rs1554089895

This study reports two novel SPINK1 signal peptide variants (c.41T>G/p.L14R and c.36G>C/p.L12F) associated with pancreatitis. The p.L14R variant was found in two European families with autosomal dominant hereditary pancreatitis with high penetrance, while p.L12F was identified as a common variant (11% allele frequency) in African populations with no pathogenic effect. Functional analysis demonstrated that p.L14R and the previously reported p.L14P variant abolish SPINK1 secretion through intracellular degradation, representing the first clear experimental evidence that severe loss-of-function SPINK1 alterations directly cause hereditary pancreatitis.

This case-control study identified two novel severe mutations in the SPINK1 gene (encoding pancreatic secretory trypsin inhibitor) associated with familial and hereditary pancreatitis: a microdeletion c.27delC found in two unrelated families with variable penetrance (75% in family 1, low penetrance in family 2) and a splicing mutation c.87+1G>A (also written as IVS2+1G>A) found in one family. The c.27delC mutation causes a frameshift producing a nonfunctional protein (p.S10fsX5), while c.87+1G>A disrupts the consensus splice donor site.