Heterogeneity in hereditary pancreatitis

Abstract

Hereditary pancreatitis (HP) is the most common form of chronic relapsing pancreatitis in childhood, and may account for approximately 25% of adult cases with chronic idiopathic pancreatitis. Recently, an arginine-histidine (R117H) mutation within the cationic trypsinogen gene was found in 5/5 families studied with HP. In this study we report on the results of linkage and direct mutational analysis for the common R117H mutation examined in 8 nonrelated families with hereditary pancreatitis. Two-point linkage analysis with the 7q35 marker D7S676, done initially in 4 families, yielded lod scores that were positive in 2, negative in one, and weakly positive in one. Direct mutational analysis of exon 3 of the cationic trypsinogen gene in 6 families showed that all symptomatic individuals tested were heterozygous for the R117H mutation. Also, several asymptomatic but at-risk relatives were found to be heterozygous for this mutation. Affected individuals in the remaining 2 families did not have the mutation. Radiation hybrid mapping using the Genebridge 4 panel assigned the trypsinogen gene to chromosome region 7q35, 2.9 cR distal to ETS WI-9353 and 3.8 cR proximal the dinucleotide repeat marker D7S676. The negative linkage and absence of the trypsinogen mutation in 2/8 families suggest locus heterogeneity in HP. Analysis of the R117H mutation is useful in identifying presymptomatic "at-risk" relatives and in genetic counseling. Also, it can be useful in identifying children and adults with isolated chronic idiopathic pancreatitis.

Hereditary Pancreatitis Caused by a Novel PRSS1 Mutation (Arg-122 → Cys) That Alters Autoactivation and Autodegradation of Cationic Trypsinogen

“…We conclude that our report of a novel, hereditary pancreatitis-associated mutation in the cationic trypsinogen gene confirms the genetic heterogeneity of the disease (26,36) and documents the requirement for a novel diagnostic screening approach, which we propose to be the widely applicable restriction enzyme digest with BstUI that makes the inferior AflIII method redundant. It further implies that the biochemistry of Cys-122 trypsinogen is compatible with the interpretation that either a gain of enzymatic function or a loss of enzymatic function could represent the triggering mechanism for hereditary pancreatitis.…”

Molecular basis of hereditary pancreatitis

“…7,[16][17][18][19][20][21][22][23][24][25][26] Whilst no one doubts its disease-causing role in HP, some 27 do argue that 'self-destruct' mechanism proposed for R122H 7 has not yet been proven. In our opinion, however, this may be due to inadequate evaluation rather than a lack of good supporting data and, accordingly, we wish to highlight several issues.…”

“…Transgenic models are attractive but certainly will be confounded by the existence of multiple functional trypsinogen genes and different protective mechanisms against trypsinogen activation in mice. The R122H mutation, in most cases, 7,[16][17][18][19][20][21][22][23][24][25][26] resulted from a single G > A (CGC > CAC) transition, which most probably occurred as a spontaneous deamination of 5-methylcytosine to give thymine in the CpG dinucleotides on the opposite strand. Interestingly, we identified a GC > AT (CGC > CAT) 2 bp nucleotide substitution, which also resulted in a R122H mutation but clearly arose via a different genetic mechanism -gene conversion.…”

“…Since a single G > A nucleotide change creates a novel Alf III site (A ᭢ CRYGT), the amplification of exon 3 followed by Alf III digestion 7 has been widely adopted to screen for the R122H mutation. [16][17][18][19]21 Obviously, if R122H mutation arose as a result of a gene conversion event, it would not be detected by this simple method.…”

Genetische Risikofaktoren bei Pankreaserkrankungen - Bedeutung für die Praxis

“…). Bei etwa 20-25% der Familien mit autosomal-dominant vererbtem Krankheitsbild sind die zugrunde liegenden Mutationen bisher nicht bekannt [12]. Hier kommt u.a.…”