IDENTIFICATION OF A HEREDITARY PANCREATITIS MUTATION IN 4 WEST-VIRGINIA FAMILIES

Hereditary pancreatitis (HP) is the second most common cause of chroni c childhood pancreatitis in the United States. Mutations in the cation ic trypsinogen gene on chromosome 7 are known to cause HP. We identifi ed four families in West Virginia with symptoms consistent with HP. To determine whether members of these families had defects in the trypsi nogen gene, we tested for linkage between the HP gene and simple tande m repeat markers on chromosome 7q and screened for a specific mutation in the cationic trypsinogen gene. Two-point linkage analysis indicate d that the disease gene is closely linked to three 7q markers (D7S661, D7S2511, and D7S1805). Restriction fragment length polymorphism analy sis showed that all clinically affected members and nonpenetrant carri ers from the four families carried a G to A mutation in the third exon of the trypsinogen gene. These findings indicate that this mutation i s the cause of HP in the families in our study. The observation that m ost individuals who carry the mutation have symptoms of HP is consiste nt with the high but incomplete penetrance of the trait. The presence of a single mutation and a common linked haplotype indicates that the defective allele arose in an ancestor common to all four families.