but confer increased susceptibility and genetic testing rarely changes disease management. However, in patients with recurrent pancreatitis episodes of unknown etiology after intensive diagnostic work-up, in patients with a family history of pancreatitis, relatives of patients with hereditary pancreatitis, and patients with disease onset at young age, genetic testing and counseling is recommended. Besides well-established susceptibility genes such as PRSS1, SPINK1, CPA1, and CFTR, additional genes such as TRPV6 and rare genetic alterations in established risk genes have been recently identified which significantly contribute to the risk of pancreatitis, involving different molecular mechanisms. Summary When genetic testing is considered, we propose screening at least for PRSS1, SPINK1, CPA1, and CFTR gene variants. The emergence of next-generation sequencing methods could also render larger gene panels possible and clinically meaningful to detect rare variants with high-risk phenotypes. Here we summarize, evaluate, and convey in the form of practical recommendations the current level of knowledge with respect to definition, etiology, and genetic diagnostics of all forms of inherited pancreatitis.

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Common calcium-sensing receptor (CASR) gene variants do not modify risk for chronic pancreatitis in a Hungarian cohort

Cited by 7 publications

References 34 publications

A novel frameshift mutation in TRPV6 is associated with hereditary pancreatitis

A novel frameshift mutation in TRPV6 is associated with hereditary pancreatitis

A De Novo CaSR Missense Variant in Combination with Two Inherited Missense Variants in CFTR and SPINK1 Detected in a Patient with Chronic Pancreatitis

Genetic Testing in Acute and Chronic Pancreatitis

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