High frequency of cystic fibrosis transmembrane regulator mutation L997F in patients with recurrent idiopathic pancreatitis and in newborns with hypertrypsinemia.

To the Editor: Cystic fibrosis (CF) (MIM 219700) is a genetic disease with multisystem involvement and in which defective chloride transport across membranes causes dehydrated secretion. The protein encoded by the CF gene (CFTR) is a transmembrane conductance regulator. The ability to detect CFTR mutations has led to the recognition of its association with a variety of conditions, including bronchiectasis, sinusitis with polyps, and male infertility (Estivill et al. 1996). A high frequency of mutations in the CFTR has more recently been shown in patients with chronic idiopathic pancreatitis (Sharer et al. 1998) and in newborns with hypertrypsinemia (Castellani et al. 1999). The exocrine pancreas is almost invariably affected in CF, even if not always with clinical manifestations (Lebenthal et al. 1993). In CF and in idiopathic pancreatitis, the earliest pathological finding is probably pancreatic ductular obstruction due to inspissated secretions (Oppenheimer et al. 1975; De Angelis et al. 1992). Hypertrypsinemia is thought to derive from pan-creatic ductular obstruction and leakage of trypsinogen into the bloodstream (Crossley et al. 1979). Therefore, we postulated that there might be particular CFTR gene mutations involved in pancreatic ductular obstruction, as manifested in idiopathic pancreatitis or in neonatal hypertrypsinemia. Since routine CF mutation testing may miss rare gene alterations that can occur in these CF-related pathologies, a complete screening of the CFTR gene was performed in a group of 32 patients with idiopathic pancreatitis (14 of whom carried a CF mutation—the 5T variant—or borderline sweat chloride level, and 18 of whom were without common CF mutations or any other CF characteristic) and in 49 new-borns with hypertrypsinemia and normal sweat chloride (32 of whom had a common CF mutation [some of these reported by Castellani et al. 1999], and 17 of whom did not have a common CF mutation). The 27 exons of the CFTR gene and their intronic flanking regions were analyzed by denaturing gradient-gel elec-trophoresis (DGGE) and by automatic sequencing, as described elsewhere (Bombieri et al. 1998). Aside from some common CFTR mutations, none of which appeared to be more represented than expected, in comparison with the CFTR gene mutation distribution in CF patients in the same population, rare mutations were found in 9 of 32 patients with idiopathic pancreatitis and in 21 of 49 newborns with hypertryp-sinemia. Among these rare mutations, L997F was identified in 4 (12.5%) of 32 patients with idiopathic pan-creatitis (genotypes L997F/DF508, L997F/5T, and twice L997F/no mutation identified, …