A new polymorphism for the RI22H mutation in hereditary pancreatitis

Area of Science:

• Genetics
• Gastroenterology
• Molecular Biology

Background:

• Hereditary pancreatitis (HP) is a rare genetic disorder.
• Mutations in the cationic trypsinogen (protease serine 1, PRSS1) gene cause HP.
• The R122H mutation is the most common cause of HP.

Purpose of the Study:

• To examine the frequency of a neutral polymorphism that can cause false negatives in R122H mutation detection.
• To evaluate the impact of this polymorphism on PCR/RFLP-based genetic testing for HP.

Main Methods:

• Screening of 51 families with HP for PRSS1 mutations (R122H, N29I, A16V) using standard techniques and direct sequencing.
• Investigating a specific neutral polymorphism affecting the AflIII restriction site in R122H testing.
• Developing a novel mutation-specific PCR assay to overcome detection limitations.

Main Results:

• Standard testing identified 15 families with R122H, N29I, or A16V mutations.
• Direct sequencing revealed an additional family with the R122H mutation.
• A neutral C-->T polymorphism, not present in controls, was found in one family, causing a false negative R122H result by destroying the AflIII site.

Conclusions:

• A neutral polymorphism can lead to false-negative results in standard R122H mutation testing for hereditary pancreatitis.
• Alternative R122H assay methods are crucial for accurate genetic diagnosis in individuals with suspected HP.
• The study developed a novel PCR assay to prevent false negatives.