Chen J M, Ferec C
Centre de Biogénétique, University Hospital, EFS-Bretagne, Brest, France.
Eur J Hum Genet. 2000 Jul;8(7):473-9. doi: 10.1038/sj.ejhg.5200492.
Hereditary pancreatitis (HP) is an autosomal dominant disease. Two heterozygous missense mutations, R122H (R117H) and N29I (N21I), in the cationic trypsinogen gene have been clearly associated with HP. The 'self-destruct' model proposed for the R122H mutation is discussed in connection with the existing theory of pancreatitis, and the basic biochemistry and physiology of trypsinogen, with particular reference to R122 as the primary autolysis site of the cationic trypsinogen. Two different genetic mechanisms are identified which cause the R122H mutation, and gene conversion is the likely cause of the N29I mutation. A unifying model, which highlights an indirect impairment on the R122 autolysis site is hypothesised for the N29I mutation. Possible predisposition to pancreatitis by additional DNA variants in the gene, such as the A16V signal peptide cleavage site mutation and the K23R activation peptide cleavage site mutation is suspected, but not proven. Evidence of genetic heterogeneity of HP is reviewed and cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations detected in HP families are re-evaluated. Finally, large scale association studies are expected to clarify the additional variants' role in pancreatitis and to identify new HP genes.
遗传性胰腺炎（HP）是一种常染色体显性疾病。阳离子胰蛋白酶原基因中的两个杂合错义突变，即R122H（R117H）和N29I（N21I），已被明确与HP相关。结合现有的胰腺炎理论以及胰蛋白酶原的基础生物化学和生理学，特别是将R122作为阳离子胰蛋白酶原的主要自溶位点，讨论了针对R122H突变提出的“自我破坏”模型。确定了导致R122H突变的两种不同遗传机制，基因转换可能是N29I突变的原因。针对N29I突变提出了一个统一模型，该模型强调对R122自溶位点的间接损害。怀疑基因中的其他DNA变异，如A16V信号肽切割位点突变和K23R激活肽切割位点突变，可能会导致胰腺炎易感性，但尚未得到证实。回顾了HP遗传异质性的证据，并重新评估了在HP家族中检测到的囊性纤维化跨膜传导调节因子（CFTR）基因突变。最后，大规模关联研究有望阐明其他变异在胰腺炎中的作用，并鉴定出新的HP基因。
