Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1997-10-14
2002-06-18
Arthur, Lisa B. (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C536S024330
Reexamination Certificate
active
06406846
ABSTRACT:
FIELD OF THE INVENTION
The present invention is related to determining whether a human patient is susceptible to hereditary pancreatitis. More specifically, the present invention is related to determining whether a human patient is susceptible to hereditary pancreatitis by identifying a single G to A transition mutation in the third exon of cationic trypsinogen, or digesting the trypsinogen gene in exon III with Afl III.
BACKGROUND OF THE INVENTION
Hereditary pancreatitis (HP) is an autosomal dominant disorder with 80% penetrance and variable expressivity [Perrault, J. Hereditary pancreatitis.
Gastroenterol. Clin. North Am
. 23:743-752 (1994); Madraso-de la Garza, J., Hill, I., Lebenthal, E. Hereditary pancreatitis. In: Go V, ed. The Pancreas: Biology, Pathobiology, and Disease. 2nd ed. New York: Raven, 1095-1101 (1993); Whitcomb, D. C., Preston, R. A., Aston, C. E., Sossenheimer, M. J., Barua, P. S., Zhang, Y., Wong-Chong, A., White, G., Wood, P., Gates, L. K., Jr., Ulrich, C., Martin, S. P., Post, J. C., and Ehrlich, G. D. A gene for hereditary pancreatitis maps to chromosome 7q35
. Gastroenterology
110, 1975-1980 (1996); Bodic, L. L., Bignon, J. D., Raguenes, O., Mercier, B., Georgelin, T., Schnee, M., Soulard, F., Gagne, K., Bonneville, F., Muller, J. Y., Bachner, L., and Ferec, C. The hereditary pancreatitis gene maps to long arm of chromosome 7
. Hum. Molec. Genet
. 5, 549-554 (1996)]. Nearly 100 kindreds have been reported world-wide since the genetic nature of this disorder was recognized by Comfort and Steinberg in 1952 [Madraso-de la Garza, J., Hill, I., Lebenthal, E. Hereditary pancreatitis. In: Go V, ed.
The Pancreas: Biology, Pathobiology, and Disease
. 2nd ed. New York: Raven, 1095-1101 (1993); Comfort, M. and Steinberg, A. Pedigree of a family with hereditary chronic relapsing pancreatitis.
Gastroenterology
21, 54 (1952)]. The majority of the families are of white European ancestry, but affected kindreds have been reported in Japan, India, and among other ethnic groups [Perrault, J. Hereditary pancreatitis.
Gastroenterol. Clin. North Am
. 23:743-752 (1994)]. HP is characterized by recurrent bouts of severe epigastric pain with onset, usually developing before ten years of age. The clinical, laboratory and pathologic features of HP are indistinguishable from attacks of pancreatitis from other causes. In addition to recurrent acute attacks, many HP patients progress to complicated chronic pancreatitis characterized by pancreatic calcifications, pseudocysts, chronic abdominal pain, pancreatic exocrine failure, diabetes mellitus and/or pancreatic cancer [Perrault, J. Hereditary pancreatitis.
Gastroenterol. Clin. North Am
. 23:743-752 (1994); Madraso-de la Garza, J., Hill, I., Lebenthal, E. Hereditary pancreatitis. In: Go V, ed.
The Pancreas: Biology, Pathobiology, and Disease
. 2nd ed. New York: Raven, 1095-1101 (1993)]. Despite years of research, no unique morphologic or biochemical markers have been identified for HP, and the pathophysiologic mechanisms that lead to intermittent attacks of acute pancreatitis remain obscure. Therefore, no rational or effective preventative strategies have been developed, and treatment consists solely of supportive care.
Because of the absence of biochemical markers specific for HP, attention has focused on identifying the HP disease gene. The availability of a high-density map of the human genome, based on polymorphic simple tandem repeat (STR) markers, and familial S0 linkage analysis made it possible to identify an HP gene locus within the q35 region of chromosome seven [Whitcomb, D. C., Preston, R. A., Aston, C. E., Sossenheimer, M. J., Barua, P. S., Zhang, Y., Wong-Chong, A., White, G., Wood, P., Gates, L. K., Jr., Ulrich, C., Martin, S. P., Post, J. C., and Ehrlich, G. D. A gene for hereditary pancreatitis maps to chromosome 7q35
. Gastroenterology
110, 1975-1980 (1996); Bodic, L. L., Bignon, J. D., Raguenes, O., Mercier, B., Georgelin, T., Schnee, M., Soulard, F., Gagne, K., Bonneville, F., Muller, J. Y., Bachner, L., and Ferec, C. The hereditary pancreatitis gene maps to long arm of chromosome 7
. Hum. Molec. Genet
. 5, 549-554 (1996)]. It was thus desired to identify and sequence the HP gene to determine the site of the disease-causing mutation(s) in an effort to understand the molecular mechanism leading to HP. Several previously mapped genes on chromosome 7q were considered candidates for the HP disease gene because they are known to be expressed in the exocrine pancreas and encode enzymes that could potentially activate digestive enzymes within the pancreas. The hypothesis that pancreatitis results from inappropriate activation of pancreatic proenzymes was first promulgated 100 years ago and subsequently was demonstrated to be an experimental model for pancreatitis [Chiara, H. Ueber selbstverdauung des menschlichen pankreas.
Zeitschrift fur heilkunde
17, 69-96 (1896); Steer, M. L., and Meldolesi, J. The cell biology of experimental pancreatitis.
N. Engl. J. Med
. 316 (3), 144-50, (1987)]. Although carboxypeptidase A1 (CPA1) was considered the primary candidate by Le Bodic [Bodic, L. L., Bignon, J. D., Raguenes, O., Mercier, B., Georgelin, T., Schnee, M., Soulard, F., Gagne, K., Bonneville, F., Muller, J. Y., Bachner, L., and Ferec, C. The hereditary pancreatitis gene maps to long arm of chromosome 7
. Hum. Molec. Genet
. 5, 549-554 (1996)], this gene mapped centromeric to the HP locus defined by obligate recombinations in an HP linkage study [Whitcomb, D. C., Preston, R. A., Aston, C. E., Sossenheimer, M. J., Barua, P. S., Zhang, Y., Wong-Chong, A., White, G., Wood, P., Gates, L. K., Jr., Ulrich, C., Martin, S. P., Post, J. C., and Ehrlich, G. D. A gene for hereditary pancreatitis maps to chromosome 7q35
. Gastroenterology
110, 1975-1980 (1996); Stewart, E. A., Craik, C. S., Hake, L., and Bowcock, A. M. Human carboxypeptidase A identifies a Bg1II RFLP and maps to 7q31-qter.
Am. J. Hum. Genet
. 46 (4): 795-800, (1990); Rommens, J. M., Zengerling, S., Burns, J., Melmer, G., Kerem, B. S., Plavsic, N., Zsiga, M., Kennedy, D., Markiewicz, D., Rozmahel, R., et al. Identification and regional localization of DNA markers on chromosome 7 for the cloning of the cystic fibrosis gene.
Am. J. Hum. Genet
. 43 (5), 645-63 (1988); Rommens, J. M., Iannuzzi, M. C., Kerem, B., Drumm, M. L., Melmer, G., Dean, M., Rozmahel, R., Cole, J. L., Kennedy D., Hidaka, N., et al. Identification of the cystic fibrosis gene: chromosome walking and jumping.
Science
. 245 (4922): 1059-65 (1989); Martise, T. C., Perlin, M., and Chakravarti, A. Automated construction of genetic linkage maps using an expert system (MultiMap): a human genome linkage map.
Nature Genetics
. 6 (4), 384-90 (1994)] and was, therefore, excluded from further consideration. However, at least eight trypsinogen genes are located on chromosome 7q35 between the STR markers D7S495 and D7S498 and within the V and D-C segments of the complex T-cell receptor &bgr; chain gene locus (TCR&bgr;) [Rowen, L., Koop, B. F., Hood, L. The Complete 685-Kilobase DNA Sequence of the Human_T Cell Receptor Locus.
Science
(1996)]. Trypsinogen is an inactive proenzyme for trypsin, which becomes active when an eight amino acid amino-terminal peptide is removed. Although small amounts of trypsin are normally generated within the pancreas, this active trypsin is usually rapidly inactivated before pancreatic autodigestion occurs. Thus, the trypsinogen genes were considered primary candidates for the HP disease gene.
The entire 685 kilobase (kb) TCR&bgr;-trypsinogen locus has recently been sequenced by Rowen et al., as part of the largest human genome sequencing project completed to date [Rowen, L., Koop, B. F., Hood, L. The Complete 685-Kilobase DNA Sequence of the Human_T Cell Receptor Locus.
Science
(1996) ]. As a result of this study, eight trypsinogen-like genes were sequenced and identified that map within the TCR &bgr; locus. Three were located at the 5′ end of the locus and were
Ehrlich Garth D.
Gorry Michael C.
Whitcomb David
Arthur Lisa B.
Schwartz Angel M.
Whitcomb David
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