The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families.
OBJECTIVE
To characterise the phenotypes associated with the p.A16V mutation of PRSS1.


METHODS
Clinical and epidemiological data were collected for any family in which a p.A16V mutation was identified, either referred directly to the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer or via a collaborator. DNA samples were tested for mutations in PRSS1, SPINK1, CFTR and CTRC.


METHODS
Participants were recruited on the basis of either family history of pancreatitis (acute or chronic) or the results of genetic testing. Families were categorised as having hereditary pancreatitis (HP), idiopathic disease or pancreatitis in a single generation. HP was defined as >or=2 cases in >or=2 generations. Main outcome measures Onset of painful episodes of pancreatitis, death from pancreatic cancer, diagnosis of diabetes mellitus and exocrine pancreatic failure.


RESULTS
Ten families with p.A16V mutations were identified (22 affected individuals): six HP families, three with idiopathic disease and one with only a single generation affected. The median age of onset, ignoring non-penetrants, was 10 years (95% CI 5 to 25). There were eight confirmed cases of exocrine failure, four of whom also had diabetes mellitus. There were three pancreatic cancer cases. Two of these were confirmed as p.A16V carriers, only one of whom was affected by pancreatitis. Those with p.A16V pancreatitis were compared to affected individuals with p.R122H, p.N29I and no PRSS1 mutation. No significant differences were proven using logrank or Mann-Whitney U tests.


CONCLUSIONS
Penetrance of p.A16V is highly variable and family dependent, suggesting it contributes to multigenic inheritance of a predisposition to pancreatitis.
Grocock
Christopher J
CJ
School of Cancer Studies, University of Liverpool, UCD Building, Daulby Street, Liverpool, UK.
Rebours
Vinciane
V
Delhaye
Myriam N
MN
Andrén-Sandberg
Ake
A
Weiss
Frank Ulrich
FU
Mountford
Roger
R
Harcus
Matthew J
MJ
Niemczyck
Edyta
E
Vitone
Louis J
LJ
Dodd
Susanna
S
Jørgensen
Maiken Thyregod
MT
Ammann
Rudolf W
RW
Schaffalitzky de Muckadell
Ove
O
Butler
Jane V
JV
Burgess
Phillip
P
Kerr
Bronwyn
B
Charnley
Richard
R
Sutton
Robert
R
Raraty
Michael G
MG
Devière
Jacques
J
Whitcomb
David C
DC
Neoptolemos
John P
JP
Lévy
Philippe
P
Lerch
Markus M
MM
Greenhalf
William
W
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics; D010195:Pancreatitis / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D014357:Trypsin / Q000235:genetics*; D014359:Trypsin Inhibitor, Kazal Pancreatic; D055815:Young Adult
D002352:Carrier Proteins; D009363:Neoplasm Proteins; C486642:SPINK1 protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014359:Trypsin Inhibitor, Kazal Pancreatic; C489303:PRSS1 protein, human; D014357:Trypsin