Hereditary pancreatitis

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  • Whitcomb 2000

    Pancreatic Diseases:Insights from Hereditary

    PancreatitisWritten byWritten by

    David C Whitcomb MD PhDDavid C Whitcomb MD PhDDepartment of Medicine, University Department of Medicine, University ofof Pittsburgh Pittsburgh

    Educational Use ONLY

  • Whitcomb 2000

    Hereditary Pancreatitis

    Hereditary pancreatitis Hereditary pancreatitis (HP) is an unusual form of (HP) is an unusual form of acute and chronic pancreatitis that runs in families. acute and chronic pancreatitis that runs in families. The risk of pancreatic cancer is >50 times normal.The risk of pancreatic cancer is >50 times normal.

    Although HP is only responsible for 2-3% of all Although HP is only responsible for 2-3% of all cases of chronic pancreatitis, study of this disease cases of chronic pancreatitis, study of this disease has revolutionized our understanding of pancreatic has revolutionized our understanding of pancreatic diseasesdiseases

    PancreasPancreas

  • Whitcomb 2000

    Discovery of the Pancreatitis Gene

    ccaccaccagtcaggcacactctaccaccATGAATCCACTCCTGATCCTTACCTTTGT

    GG/ACAGCTGC TCgtgagtatcatgccctgcctcaggccccaaccacccccccgttcctggccgaDNA

    1. Family 2. Genetic Mapping 3. Mutation 4. Mechanism

    Chromosome 7

    HereditaryPancreatitisgene

    Functional significancedetermined

    Mutation in the trypsinogenDNA sequenceRecruitment

    Trypsinogen

  • Whitcomb 2000

    Family Tree (S-Family)

    I

    II

    III

    IV

    V

    VI

    MaleFemaleAffectedCarrier

  • Whitcomb 2000

    Linkage of HP to Chromosome 7q35

    D7S

    505

    D7S

    661

    D7S

    684

    D7S

    523

    D7S

    461

    D7S

    495

    D7S

    483

    D7S

    550

    D7S

    559-5

    3

    0

    LO

    D S

    core

    s

    HP GENE

    5

    Whitcomb et al. GASTROENTEROLOGY 110:1975, 1996Whitcomb et al. GASTROENTEROLOGY 110:1975, 1996

    0.00001

    0.001

    0.1

    (P v

    alue

    )

    0.01

    0.00014

    21

    Markers on chromosome 7

    HereditaryHereditaryPancreatitis Pancreatitis

    GeneGene

    Cystic Cystic FibrosisFibrosisGeneGene

    Chromosome 7

    TCRBTCRB

  • Whitcomb 2000

    Cationic Trypsinogen GenectgatgcaagacccTGGGAagaggaaagctgCAggtgtgtttgtgcTGGGAggagtggtgaccctcacctcacagtcacctcctctctggatcctcgtgaggtataaagacgagtcct130801ccaccaccagtcaggcacactctaccaccATGAATCCACTCCTGATCCTTACCTTTGTGGCAGCTGCTCgtgagtatcatgccctgcctcaggccccaaccacccccccgttcctggccgaCAaatgcccttccattcttaccacctctcctcttttgactgtgctctgatattccgtttcctcCAtctggcatatctccttcccatcctccttgggctctttttaagtctCAcctgttcaccttctccttgacttcactcccaccactgtcattcatccatatccgagttgtggttggagaagcTGGGAagggggcCAggtggggctgtcccacgaaatgaagcagcaggcttcaggcttggctccgacagcaacagaatagcaccactatagctgctcctaacctcgaatgcacctggggaggttgaaaaattactcatgccagagactcagctctagaaattctaacttCAattgtctggggtagagcttgtgttctgggcttttaagcttccCAggtgatttttaatatttccagccatgcagccaaggttaagaattgctgtcctattggccaataacaaagtctacctttgttctgccaaagtgagcctgggggctgccctcaactctgccctgactgcacagatctgagctatgggggaaggtggtcatggccaggtctatgcagacagggggttttcctagcttggcaaaagaatcctgacaatccagggcccaaatagccaggggaagtacaCAggtgatgaataaaagagagaagcactcagTGGGAgagacaaccacatcccaactcctatcccactggaagcattgtgaggacattccttgcgacttcagcctggtgaccccaggagagctcggatcctccgcagggtacctagctatgtgccctgcaggcacagagactTGGGAgccacaggcagtgatgatcaccaggggtggcagagctccctcccttgcctagcctcactgtgcttgttaaggatttctaattagcagaaagcaatcacaggcTGGGAgcgccacccctaacatgctattgacttgccttctcccttcccatctccactcCAgTTGCTGCCCCCTTTGATGATGATGACAAGATCGTTGGGGGCTACAACTGTGAGGAGAATTCTGTCCCCTACCAGGTGTCCCTGAATTCTGGCTACCACTTCTGTGGTGGCTCCCTCATCAACGAACAGTGGGTGGTATCAGCAGGCCACTGCTACAAGTcgtaagtgtggggcccccgactgcaaagctcccggccagtctgccTGGGAgagcttggcttcagcccagggaactactgaggttgggtaagatggaTGGGAgaggtggtggagaagaaaacttgttggCAgctgcggactctccagagcagagagtgaacacaagacaggaacctctcacacccaggcaaatccatgaaacagcaagggttgtggtcataaaagcaggcagggatgatcttggggtggtgagagctagtgagaaaagcaggcaagtatcttttgctggttagctacacattaaagccaactaagaaagactttttaaaaataCAgatgcctttgtcctatcccagggcaattaagtcaaaattttcaggaagagggtgtgaatatcagtgagaattttacactctacctctgctaactgtagagtgtatagacagagctgagaactgctgcctacaccaagaactctcaaacctgagtatgcatcagaacgccctgcaggcttgttaaggcacaaatcactgggccccttccccaaggttctgatcagtaggtgggggtaaggaccaagaattcacatttctaacaagttcccaggagatgctaatgctatggctacccttggattagattacacagaagggtggttctcaccaggccaagaatggagggaggaacaggcactgtgcaCAgttggcaaaggcctggggtgaagaatgcTGGGAaaacttcaaggagctccttgtgcccacagtgctagtgactgtggagattgTGGGAaagagtctggggaggcaggttgaggagcagcctctggTGGGAtccctttgactcttccccaccccactaccaccaacctctggagcagataggtcctgggtctcataccttcactgacccacatccctctgctgcccatgcgatatggccacacaccccaccccatgcctccagagctgtccatgagcagagagcttgaggaacctggggaaggTGGGAtaggtgccctggctgTGGGAgaaggtcttcaccatgcctgccctgcccatcagCCGCATCCAGGTGAGACTGGGAGAGCACAACATCGAAGTCCTGGAGGGGAATGAGCAGTTCATCAATGCAGCCAAGATCATCCGCCACCCCCAATACGACAGGAAGACTCTGAACAATGACATCATGTTAATCAAGCTCTCCTCACGTGCAGTAATCAACGCCCGCGTGTCCACCATCTCTCTGCCCACCGCCCCTCCAGCCACTGGCACGAAGTGCCTCATCTCTGGCTGGGGCAACACTGCGAGCTCTGGCGgtgagTGGGAcccttagtccttctacttccctccatcctcacaatttccagaacaaaccatgccccttaacttgaatcctctcacctccaggcttaagacacatttcgagtgcccattacacacagactctgcactgggcaccagagagatgcaaactatcaaggacttggctcctaaaatcaagagacaggaCAaatggagaacttgatatgatcacatctTGGGAggggttcaacaatgatcattcTGGGAactaaaagccagagtctcttgccaggacttatgttctggagtcctctccaggggctgtgttcctcttcagttttccatccaagattattgtctccttctctggcctgacccacatttctacttcctttgatctcttcctgatcctcacagCCGACTACCCAGACGAGCTGCAGTGCCTGGACGCTCCTGTGCTGAGCCAGGCTAAGTGTGAAGCCTCCTACCCTGGAAAGATTACCAGCAACATGTTCTGTGTGGGCTTCCTTGAGGGAGGCAAGGATTCATGTCAGgtgatttgaccaacccttcccatgctgaggctcccactgatacctaggccccaccagggaaaaggatttgaactcaaaaggtggtggggctgaggaggctccctgcagtgcccacatggagaagtgaggaagactcccttgggctgcatcttgtctgcttaggaagaacagagaatgggccaccatgagaaggacatggagccacagagctggctggaaaggggtcttttaaggttcagagtaaatgtagctatattcctcctccatctctccatacaacttgtcccttcttccccccagGGTGATTCTGGTGGCCCTGTGGTCTGCAATGGACAGCTCCAAGGAGTTGTCTCCTGGGGTGATGGCTGTGCCCAGAAGAACAAGCCTGGAGTCTACACCAAGGTCTACAACTATGTGAAATGGATTAAGAACACCATAGCTGCCAACAGCTAAagcccccagtatctcttcagtctctataccaataaagtgaccctgttctcactgtctgtgtctgtgcctgctccctctcactccttcacactggaaagcatcctccaatttcaggttagacacgactgtcccctttaaaggtaagcagagcccc

  • Whitcomb 2000

    HP is caused by Super-Trypsin

    Whitcomb et al, Whitcomb et al, Nature Genetics Nature Genetics 19961996

    Trypsin

    Active trypsin in the pancreaswill cause the pancreas to digestitself.

    Normally, the pancreas is protected because active trypsin will destroy itself by cutting at R117. This will split the trypsin and inactivate it.

    In HP, R117 is mutated to H117. This creates a super-trypsin that cannot be inactivated and leads to acute pancreatitis.

  • Whitcomb 2000

    Conclusions

    Discovery of the Discovery of the hereditary pancreatitis hereditary pancreatitis gene is an example of how genetic research gene is an example of how genetic research can revolutionize our understanding of a can revolutionize our understanding of a disease process. disease process.

  • Whitcomb 2000

    Pancreatitis

    PancreasPancreas - - an organ that makes an organ that makes bicarbonatebicarbonate to nutralize gastric acid, to nutralize gastric acid, enzymesenzymes to digest the contents of a meal and to digest the contents of a meal and insulininsulin to signal the body to to signal the body to store ingested nutrients.store ingested nutrients.

    Acute PancreatitisAcute Pancreatitis - An acute, potentially life-threatening condition - An acute, potentially life-threatening condition presenting with severe abdominal pain in which the pancreas appears to presenting with severe abdominal pain in which the pancreas appears to digest itself. It is usually caused by gallstones, alcohol or is idiopathic.digest itself. It is usually caused by gallstones, alcohol or is idiopathic.

    Chronic Pancreatitis Chronic Pancreatitis - an- an irreversible scarring of the pancreas with irreversible scarring of the pancreas with permanent loss of pancreatic function that typically causes unrelenting permanent loss of pancreatic function that typically causes unrelenting abdominal pain.abdominal pain.

    Hereditary Pancreatitis Hereditary Pancreatitis - a unusual form of acute and chronic pancreatitis - a unusual form of acute and chronic pancreatitis that runs in families. The risk of pancreatic cancer is >50 times normal.that runs in families. The risk of pancreatic cancer is >50 times normal.

    PancreasPancreas

  • Whitcomb 2000

    Fail-safe Trypsin Inactivation

    Trypsinogen

    PSTIPSTI TrypsinTrypsinTrypsinTrypsin

    Trypsin (wt)Trypsin (wt)

    Proenzymes Enzymes

    Autodigestion

    +

    -

    (Autoactivation)

    -

    -

    -

    Whitcomb et al, Whitcomb et al, Nature Genetics Nature Genetics 19961996

    -Trypsin

    HPHP

  • Whitcomb 2000

    1) Proenzymes1) Proenzymes

    2) Low calcium2) Low calcium

    3) Compartmentalized3) Compartmentalized

    4) Trypsin inhibitor4) Trypsin inhibitor

    5) 5) Zymogen Zymogen autolysisautolysis

    6) Remote activation6) Remote activation

    7) 7) 11- antitrypsin, - antitrypsin,

    22 microglobulinmicroglobulin

    Super-trypsin in HP

    NucleusNucleus

    R.E.R.R.E.R.

    EnterokinaseEnterokinase(normal trypsin trigger)(normal trypsin trigger)

    LysosomesLysosomes

    ZymogensZymogens(digestive(digestive enzymes)enzymes)

    CVZ

    TrypsinTrypsin

    GolgiGolgi

    Pancreatic Acinar CellPancreatic Acinar Cell

    Pancreas Intestine

    Premature Activation

    Normal Normal (autolysis)(autolysis)

    HereditaryHereditaryPancreatitisPancreatitis(trypsin (trypsin activates activates cascade)cascade)

  • Whitcomb 2000

    Implications of the HP Discovery

    Acute pancreatitisAcute pancreatitis starts with trypsin activation