Evidence that hereditary pancreatitis is genetically heterogeneous disorder

Hereditary pancreatitis (HP) is an autosomal dominant disorder characterize d by recurrent acute attacks of severe abdominal pain with an onset in earl y childhood. Many HP patients progress to complicated chronic pancreatitis and/or pancreatic cancer. Initially, a single mutation R117H in the cationi c trypsinogen gene was detected in all affected members of five unrelated H P families. Further studies identified a second mutation (N21L) in two HP f amilies without the R117H mutation. Before the association between cationic trypsinogen and HP was found, we detected a cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation (L327R) in all affected individu als of a family with HP. We therefore performed a mutational analysis for R 117H and N21L in cationic trypsinogen in this and three additional unrelate d families with HP. The R117H mutation was detected in all 9 affected membe rs of three HP families and in 3 asymptomatic but at-risk relatives. Howeve r, neither the R117H nor the N21L mutation in the cationic trypsinogen were found in the HP family with the L327R alteration in CFTR. The L327R allele segregates with the disease within this HP family and was not detected on 360 unrelated Caucasian non-CF chromosomes. Although close to 800 different mutations have been detected in the CF gene of cystic fibrosis patients, L 327R is a new alteration, not yet reported in connection with CF. The resul ts of this study indicate that the CFTR gene may play a role in the etiolog y of minority of cases with HP and suggest that hereditary pancreatitis is genetically heterogeneous disease.