trypsinogen and Genetic-Diseases--Inborn

When the chimpanzee genome sequence was released, human deleterious alleles associated with simple mendelian diseases were observed as wild-type alleles in six genes (AIRE, MKKS, MLH1, MYOC, OTC and PRSS1). The absence of recognizable phenotypic effects in chimpanzee, contrary to the clinical effect observed in humans, is attributed to epistatic interactions (compensation) between potentially deleterious and compensatory alleles. In this report we investigate the possible evolutionary histories by which substitution of alternative variants in these six genes either ameliorates or avoids pathological consequences.

Topics: Adaptation, Biological; Adaptor Proteins, Signal Transducing; AIRE Protein; Alleles; Animals; Biological Evolution; Carrier Proteins; Cytoskeletal Proteins; Dosage Compensation, Genetic; Epistasis, Genetic; Eye Proteins; Genetic Diseases, Inborn; Glycoproteins; Group II Chaperonins; Humans; Models, Molecular; Molecular Chaperones; Mutation; MutL Protein Homolog 1; Nuclear Proteins; Pan troglodytes; Recombination, Genetic; Transcription Factors; Trypsin; Trypsinogen

Topics: Acute Disease; Animals; Antigens, Neoplasm; Biomarkers, Tumor; Chronic Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Genetic Diseases, Inborn; Genetic Heterogeneity; Humans; Lectins, C-Type; Mice; Molecular Biology; Mutation; Pancreatitis; Pancreatitis-Associated Proteins; Proteins; Rats; Risk Factors; Trypsinogen

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.

Topics: Amino Acid Sequence; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Diseases, Inborn; Humans; Molecular Sequence Data; Mutation, Missense; Pancreatitis; Sequence Alignment; Trypsinogen

Hereditary pancreatitis is an unusual form of acute and chronic pancreatitis with a familial predisposition. Recently, the gene mutations causing most cases of hereditary pancreatitis have been identified in the cationic trypsinogen gene. The known mutations are trypsinogen R117H and N211. These may predispose to acute pancreatitis by eliminating one of the fail-safe mechanisms used by the pancreas to eliminate prematurely activated trypsin. Accumulation of active trypsin mutants are hypothesized to initiate a digestive enzyme activation cascade in the pancreatic acinar cells leading to autodigestion, an intense inflammatory response, and acute pancreatitis. The observation that these patients also develop typical chronic pancreatitis and may later develop pancreatic cancer provides strong evidence that these conditions are linked. Knowledge of the pathophysiological conditions leading to acute and chronic pancreatitis and the development of a transgenic mouse expressing the mutant human trypsinogen genes will provide directions and tools necessary for the effective treatment or prevention of this human disease.

Topics: Animals; Chronic Disease; Disease Models, Animal; Genetic Diseases, Inborn; Humans; Mice; Pancreatic Neoplasms; Pancreatitis; Prognosis; Sensitivity and Specificity; Trypsinogen

Hereditary pancreatitis, an autosomal dominant disease with approximately 80% penetrance, can be caused by both 'gain-of-function' missense and copy number mutations in the cationic trypsinogen gene (PRSS1). Here we demonstrate a heterozygous hybrid PRSS2 (encoding anionic trypsinogen)/PRSS1 gene in a French white family with hereditary pancreatitis, by means of quantitative fluorescent multiplex PCR and RT-PCR analyses. The hybrid gene, in which exons 1 and 2 are derived from PRSS2 and exons 3-5 from PRSS1, apparently resulted from a non-allelic homologous recombination (NAHR) event between the chromosome 7 homologs or sister chromatids during meiosis. Interestingly, this hybrid gene causes the disease through a combination of its inherent 'double gain-of-function' effect, acting simultaneously as a 'quantitative' copy number mutation and a 'qualitative' missense mutation (i.e. the known disease-causing p.N29I mutation). Our finding reveals a previously unknown mechanism causing human inherited disease, enriches the lexicon of human genetic variation and goes beyond the known interaction between copy number variations (CNVs) and single nucleotide substitutions in health and disease. Our finding should also stimulate more interest in analyzing both types of genetic variation whenever one tries to determine the contribution of a specific locus to a given disease phenotype.

Topics: Amino Acid Sequence; Amino Acid Substitution; Base Sequence; Chronic Disease; Female; Genetic Diseases, Inborn; Humans; Male; Molecular Sequence Data; Mutant Chimeric Proteins; Mutation, Missense; Pancreatitis; Pedigree; Trypsin; Trypsinogen

Hereditary pancreatitis is an autosomal dominant disease that is mostly caused by cationic trypsinogen (PRSS1) gene mutations. The aim was to determine phenotype-genotype correlations of families in Europe.. Analysis of data obtained by the European Registry of Hereditary Pancreatitis and Pancreatic Cancer was undertaken using multilevel proportional hazards modelling.. There were 112 families in 14 countries (418 affected individuals): 58 (52%) families carried the R122H, 24 (21%) the N29I, and 5 (4%) the A16V mutation, 2 had rare mutations, and 21 (19%) had no PRSS1 mutation. The median (95% confidence interval [CI]) time to first symptoms for R122H was 10 (8, 12) years of age, 14 (11, 18) years for N29I, and 14.5 (10, 21) years for mutation negative patients (P = 0.032). The cumulative risk (95% CI) at 50 years of age for exocrine failure was 37.2% (28.5%, 45.8%), 47.6% (37.1%, 58.1%) for endocrine failure, and 17.5% (12.2%, 22.7%) for pancreatic resection for pain. Time to resection was significantly reduced for females (P < 0.001) and those with the N29I mutation (P = 0.014). The cumulative risk (95% CI) of pancreatic cancer was 44.0% (8.0%, 80.0%) at 70 years from symptom onset with a standardized incidence ratio of 67% (50%, 82%).. Symptoms in hereditary pancreatitis start in younger patients and endpoints take longer to be reached compared with other forms of chronic pancreatitis but the cumulative levels of exocrine and endocrine failure are much higher. There is an increasingly high risk of pancreatic cancer after the age of 50 years unrelated to the genotype.

Topics: Adult; Age Distribution; Age of Onset; Confidence Intervals; Europe; Female; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Heterozygote; Humans; Incidence; Male; Middle Aged; Multivariate Analysis; Pancreatitis; Pedigree; Point Mutation; Probability; Prognosis; Registries; Reproducibility of Results; Risk Assessment; Severity of Illness Index; Sex Distribution; Survival Rate; Trypsin; Trypsinogen

Hereditary pancreatitis is an autosomal dominant condition characterized by recurrent episodes of acute pancreatitis, usually starting in childhood. We present a family who was ascertained when an 11-year-old girl presented with an episode of acute pancreatitis. Her father and other family members had also had recurrent bouts of acute pancreatitis. Genetic testing revealed a pathogenic mutation in the cationic trypsinogen gene in the proband, her father and her paternal grandmother. As far as we are aware, this is the first Aboriginal kindred with mutation-proven hereditary pancreatitis. Hereditary pancreatitis is an important differential diagnosis to consider in a patient with recurrent episodes of acute pancreatitis with no obvious precipitating cause. This family is of Aboriginal descent and the implications of the family's background are also discussed when considering the aetiology of the condition. We emphasize the need to ascertain a full family history from patients with a history of repeated episodes of acute pancreatitis and also emphasize the need to avoid ethnic stereotypes when assessing patients.

Topics: Child; Exons; Family; Female; Genetic Diseases, Inborn; Humans; Mutation; Native Hawaiian or Other Pacific Islander; Pancreatitis; Trypsinogen

Hereditary pancreatitis (HP) is a rare inherited disorder, characterised by recurrent episodes of pancreatitis often beginning in early childhood. The mode of inheritance suggests an autosomal dominant trait with incomplete penetrance. The gene, or at least one of the genes, responsible for hereditary pancreatitis has been mapped to the long arm of chromosome 7 and a missense mutation, an arginine to histidine substitution at residue 117 in the trypsinogen cationic gene (try4) has been shown to segregate with the HP phenotype. The aim of this work was to investigate the molecular basis of hereditary pancreatitis. This study was performed on 14 HP families. The five exons of the trypsinogen cationic gene were studied using a specific gene amplification assay combined with denaturing gradient gel electrophoresis (DGGE). The present paper describes three novel mutations, namely K23R and N29I and a deletion -28delTCC in the promoter region. We also found a polymorphism in exon 4, D162D. In eight of these families we found a mutation which segregates with the disease. A segregation analysis using microsatellite markers carried out on the other families suggests genetic heterogeneity in at least one of them. Our findings confirm the implication of the cationic trypsinogen gene in HP and highlight allelic diversity associated with this phenotype. We also show that the pattern of inheritance of HP is probably complex and that other genes may be involved in this genetic disease.

Topics: Cations; Exons; Female; Genetic Diseases, Inborn; Genetic Heterogeneity; Humans; Male; Mutation; Pancreatitis; Pedigree; Trypsinogen