Clinicians should suspect PTTM in cancer patients who exhibit acute worsening respiratory insufficiency accompanied by a hypercoagulative state without embolism in major pulmonary arteries. The PTTM patients evaluated in our study had very poor prognoses. Vascular endothelial growth factor and tissue factor may play important roles in PTTM.
Probing of the mouse EST data base at GenBank TM with known tryptase cDNAs resulted in the identification of undiscovered serine protease transcripts whose genes reside at a 1.5-Mb complex on mouse chromosome 17A3.3. Mouse tryptase-5 (mT5), tryptase-6 (mT6), and mast cell protease-11 (mMCP-11) are new members of this serine protease superfamily whose amino acid sequences are 36 -54% identical to each other and to their other 10 family members. The 13 functional mouse proteases can be subdivided into two subgroups based on conserved features in their propeptides. Of the three new serine proteases, mT6 is most widely expressed in tissues. mT5 is preferentially expressed in smooth muscle, whereas mMCP-11 is preferentially expressed in the spleen and bone marrow. In contrast to mT5 and mT6, mMCP-11 is also expressed in mast cells. Although mT6 and mMCP-11 are constitutively secreted when expressed in mammalian and insect cells, mT5 remains membrane-associated. The fact that recombinant mT5, mT6, and mMCP-11 possess non-identical expression patterns and substrate specificities suggests that each protease has a unique function in vivo. Of the 13 functional mouse tryptase genes identified at the complex, 12 have orthologs that reside in the syntenic region of human chromosome 16p13.3. The establishment of these ortholog pairs helps clarify the evolutionary relationship of the serine protease locus in the two species. This information provides a useful framework for the functional analysis of each protease using gene targeting and other molecular approaches.The serine protease gene cluster at chromosome 16p13.3 contains the genes that encode human tryptase ␣ (1), tryptase I (2), tryptase II (2, 3), tryptase III (2), transmembrane tryptase (TMT) 1 /tryptase ␥ (4, 5), tryptase ␦ (6), tryptase ⑀/protease serine member S22 (PRSS22) (7), pancreasin/marapsin/ PRSS27 (8), eosinophil serine protease-1 (Esp-1)/testisin/ PRSS21 (9, 10), and EOS (11). There are five additional nonpeptidase homolog genes (currently designated as hSPL-2, -3, -4, -6, and -7) within the locus that probably encode nonfunctional proteins due to the presence of premature translation-termination codons (7). The subtelomeric region of human chromosome 16 where these genes reside is mutating at a rate ϳ300-fold faster than the rest of the genome in males (12). One explanation for this finding is that there is strong evolutionary pressure to expand some of the genes and delete others because of the respective beneficial and adverse roles.The corresponding serine protease locus in the mouse genome resides at chromosome 17A3.3. When this study was initiated, 10 genes had been identified at the site that encode mouse mast cell protease (mMCP) 6 (13), mMCP-7 (14), mTMT (4), tryptase-4 (mT4)/mEsp-1/mTesp5/mTestisin/mPrss21 (15-17), testis serine protease-1 (mTessp1), 2 distal intestinal serine protease (mDisp) (18), brain-specific serine protease-4 (mBssp-4) 2 /4733401N09Rik, pancreasin (8), implantation serine protease (mIsp) 1 (19), and mIsp-2 (20). Of these...
Ischemia with subsequent reperfusion (IR) injury is a significant clinical problem that occurs after physical and surgical trauma, myocardial infarction, and organ transplantation. IR injury of mouse skeletal muscle depends on the presence of both natural IgM and an intact C pathway. Disruption of the skeletal muscle architecture and permeability also requires mast cell (MC) participation, as revealed by the fact that IR injury is markedly reduced in c-kit defective, MC-deficient mouse strains. In this study, we sought to identify the pathobiologic MC products expressed in IR injury using transgenic mouse strains with normal MC development, except for the lack of a particular MC-derived mediator. Histologic analysis of skeletal muscle from BALB/c and C57BL/6 mice revealed a strong positive correlation (R2 = 0.85) between the extent of IR injury and the level of MC degranulation. Linkage between C activation and MC degranulation was demonstrated in mice lacking C4, in which only limited MC degranulation and muscle injury were apparent. No reduction in injury was observed in transgenic mice lacking leukotriene C4 synthase, hemopoietic PGD2 synthase, N-deacetylase/N-sulfotransferase-2 (enzyme involved in heparin biosynthesis), or mouse MC protease (mMCP) 1. In contrast, muscle injury was significantly attenuated in mMCP-5-null mice. The MCs that reside in skeletal muscle contain abundant amounts of mMCP-5 which is the serine protease that is most similar in sequence to human MC chymase. We now report a cytotoxic activity associated with a MC-specific protease and demonstrate that mMCP-5 is critical for irreversible IR injury of skeletal muscle.
Congenital bilateral absence of the vas deferens (CBAVD) is a monosymptomatic disease confined to the male reproductive system with similarity to the phenotype of cystic fibrosis (CF), and mutations in the CFTR gene are highly prevalent in Caucasian CBAVD patients. While CF is very rare in Japan, CBAVD is not. Our previous study demonstrated high prevalence of the 5T allele in the CFTR gene in Japanese CBAVD patients. We analyzed whole exons of the CFTR gene in 19 CBAVD patients and 53 normal individuals using polymerase chain reaction amplification-single strand conformation polymorphism analysis and direct sequencing. Three missense mutations (W216X, G1349S, Q1352H) were found in seven CFTR alleles, and the 5T allele was positive in 11 of 38 CFTR patient alleles. Consequently, 47% of CFTR chromosomes in the patients were affected, and 11 individuals (58%) had at least one mutated CFTR allele. In contrast, three of 53 normal individuals (5.7%) had a missense mutation in one of the CFTR genes, but no 5T allele was detected (both P<0.0001). Mutations of the CFTR gene are closely associated with Japanese patients with CBAVD.
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