New variant of CFTR gene in recurrent idiopathic pancreatitis: Potential role of IVS-8 polyt

Abstract

Background: Acute and chronic pancreatitis in childhood cause occasional and significant morbidity, but our understanding of pancreatic inflammation is rudimentary. Recent advances in cell biology, genetics and imaging technology provide hope that improved understanding of pancreatitis will facilitate novel therapeutic strategies. Examples include the identification of genes predisposing patients to pancreatitis. Genetic pancreatitis (GP) is associated with mutations of cystic fibrosis transmembrane conductor regulator gene (CFTR), cationic trypsinogen (PRSS1) gene, and serine protease inhibitor Kazal type 1 (SPINK1). In 1988, two groups reported an association between idiopathic chronic pancreatitis (ICP) and CFTR mutations. Several mild pancreatic sufficient CFTR mutations were found to be associated with ICP. Those with a single mutation are carriers and those who compound heterozygotes with one severe and one mild mutation are at risk of developing pancreatitis. Whereas a diverse range of loss-of-function CFTR variants have been reported to be associated with idiopathic pancreatitis, their functional effects remain to be clarified in most cases. The 5T variant is a stretch of five contiguous thymidines at the 3′ of the intron 8 of CFTR gene that exacerbates skipping of exon 9, resulting in reduced levels of functional CFTR protein. This process seems to be influenced by the number of TG repeats immediately adjacent to 5T. Individuals carrying 5T adjacent to either 12 or 13TG repeats are more likely to exhibit an abnormal phenotype with a risk of ICP. Materials and methods: We have investigated the cases of 4 children (aged 12, 10, 6 and 3 years) affected by ICP. The diagnosis of pancreatitis was made by the presence of typical abdominal pain, serum amylase and/or lipase 3 times greater than the upper limit of normal and characteristic imaging findings detected by US e CT (volume increase of the pancreas, inhomogeneous structure and peripancreatic fluid collection). Sequence analysis of PRSS1, SPINK1 and CFTR genes was performed. Results: Sequence analysis showed the absence of mutations in PRSS1 and SPINK1 genes. CFTR gene sequencing in three boys showed the presence of following IVS-8 polyT polymorphisms: 5T/5T 12TG/12TG; 5T/5T 11TG/12TG; 5T/9T 13TG/11TG. The 3-years old girl with the most severe form of idiopathic pancreatitis showed 5T/7T 13TG/9TG. In this girl the 5T allele, in cis with 13TG, was associated in trans with F508del, a severe CFTR mutation. Conclusions: Our results even in a limited number of cases have shown the high prevalence of 5T carriers that makes the assessment of the TG repeat number of great interest as a reliable predictor of the IPA risk. The knowledge of TG repeat number in individuals with 5T can be of diagnostic value. The TG repeat number proves to be a reliable predictor of penetrance for 5T but further studies are needed to comparing the prevalence of the 5T-poly(TG) in the general population. IPA in children remain enigmatic with more questions, but it's possible that 5T-poly (TG) has both a diagnostic and predictive role.