Biomedical subjects
Publications and source records attributed to M F Seldin.
Adam9, Adam15 and Adam21, genes encoding members of the ADAM or MDC family of metalloproteases, have been mapped to mouse chromosomes 8, 1, and 12, respectively, using an interspecific cross. The mapping of these mouse loci and the extrapolated loci for their human orthologs may facilitate the mapping of diseases involving these genes.
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The genetic basis of autoimmunity is receiving increased attention. Organ-specific diseases, such as primary biliary cirrhosis, may be considered model diseases to use for development of databases and extrapolation to other autoimmune diseases. PBC is an enigmatic autoimmune disease that predominantly affects females and leads to destruction of intrahepatic bile ducts. The serologic hallmark of this disease is anti-mitochondrial antibodies that specifically react with the E2 components of 2-oxodehydrogenase enzymes, including PDC-E2. There are no clear major histocompatibility complex associations with the development of PBC, despite the observation that first-degree relatives of index patients with PBC have a 4-6% prevalence of development of PBC. This risk factor is comparable or higher than any other human autoimmune disease and suggests that a genome-wide approach towards dissection of genetic associations would lead to valuable new insights. In this review we place these concepts in perspective and highlight in particular the genetic associations in primary biliary cirrhosis.
A disintegrin-like and metalloprotease domain with thrombospondin type I modules (ADAM-TS) describes a novel family of zinc metalloendopeptidases. Its members have a common domain organization, which includes, typically, a pre-pro-metalloprotease domain, a disintegrin-like domain, and one or more thrombospondin-like (TS) modules. We describe here the complete primary structure of mouse ADAM-TS8, through cloning of Adamts8 cDNA. This novel member of the family contains two TS modules and is highly similar in sequence and domain organization to three other recently described gene products, ADAM-TS5, ADAM-TS6, and ADAM-TS7. Adamts8 is expressed at low levels throughout development and in adult mouse lung and heart. Through analysis of an interspecific backcross panel, we place the Adamts8 locus on mouse chromosome 9 at a consensus position of 11 cM and its human ortholog, recently reported as the METH2 gene, on human chromosome 11q25.
We report the primary structure of three novel, putative zinc metalloproteases designated ADAM-TS5, ADAM-TS6, and ADAM-TS7. All have a similar domain organization, comprising a preproregion, a reprolysin-type catalytic domain, a disintegrin-like domain, a thrombospondin type-1 (TS) module, a cysteine-rich domain, a spacer domain without cysteine residues, and a COOH-terminal TS module. These genes are differentially regulated during mouse embryogenesis and in adult tissues, with Adamts5 highly expressed in the peri-implantation period in embryo and trophoblast. These proteins are similar to four other cognate gene products, defining a distinct family of human reprolysin-like metalloproteases, the ADAM-TS family. The other members of the family are ADAM-TS1, an inflammation-induced gene, the procollagen I/II amino-propeptide processing enzyme (PCINP, ADAM-TS2), and proteins predicted by the KIAA0366 and KIAA0688 genes (ADAM-TS3 and ADAM-TS4). Individual ADAM-TS members differ in the number of COOH-terminal TS modules, and some have unique COOH-terminal domains. The ADAM-TS genes are dispersed in human and mouse genomes.
Ligation of the Fas receptor induces death-inducing signaling complex (DISC) formation, caspase activation, and subsequent apoptotic death of several cell types. Epstein-Barr virus (EBV)-positive group III Burkitt's lymphoma (BL) cell lines have a marked resistance to Fas-mediated apoptosis, although expressing each of the DISC components, Fas/ APO-1-associated death domain protein (FADD), and caspase-8 (FLICE/MACH/Mch5). The apoptotic pathway distal to the DISC is intact because ceramide analogs, staurosporine, and granzyme B activate caspase-3 and induce apoptosis. Fas resistance was not explained by the putative death-attenuating caspase-8 isoforms. However, while Fas-activated cytosolic extracts from sensitive cells were capable of processing both procaspase-8 and procaspase-3 into active subunit forms, resistant cell extracts did not possess either of these activities. Accordingly, reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed higher transcript levels for the FLICE-inhibitory protein (FLIP(L)) in resistant cells and the ratio of caspase-8 to FLIP(L) measured by competition RT-PCR analysis directly correlated with susceptibility to Fas-mediated apoptosis of all cell lines. In addition, modification of the caspase-8/FLIP(L) ratio by caspase-8 or FLIP(L) overexpression was able to alter the susceptibility status of the cell lines tested. Our results imply that the relative levels of caspase-8 and FLIP(L) are an important determinant of susceptibility to Fas-mediated apoptosis.
To determine the biological role of caudal-like homeobox gene CDX2, we constructed knockout mice in which its mouse homologue Cdx2 was inactivated by homologous recombination, placing a bacterial lacZ gene under the control of the Cdx2 promoter. Although the homozygous mutants died in utero around implantation, the heterozygotes were viable and fertile and expressed lacZ in the caudal region in early embryos and in the gut tissues in adults. The heterozygotes developed cecal and colonic villi by anteriorization and formed hamartomatous polyps in the proximal colon. The hamartoma started to develop at 11.5 days of gestation as an outpocket of the gut epithelium, which ceased to express the remaining Cdx2 allele. The outpocket then expanded as a partially duplicated gut but was contained as a hamartoma after birth. In adult mice, these hamartomas grew very slowly and took a benign course. None of them progressed into invasive adenocarcinomas, even at 1.5 years of age. Whereas the cecal and colonic villi expressed lacZ, the hamartoma epithelium did not, nor did it express Cdx2 mRNA from the wild-type allele. However, genomic DNA analysis of the polyp epithelium did not show a loss of heterozygosity of the Cdx2 gene, suggesting a mechanism of biallelic Cdx2 inactivation other than loss of heterozygosity. These results indicate that the Cdx2 haploin-sufficiency caused cecal and colonic villi, whereas the biallelic inactivation of Cdx2 triggered anomalous duplications of the embryonic gut epithelium, which were contained as hamartomas after birth.
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OBJECTIVE: To develop diagnostic criteria for a familial form of antiphospholipid antibody syndrome (APS), identify families with >1 affected member, examine possible modes of inheritance, and determine linkage to potential candidate genes. METHODS: Family members of probands with primary APS were analyzed for clinical and laboratory abnormalities associated with APS. Families with > or =2 affected members were analyzed by segregation analysis and typed for candidate genetic markers. RESULTS: Seven families were identified. Thirty of 101 family members met diagnostic criteria for APS. Segregation studies rejected both environmental and autosomal recessive models, and the data were best fit by either a dominant or codominant model. Linkage analysis showed independent segregation of APS and several candidate genes. CONCLUSION: Clinical and laboratory criteria are essential to identify the spectrum of disease associated with APS. We believe a set of criteria was developed that can precisely define affected family members with APS. Modeling studies utilizing these criteria strongly support a genetic basis for disease in families with APS and suggest that a susceptibility gene is inherited in an autosomal dominant pattern. However, in these families, APS was not linked with HLA, Fas, or other candidate genes, including beta2-glycoprotein 1, HLA, T cell receptor beta chain, Ig heavy chain, antithrombin III, Fas ligand, factor V, complement factor H, IgK, and Fas.
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To examine the genetic contribution of HLA and non-HLA genes in the etiopathogenesis of rheumatoid arthritis (RA), 60 Caucasian multiplex families were identified and DNA analyzed for over 52 markers including DRB1, DQA1 and DQB1 alleles. Many of the markers were chosen because of close proximity to candidate genes suggested by previous studies or models of pathogenesis. Sibling pair analysis (SIBPAL), relative pair analysis (RELPAL) and linkage studies using two different models of inheritance suggested linkage for the MHC and two additional chromosomal regions: chromosome 2 (D2S443 near CD8 and IGk; 2p13-2p11.1), and chromosome 15 (CYP19-estrogen synthase; 15q15). No support was found for two chromosomal regions, 1p36 and 3q13, recently suggested by other studies. We used transmission disequilibrium testing (TDT), conditional logistic regression, and segregation analysis to study the contributions that the shared epitope and TNF-c have in contributing to risk for RA. These studies provide additional evidence that the association of HLA alleles in RA patients from multiplex families is similar to that observed in sporadic disease, suggest candidate regions for further analysis and find additional support for an association of TNF-c alleles with RA susceptibility.
Muscarinic acetylcholine receptors in mammals consist of five subtypes (M1-M5) encoded by distinct genes. They are widely expressed throughout the body and play a variety of roles in the peripheral and central nervous systems. Although their pharmacological properties have been studied extensively in vitro, colocalization of the multiple subtypes in each tissue and lack of subtype-specific ligands have hampered characterization of the respective subtypes in vivo. We have mapped mouse genomic loci for all five genes (Chrm1-5) by restriction fragment length variant (RFLV) analyses in interspecific backcross mice. Chrm1, Chrm2, and Chrm3 were mapped to chromosome (Chr) 19, 6, and 13, respectively. Both Chrm4 and Chrm5 were mapped to Chr 2. Although a comparison of their map positions with other mutations in their vicinities suggested a possibility that the El2 (epilepsy 2) allele might be a mutation in Chrm5, sequencing analyses of the Chrm5 gene in the El2 mutant mice did not support such a hypothesis.