Cystic Fibrosis Mutations in Heterozygous Newborns with Hypertrypsinemia and Low Sweat Chloride

Abstract

Cancer results from the expansion of cell clones that progressively lose control of proliferation, differentiation, and death, owing to accumulation of mutational events in genes that control the cell cycle and apoptosis. Nuclear protein p53 is thought to play a major role in malignancy, since it induces genes that determine apoptosis and cell-cycle arrest, interacts with proteins employed in DNA repair, and binds to DNA strand breaks. As expected, somatic mutations in p53 are found in a variety of human cancers. Mutations are predominantly inactivating, thus eliminating the "guardian of the genome" from the proliferating cells. Germ-line mutations

Neonatal Screening for Cystic Fibrosis: Long-Term Clinical Balance

“…This strategy resulted in high sensitivity and specificity, with a positive predictive value of 1/3. Unfortunately, a high rate of CF carrier detection was observed (1/12, much higher than the 1/32 expected for the tested mutations), with complex genetic counseling implications [10].…”

High Frequency of Cystic Fibrosis Transmembrane Regulator Mutation L997F in Patients with Recurrent Idiopathic Pancreatitis and in Newborns with Hypertrypsinemia

“…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).…”

“…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 newborns 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 electrophoresis (DGGE) and by automatic sequencing, as described elsewhere (Bombieri et al 1998).…”

Cationic trypsinogen and pancreatic secretory trypsin inhibitor gene mutations in neonatal hypertrypsinaemia

“…The implication of CFTR gene mutations in the development of transient hypertrypsinaemia was already described. 13,14 This study detected the presence of polymorphisms in the PRSS1 and in the PSTI genes in hypertrypsinaemic neonates. These polymorphisms do not seem to have a functional significance in gene expression or disease modification and have been previously reported not to be related to hereditary pancreatitis or sporadic chronic pancreatitis.…”

“…13 A panel of 15 common mutations, covering 85% of the CF alleles in our area, and denaturing gradient gel electrophoresis (DGGE) of all 27 exons and intron flanking regions of the CFTR gene had been previously performed as described for 18 of them, 14 33 out of 50 neonates had one CFTR mutation from the panel, and 15 of them also had other CFTR gene mutations; 17/50 had no mutation from the panel, and seven of them had other CF mutations, as shown in Table 1. 13,14 PRSS1 gene mutations R122H and A16V were analysed by enzymatic restriction with the appropriate endonuclease as described. 4,6 PRSS1 gene exons 1 -4 were analysed by DGGE as described, 7 and exon 5 was analysed by direct DNA sequencing with Big Dye terminator kit (Perkin Elmer).…”