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SERINE PROTEASE INHIBITOR, KAZAL-TYPE, 1; SPINK1

Alternative titles; symbols

PANCREATIC SECRETORY TRYPSIN INHIBITOR; PSTI

TUMOR-ASSOCIATED TRYPSIN INHIBITOR; TATI

Gene map locus Chr.5

TEXT

Pancreatic secretory trypsin inhibitor is secreted from pancreatic acinar cells

into pancreatic juice. Its physiologic role has been thought to be the

prevention of trypsin-catalyzed premature activation of zymogens within the

pancreas and the pancreatic duct. Since it is also found in serum and in various

normal and malignant tissues, it may have other roles as well. Horii et al.

(1987) cloned and characterized the entire PSTI gene. It is approximately 7.5 kb

long and is separated into 4 exons by 3 introns. The gene has multiple

transcription start points. Hybridization to sorted chromosomes showed that the

gene is located on chromosome 5.

Tumor-associated trypsin inhibitor (TATI) is identical to PSTI. TATI is a 6-kD

peptide that is synthesized by several tumors and cell lines. It was initially

detected in urine of patients with ovarian cancer (Stenman et al., 1982; Huhtala

et al., 1982). This peptide is also produced by the mucosa of the

gastrointestinal tract where it may protect the mucosal cells from proteolytic

breakdown. Elevated serum and urine levels occur particularly with mucinous

ovarian cancer and may occur in nonmalignant diseases, e.g., pancreatitis,

severe infections, and tissue destruction (Stenman et al., 1991).

Pancreatitis is a continuing or relapsing inflammatory disease of the pancreas.

In approximately one-third of all cases, no etiologic factor can be found, and

these patients are classified as having idiopathic disease. Mutations in the

cationic trypsinogen gene (PRSS1; 276000) have been identified in patients with

hereditary or idiopathic chronic pancreatitis (167800). It appears that these

mutations result in increased trypsin activity within the pancreatic parenchyma.

Most patients with idiopathic or hereditary chronic pancreatitis, however, do

not have mutations in PRSS1. Witt et al. (2000) analyzed 96 unrelated children

and adolescents for mutations in the gene encoding the Kazal-type serine

protease inhibitor-1 (SPINK1), a pancreatic trypsin inhibitor. This study was

prompted by the likelihood that autodigestion and inflammation in the pancreas

may be caused by either increased proteolytic activity or decreased protease

inhibition. Witt et al. (2000) found mutations in 23% of the patients. In 18

patients, they detected an asn34-to-ser (N34S; 167790.0001) mutation, which was

homozygous in 6 patients. They also found 4 other sequence variants.

Chen et al. (2000) reported mutation analysis in the PSTI (SPINK1) gene in 14

families with hereditary pancreatitis and in 30 individuals with sporadic

chronic pancreatitis. A total of 7 polymorphisms, but no pathogenic mutations,

were detected.

Kaneko et al. (2001) analyzed genetic variation in the PSTI gene in 32 unrelated

Japanese patients with chronic pancreatitis who had juvenile onset or a family

history of the disorder. They found the N34S (167790.0001) mutation in 5

patients. This frequency was significantly lower than that reported previously

in Caucasian patients. They identified a novel homozygous G-to-A transition in

the promoter region of PSTI 215 bp upstream from the translation initiation site

in 2 patients (-215G-A; 167790.0003).

Audrezet et al. (2002) analyzed the entire coding sequence and exon/intron

junctions of the SPINK1 gene by denaturing gradient gel electrophoresis (DGGE)

and direct sequencing in 39 white French patients with idiopathic chronic

pancreatitis. The N34S (167790.0001) missense mutation was detected in 4

patients (3 heterozygotes and 1 homozygote), as compared with 3 out of 200 blood

donors (P = 0.01). In addition, 2 variants were identified in the

5-prime-untranslated region, each identified once in different patients.

Fibrocalculous pancreatic diabetes is a secondary cause of diabetes due to

chronic pancreatitis. In addition to diabetes, patients show evidence of chronic

pancreatitis of unknown origin with large intraductal pancreatic stones (Mohan

et al., 1998). Patients frequently have a low body mass and a history of chronic

abdominal pain and require insulin treatment, although, unlike patients with

type I diabetes, they are not prone to ketosis. A multifactorial basis for the

disease, with genetic and environmental components to both the diabetes and the

chronic pancreatitis, is likely. Mohan et al. (1989) demonstrated familial

clustering of the disease. Because the N34S variant (167790.0001) of the SPINK1

gene partially accounts for genetic susceptibility to chronic pancreatitis,

Hassan et al. (2002) used a family-based and case-control approach in 2 separate

ethnic groups from the Indian subcontinent to determine whether N34S was

associated with susceptibility to fibrocalculous pancreatic diabetes. In 69

Bangladeshi families, they found excess transmission of SPINK1 N34S to probands

with the disorder. In the total study group (Bangladeshi and southern Indian),

the N34S variant was present in 33% of 180 subjects with fibrocalculous

pancreatic diabetes, 4.4% of 861 nondiabetic subjects (odds ratio = 10.8; P less

than 0.0001 compared with fibrocalculous pancreatic diabetes), 3.7% of 219

subjects with type II diabetes, and 10.6% of 354 subjects with early-onset

diabetes (age less than 30 years). Hassan et al. (2002) suggested that the N34S

variant of SPINK1 confers susceptibility to fibrocalculous pancreatic diabetes

in the Indian subcontinent, although by itself it is not sufficient to cause the

disease.

ALLELIC VARIANTS

(selected examples)

..0001 PANCREATITIS, CHRONIC [sPINK1, ASN34SER ]

FIBROCALCULOUS PANCREATIC DIABETES, SUSCEPTIBILITY TO, INCLUDED

Witt et al. (2000) studied 96 children and adolescents with chronic pancreatitis

(167800) and in 18 found an asn34-to-ser (N34S) missense mutation in the SPINK1

gene. In 6 of the patients, the mutation was homozygous. In 279 healthy

controls, only 1 individual was heterozygous for the N34S mutation, and no

homozygous individuals were found. To exclude compound heterozygosity in the 12

individuals heterozygous for the N34S mutation, Witt et al. (2000) analyzed the

complete intronic sequence of the SPINK1 gene after long-range PCR.

Hassan et al. (2002) presented evidence suggesting that the N34S variant of

SPINK1 confers susceptibility to fibrocalculous pancreatic diabetes in the

Indian subcontinent, although by itself it did not appear to be sufficient to

cause the disease.

..0002 PANCREATITIS, CHRONIC [sPINK1, MET1THR ]

In a patient with hereditary pancreatitis (167800), Witt et al. (2000) found a

heterozygous mutation destroying the only translation initiation codon of SPINK1

(2T-C, met1 to thr; M1T). The mutation was also found in the affected

grandfather and in the unaffected father.

..0003 PANCREATITIS, CHRONIC [sPINK1, -215G-A ]

Kaneko et al. (2001) identified a promoter mutation (-215G-A) in 2 patients with

chronic pancreatitis (167800) and in none of 117 normal persons.

REFERENCES

1. Audrezet, M.-P.; Chen, J.-M.; Le Marechal, C.; Ruszniewski, P.;

Robaszkiewicz, M.; Raguenes, O.; Quere, I.; Scotet, V.; Ferec, C. :

Determination of the relative contribution of three genes--the cystic fibrosis

transmembrane conductance regulator gene, the cationic trypsinogen gene, and the

pancreatic secretory trypsin inhibitor gene--to the etiology of idiopathic

chronic pancreatitis. Europ. J. Hum. Genet. 10: 100-106, 2002.

PubMed ID : 11938439

2. Chen, J.-M.; Mercier, B.; Audrezet, M.-P.; Ferec, C. :

Mutational analysis of the human pancreatic secretory trypsin inhibitor (PSTI)

gene in hereditary and sporadic chronic pancreatitis. J. Med. Genet. 37: 67-69,

2000.

PubMed ID : 10691414

3. Hassan, Z.; Mohan, V.; Ali, L.; Allotey, R.; Barakat, K.; Faruque, M. O.;

Deepa, R.; McDermott, M. F.; , A. E.; Cassell, P.; Curtis, D.; Gelding,

S. V.; Vijayaravaghan, S.; Gyr, N.; Whitcomb, D. C.; Khan, A. K. A.; Hitman, G.

A. :

SPINK1 is a susceptibility gene for fibrocalculous pancreatic diabetes in

subjects from the Indian subcontinent. Am. J. Hum. Genet. 71: 964-968, 2002.

PubMed ID : 12187509

4. Horii, A.; Kobayashi, T.; Tomita, N.; Yamamoto, T.; Fukushige, S.; Murotsu,

T.; Ogawa, M.; Mori, T.; Matsubara, K. :

Primary structure of human pancreatic secretory trypsin inhibitor (PSTI) gene.

Biochem. Biophys. Res. Commun. 149: 635-641, 1987.

PubMed ID : 3501289

5. Huhtala, M.-L.; Pesonen, K.; Kalkkinen, N.; Stenman, U.-H. :

Purification and characterization of a tumor-associated trypsin inhibitor from

the urine of a patient with ovarian cancer. J. Biol. Chem. 257: 13713-13716,

1982.

PubMed ID : 7142173

6. Kaneko, K.; Nagasaki, Y.; Furukawa, T.; Mizutamari, H.; Sato, A.; Masamune,

A.; Shimosegawa, T.; Horii, A. :

Analysis of the human pancreatic secretory trypsin inhibitor (PSTI) gene

mutations in Japanese patients with chronic pancreatitis. J. Hum. Genet. 46:

293-297, 2001.

PubMed ID : 11355022

7. Mohan, V.; Chari, S. T.; Hitman, G. A.; Suresh, S.; Madanagopalan, N.;

Ramachandran, A.; Viswanathan, M. :

Familial aggregation in tropical fibrocalculous pancreatic diabetes. Pancreas

4: 690-693, 1989.

PubMed ID : 2813331

8. Mohan, V.; Nagalotimath, S. J.; Yajnik, C. S.; Tripathy, B. B. :

Fibrocalculous pancreatic diabetes. Diabetes Metab. Rev. 14: 153-170, 1998.

PubMed ID : 9679668

9. Stenman, U.-H.; Huhtala, M.-L.; Koistinen, R.; Seppala, M. :

Immunochemical demonstration of an ovarian cancer-associated urinary peptide.

Int. J. Cancer 30: 53-57, 1982.

PubMed ID : 6811446

10. Stenman, U.-H.; Koivunen, E.; Itkonen, O. :

Biology and function of tumor-associated trypsin inhibitor, TATI. Scand. J.

Clin. Lab. Invest. 51 (suppl. 207): 5-9, 1991.

11. Witt, H.; Luck, W.; Hennies, H. C.; Classen, M.; Kage, A.; Lass, U.;

Landt, O.; Becker, M. :

Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are

associated with chronic pancreatitis. Nature Genet. 25: 213-216, 2000.

PubMed ID : 10835640

CONTRIBUTORS

Victor A. McKusick - updated : 10/30/2002

B. sen - updated : 10/8/2002

J. - updated : 1/10/2001

Victor A. McKusick - updated : 5/26/2000

Mark E. Armstrong

www.top5plus5.com

NW Chapter Rep

Pancreatitis Association, International