Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3.

To contribute to the development of the transcription map of human chromosome 21 (HC21), we have used exon trapping from pools of HC21-specific cosmids. Using selected trapped exons, we have identified a novel gene (named TMPRSS2) that encodes a multimeric protein with a serine protease domain. The TMPRSS2 3.8-kb mRNA is expressed strongly in small intestine and weakly in several other tissues. The full-length cDNA encodes a predicted protein of 492 amino acids that contains the following domains: (i) A serine protease domain (aa 255-492) of the S1 family that probably cleaves at Arg or Lys residues. (ii) An SRCR (scavenger receptor cysteine-rich) domain (aa 149-242) of group A (6 conserved Cys). This type of domain is involved in the binding to other cell surface or extracellular molecules. (iii) An LDLRA (LDL receptor class A) domain (aa 113-148). This type of domain forms a binding site for calcium. (iv) A predicted transmembrane domain (aa 84-106). No typical signal peptide was recognized. The gene was mapped to 21q22.3 between markers ERG and D21S56 in the same P1 as MX1. The physiological role of TMPRSS2 and its involvement in trisomy 21 phenotypes or monogenic disorders that map to HC21 are unknown.

[1]  H. Pétursson,et al.  Two-locus admixture linkage analysis of bipolar and unipolar affective disorder supports the presence of susceptibility loci on chromosomes 11p15 and 21q22. , 1997, Genomics.

[2]  M. Gorry,et al.  Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene , 1996, Nature Genetics.

[3]  S. Antonarakis,et al.  Cloning of 559 potential exons of genes of human chromosome 21 by exon trapping. , 1996, Genome research.

[4]  M. Passos-Bueno,et al.  A gene which causes severe ocular alterations and occipital encephalocele (Knobloch syndrome) is mapped to 21q22.3. , 1996, Human molecular genetics.

[5]  L. Farrer,et al.  Linkage of congenital recessive deafness (gene DFNB10) to chromosome 21q22.3. , 1996, American journal of human genetics.

[6]  M C Peitsch,et al.  ProMod and Swiss-Model: Internet-based tools for automated comparative protein modelling. , 1996, Biochemical Society transactions.

[7]  M. Tessier-Lavigne,et al.  Physical mapping of the holoprosencephaly critical region in 21q22.3, exclusion of SIM2 as a candidate gene for holoprosencephaly, and mapping of SIM2 to a region of chromosome 21 important for Down syndrome. , 1995, American journal of human genetics.

[8]  R. Bronson,et al.  A mouse model for Down syndrome exhibits learning and behaviour deficits , 1995, Nature Genetics.

[9]  N. Daly,et al.  Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Manuel C. Peitsch,et al.  Protein Modeling by E-mail , 1995, Bio/Technology.

[11]  Neil D. Rawlings,et al.  [2] Families of serine peptidases , 1994, Methods in Enzymology.

[12]  N. Rawlings,et al.  [32] Families of cysteine peptidases , 1994, Methods in Enzymology.

[13]  R. Myers,et al.  A transcript map of the Down syndrome critical region on chromosome 21. , 1994, Human molecular genetics.

[14]  K. Gardiner,et al.  High density transcriptional mapping of chromosome 21 by hybridization selection , 1994 .

[15]  J. Cheng,et al.  Isolation and mapping of human chromosome 21 cDNA: progress in constructing a chromosome 21 expression map. , 1994, Genomics.

[16]  Y. Dudai,et al.  Overexpression of urokinase-type plasminogen activator in transgenic mice is correlated with impaired learning. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Sippl.  Recognition of errors in three‐dimensional structures of proteins , 1993, Proteins.

[18]  R. Lamb,et al.  Role of NH2-terminal positively charged residues in establishing membrane protein topology. , 1993, The Journal of biological chemistry.

[19]  R. Mulivor,et al.  NIGMS human/rodent somatic cell hybrid mapping panels 1 and 2. , 1993, Genomics.

[20]  S. Antonarakis.  Human chromosome 21: genome mapping and exploration, circa 1993. , 1993, Trends in genetics : TIG.

[21]  X. Estivill,et al.  Continuum of overlapping clones spanning the entire human chromosome 21q , 1992, Nature.

[22]  D. Eisenberg,et al.  Assessment of protein models with three-dimensional profiles , 1992, Nature.

[23]  K. Kurachi,et al.  Hepsin, a cell membrane-associated protease. Characterization, tissue distribution, and gene localization. , 1991, The Journal of biological chemistry.

[24]  P. Sharp,et al.  Exon amplification: a strategy to isolate mammalian genes based on RNA splicing. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[25]  M. Freeman,et al.  An ancient, highly conserved family of cysteine-rich protein domains revealed by cloning type I and type II murine macrophage scavenger receptors. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[26]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[27]  R. Mahley,et al.  Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. , 1988, Science.

[28]  K. Kurachi,et al.  A novel trypsin-like serine protease (hepsin) with a putative transmembrane domain expressed by human liver and hepatoma cells. , 1988, Biochemistry.

[29]  T. Südhof,et al.  First cysteine-rich repeat in ligand-binding domain of low density lipoprotein receptor binds Ca2+ and monoclonal antibodies, but not lipoproteins. , 1987, The Journal of biological chemistry.

[30]  T. Südhof,et al.  The LDL receptor gene: a mosaic of exons shared with different proteins. , 1985, Science.

[31]  J. Lloyd,et al.  Intestinal enterokinase deficiency. , 1969, Lancet.

[32]  P. L. Townes.  TRYPSINOGEN DEFICIENCY DISEASE. , 1964, The Journal of pediatrics.

[33]  B. Müller-Myhsok,et al.  Autosomal recessive non-syndromic deafness locus (DFNB8) maps on chromosome 21q22 in a large consanguineous kindred from Pakistan. , 1996, Human molecular genetics.

[34]  D. Church,et al.  Isolation of genes from complex sources of mammalian genomic DNA using exon amplification , 1994, Nature Genetics.

[35]  L. Peltonen,et al.  An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21 , 1994, Nature Genetics.

[36]  M. Krieger,et al.  The SRCR superfamily: a family reminiscent of the Ig superfamily. , 1994, Trends in biochemical sciences.

[37]  D. Patterson,et al.  Physical mapping of chromosome 21. , 1993, Progress in clinical and biological research.

[38]  Kay Hofmann,et al.  Tmbase-A database of membrane spanning protein segments , 1993 .

[39]  J. Delabar,et al.  Molecular Mapping of Twenty-Four Features of Down Syndrome on Chromosome 21 , 1993, European journal of human genetics : EJHG.

[40]  Charles R.scriver.  The Metabolic basis of inherited disease , 1989 .