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Results for “HOMOLOGOUS WASTING DISEASE”

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PubMed1991

Long-term immunologic tolerance induction in chimeric mice after bone marrow transplantation across major histocompatibility barriers: persistent or redeveloping immunologic responsiveness after prolonged survival.

Employing allogeneic bone marrow chimeras [B6----C3H] (C3H/HeN mice lethally irradiated and then reconstituted with T cell-depleted C57BL/6J bone marrow), we investigated the kinetics of immunological reconstitution and the functional characteristics of the immune system at regular intervals following bone marrow transplantation (BMT). In chimeric mice, almost all spleen cells and peritoneal macrophages showed donor H-2 haplotype within 2 weeks after BMT. The differentiation and maturation of B lymphocytes and macrophages was largely complete by 2 weeks following BMT, whereas T cell functions such as Con A responsiveness and alloreactivity were not restored within 4 weeks. Newly developed T cells were found to be exclusively of donor origin but were tolerant of both donor type and host type major histocompatibility complex (MHC) determinants in assays of mixed lymphocyte reactions and capacity to generate cytotoxic T lymphocytes. Fully allogeneic chimeric mice survived up to one year after bone marrow transplantation without significant reactions or serious diseases. Neither graft-versus-host reaction (GVHR), host-versus-graft reaction (HVGR), nor the wasting diseases described. As compared to age-matched control mice, such fully allogeneic chimeras exhibited one year following BMT somewhat reduced but quite significant plaque forming cell responses to in vitro stimulation with a T-dependent antigen, SRBC. These findings suggest that BMT across MHC barriers may ultimately be useful in humans if all manifestations of GVHR are eliminated by completely removing all T cells from the bone marrow and if all hematopoietic resistance and all aspects of HVGR are eliminated by using sufficient immunosuppression and myeloablation.

Animals↗

PubMed1980

Autoimmunity induced by syngeneic splenocyte membranes carrying irreversibly adsorbed paramyxovirus.

Newcastle disease virus was adsorbed to a membrane fraction prepared from splenocytes, and the resulting preparation was injected into syngeneic C3H mice. Complement fixing and cytotoxic antibodies reactive with syngeneic tissue and intact cells developed, and some mice died with autoimmune disease characterized by wasting, severe kidney damage, and loss of lymphoid tissue as described previously for animals receiving the membrane fraction of a syngeneic lymphoma in which Newcastle disease virus had grown. Similar experiments were done with L929 mouse fibroblasts and allogeneic spleen membrane fractions. With syngeneic spleen tissue and L929 fibroblasts, serological evidence of autoimmunity appeared after several injections, but deaths from autoimmunity were considerably delayed unless Freund's complete adjuvant was given with the antigen. The results suggest that antigen modification occurs after adsorption of the paramyxovirus to normal tissue as well as lymphoma cell membranes.

Adsorption↗

PubMed2001

Molecular identification of food-borne and water-borne protozoa.

Cryptosporidium and Giardia can be transmitted to humans by contaminated food and water, resulting in large outbreaks of diarrheal disease. Sensitive methods for detecting these parasites are needed to control and prevent infection. However, this issue is complicated by the fact that there is still uncertainty about the role played by different species/genotypes with respect to human disease. We are in the process of collecting samples from clinical cases (both sporadic and outbreak-related human infections) and from the environment (tap and waste water samples from different geographic regions), to test the efficacy of methods for detection and genotyping. Concerning Cryptosporidium parvum, we have developed new genotyping methods based on highly polymorphic microsatellite markers. The use of microsatellite markers allows the route of transmission to be traced; these methods can also be used not only to distinguish between anthroponotic and zoonotic transmission but also to identify the source(s) of infection. Regarding Giardia, which was found very frequently in environmental water samples, we are testing the beta-giardin gene as a marker to discriminate among species/genotypes.

Animals↗

PubMed1992

MRL/lpr-->severe combined immunodeficiency mouse allografts produce autoantibodies, acute graft-versus-host disease or a wasting syndrome depending on the source of cells.

MRL/lpr (lpr) mice spontaneously develop a lupus-like illness as well as massive lymphadenopathy. Attempts to transfer autoimmunity by adoptive transfer or radiation bone marrow chimeras have been unsuccessful. Since severe combined immunodeficiency (SCID) mice have been engrafted with human and rat xenografts without apparent graft-versus-host disease (GVHD), we subjected SCID mice to low-dose irradiation and reconstituted the mice with spleen cells from young or old lpr mice or with lpr bone marrow. Fourteen out of twenty (70%) of SCID mice engrafted with spleen cells from old lpr mice produced autoantibodies (anti-DNA and anti-Sm) without evidence of the severe lymphoid atrophy previously described for lpr spleen-->+/+ chimeras. SCID mice engrafted with spleen cells from young lpr mice developed acute GVHD and 5/6 (83%) died within 4 weeks post-transfer. Although 8/11 (73%) of lpr-->SCID bone marrow allografts survived for at least 4 months, these mice developed a wasting disease characterized by lymphoid atrophy and fibrosis without the production of autoantibodies. None of the lpr-->SCID grafts resulted in the transfer of double negative T cells or the lymphoproliferative syndrome characteristic of MRL/lpr mice. These findings indicate that SCID mice can be engrafted with splenocytes from old MRL/lpr mice and that B cells continue to secrete autoantibodies for several months in the SCID recipients. This study also demonstrates that, unlike i.p. transplant of xenogeneic cells, acute GVHD is a consistent feature of i.p. transplants of normal allogeneic mononuclear cells into SCID mice.

Animals↗

PubMed2001

Dystrophin in adult zebrafish muscle.

Mutations in the human dystrophin gene are implicated in the fatal muscle wasting disease Duchenne Muscular Dystrophy (DMD). This gene expresses a sarcolemmal-associated protein that is evolutionarily conserved, underpinning its important role in the architecture of muscle. In terms of DMD modelling, the mouse has served as a suitable vertebrate species but the pathophysiology of the disease in the mouse does not entirely mimic human DMD. We have examined the zebrafish in order to expand the repertoire of vertebrate species for muscle disease modelling, and to dissect further the functional interactions of dystrophin. We report here the identification of an apparent zebrafish orthologue of the human dystrophin gene that expresses a 400-kDa protein that is localised to the muscle membrane surface. These data suggest that the zebrafish may prove to be a beneficial vertebrate model to examine the role and functional interactions of dystrophin in disease and development.

Amino Acid Sequence↗

PubMed1994

Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked recessive disorder characterized by slowly progressing contractures, wasting of skeletal muscle and cardiomyopathy. Heart block is a frequent cause of death. The disease gene has been mapped to distal Xq28. Among many genes in this region, we selected eight transcripts expressed at high levels in skeletal muscle, heart and/or brain as the best candidates for the disease. We now report, in all five patients studied, unique mutations in one of the genes, STA: these mutations result in the loss of all or part of the protein. The EDMD gene encodes a novel serine-rich protein termed emerin, which contains a 20 amino acid hydrophobic domain at the C terminus, similar to that described for many membrane proteins of the secretory pathway involved in vesicular transport.

Amino Acid Sequence↗

PubMed1995

Molecular basis of human 3 beta-hydroxysteroid dehydrogenase deficiency.

The enzyme 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) catalyses an essential step in the biosynthesis of all classes of steroid hormones. Classical 3 beta-HSD deficiency is responsible for CAHII, a severe form of congenital adrenal hyperplasia (CAH) that impairs steroidogenesis in both the adrenals and gonads. Newborns affected by 3 beta-HSD deficiency exhibit signs and symptoms of adrenal insufficiency of varying degrees associated with pseudohermaphroditism in males, whereas females exhibit normal sexual differentiation or mild virilization. Elevated ratios of 5-ene-to 4-ene-steroids appear as the best biological parameter for the diagnosis of 3 beta-HSD deficiency. The nonclassical form has been suggested to be related to an allelic variant of the classical form of 3 beta-HSD as described for steroid 21-hydroxylase deficiency. To elucidate the molecular basis of the classical form of 3 beta-HSD deficiency, we have analysed the structure of the highly homologous type I and II 3 beta-HSD genes in 12 male pseudohermaphrodite 3 beta-HSD deficient patients as well as in four female patients. The 14 different point mutations characterized were all detected in the type II 3 beta-HSD gene, which is the gene predominantly expressed in the adrenals and gonads, while no mutation was detected in the type I 3 beta-HSD gene predominantly expressed in the placenta and peripheral tissues. The finding of a normal type I 3 beta-HSD gene provides the explanation for the intact peripheral intracrine steroidogenesis in these patients and increased androgen manifestations at puberty. The influence of the detected mutations on enzymatic activity was assessed by in vitro expression analysis of mutant enzymes generated by site-directed mutagenesis in COS-1 cells. The mutant type II 3 beta-HSD enzymes carrying mutations detected in patients affected by the salt-losing form exhibit no detectable activity in intact transfected cells, whereas those with mutations found in nonsalt-loser index cases have some residual activity ranging from approximately 1-10% compared to the wild-type enzyme. Although in general, our findings provide a molecular explanation for the enzymatic heterogeneity ranging from the severe salt-losing form to the clinically inapparent salt-wasting form of the disease, we have observed that the mutant L108W or P186L enzymes found in a compound heterozygote male presenting the salt-wasting form of the disease, has some residual activity (approximately 1%) similar to that observed for the mutant N100S enzyme detected in a homozygous male patient suffering from a nonsalt-losing form of this disorder.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Hydroxysteroid Dehydrogenases↗

PubMed1980

Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients.

This study of chronic graft-versus-host disease (GVHD) describes the clinical, pathologic and laboratory features, and the causes of morbidity and mortality in 20 patients who received allogeneic marrow transplants from HLA identical sibling donors. Chronic GVHD is a pleiotrophic syndrome with variability in the time of onset, organ systems involved and rate of progression. The clinical-pathologic features resemble an overlap of several collagen vascular diseases with frequent involvement of the skin, liver, eyes, mouth, upper respiratory tract, esophagus and less frequent involvement of the serosal surfaces, lower gastrointestinal tract and skeletal muscles. Major causes of morbidity are scleroderma with contractures and ulceration, dry eyes and mouth, pulmonary insufficiency and wasting. Chronic GVHD has features of immune dysregulation with elevated levels of eosinophils, circulating autoantibodies, hypergammaglobulinemia and plasmacytosis of viscera and lymph nodes. In this study, three patients had limited chronic GVHD with relatively favorable prognosis characterized by localized skin involvement and/or hepatic disease without chronic aggressive histology. Most patients, however, had extensive disease with a progressive course. Survival was largely determined by the presence or absence of serious recurrent bacterial infections. The over-all severity of disease was best assessed by using the Karnofsky performance rating.

Adolescent↗

PubMed1993

Altered CYP21 genes in HLA-haplotypes associated with congenital adrenal hyperplasia (CAH): a family study.

Disorders of the CYP21 gene, which is located within the major histocompatibility complex on the short arm of chromosome 6, are the leading causes of congenital adrenal hyperplasia (CAH). The coding gene and a highly homologous pseudogene are tandemly arranged with the two genes for the fourth component of complement (C4A and C4B). To analyse the prevalence rates of mutations of the CYP21 genes and the segregation of the CYP21 genes with their corresponding human leucocyte antigen (HLA)-haplotypes, 21 families with one or two children with the severe form of 21-hydroxylase deficiency were studied. Mutations of the CYP21 gene on their corresponding HLA-haplotype were detected by hybridisation of polymerase chain reaction (PCR)-amplified genomic DNA with sequence-specific oligonucleotides and solid phase direct sequencing. Our study has shown the following. (1) A single basepair mutation (A-->G or C-->G) within the second intron is the most frequent mutation leading to impaired 21-hydroxylase activity. This mutation is only detected in HLA-haplotypes associated with the salt-wasting form of CAH. (2) A large deletion of part or all of the CYP21 gene is associated with the HLA-haplotype A3, BW47, C6, DR7, DR53, DQ2 but is also observed in other HLA-haplotypes and can be detected by a simple rapid PCR restriction fragment length polymorphism method. (3) Two alleles of the coding CYP21 gene differing in a leucine codon within the first exon, (formerly described as a mutation associated with 21-hydroxylase deficiency) have been found with an equal distribution in patients with 21-hydroxylase deficiency, non-disease HLA-haplotypes and the local healthy controls.

Adrenal Hyperplasia, Congenital↗

PubMed1998

Detection of a novel strain of porcine circovirus in pigs with postweaning multisystemic wasting syndrome.

Swine infectious agents, especially viruses, are potential public health risks associated with the use of pig organs for xenotransplantation in humans. Therefore, there is a need for better characterization of swine viruses and for the development of diagnostic tests for their detection. We report here isolation of a novel strain of porcine circovirus (PCV) from pigs with postweaning multisystemic wasting syndrome (PMWS). Affected pigs exhibited severe interstitial pneumonia and lymphoid depletion. The complete nucleotide sequence (1,768 nucleotides) of the genome of the PCV isolate was determined and compared with the sequence of the PCV strain isolated from PK-15 cells. Sequence comparison revealed significant differences between the two PCV strains, with an overall DNA homology of 76%. Two major open reading frames (ORFs) were identified. ORF1 was more conserved between the two strains, with 83% nucleotide homology and 86% amino acid homology. ORF2 was more variable, with nucleotide homology of 67% and amino acid homology of 65%. PCR and in situ hybridization demonstrated abundant viral DNA in various organs of pigs with PMWS. In situ hybridization demonstrated that this strain of PCV targets multiple organs and infects macrophages, lymphocytes, endothelial cells, and epithelial cells.

Amino Acid Sequence↗

PubMed2006

Functional studies of two novel and two rare mutations in the 21-hydroxylase gene.

Congenital adrenal hyperplasia (CAH) is most commonly due to 21-hydroxylase deficiency and presents with a wide spectrum of clinical manifestations, from prenatal virilization and salt-wasting in the neonatal period to precocious pubarche and late-onset hyperandrogenic symptoms during adulthood. A limited number of mutations account for the majority of all mutated alleles, but a growing number of rare mutations are responsible for the disease in some patients. By sequence analysis of the CYP21A2 gene, we identified two novel (I171N and L446P) and two rare (R341P and R426H) mutations in seven Italian patients with CAH. One of the patients was diagnosed with mild non-classical CAH and was found to be a compound heterozygote (I171N/V281L), while all other patients showed severe phenotypes with latent or manifest salt-wasting. The residual activities measured after expression of the four mutant enzymes in COS-1 cells were all below 1% towards both natural substrates (17-OH-progesterone and progesterone) compared with the wild-type protein. All four mutations are, thus, associated with severe enzyme deficiency and are predicted to cause classic CAH if found in trans with other mutations causing severe enzyme deficiency.

17-alpha-Hydroxyprogesterone↗

PubMed2000

Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23.

Proper serum phosphate concentrations are maintained by a complex and poorly understood process. Identification of genes responsible for inherited disorders involving disturbances in phosphate homeostasis may provide insight into the pathways that regulate phosphate balance. Several hereditary disorders of isolated phosphate wasting have been described, including X-linked hypophosphataemic rickets (XLH), hypophosphataemic bone disease (HBD), hereditary hypophosphataemic rickets with hypercalciuria (HHRH) and autosomal dominant hypophosphataemic rickets (ADHR). Inactivating mutations of the gene PHEX, encoding a member of the neutral endopeptidase family of proteins, are responsible for XLH (refs 6,7). ADHR (MIM 193100) is characterized by low serum phosphorus concentrations, rickets, osteomalacia, lower extremity deformities, short stature, bone pain and dental abscesses. Here we describe a positional cloning approach used to identify the ADHR gene which included the annotation of 37 genes within 4 Mb of genomic sequence. We identified missense mutations in a gene encoding a new member of the fibroblast growth factor (FGF) family, FGF23. These mutations in patients with ADHR represent the first mutations found in a human FGF gene.

Abnormalities, Multiple↗

PubMed1994

Tarsal joint contracture in dogs with golden retriever muscular dystrophy.

Golden retriever muscular dystrophy (GRMD) is an X-linked myopathy homologous with Duchenne muscular dystrophy of human beings. Affected dogs have progressive clinical dysfunction due to muscle wasting and contractures. Deficits progress particularly rapidly between 3 and 6 months of age. To better characterize the role of contractures in this deterioration, the flexor surface, nonweight-bearing tarsal joint angle was measured in GRMD-affected dogs and clinically normal littermates at both ages. The mean +/- SD tarsal joint angle for clinically normal dogs decreased from 164.6 +/- 6.09 degrees to 145.6 +/- 8.80 degrees between 3 and 6 months (P < 0.0005). The value for GRMD-affected dogs decreased from 153.3 +/- 11.44 degrees to 117.6 +/- 24.55 degrees (P < 0.005). The angle for clinically normal dogs was greater than that for GRMD-affected dogs at both ages (P < 0.05 at 3 months and P < 0.01 at 6 months). The decrease in tarsal joint angle, at times to less than 90 degrees, correlated well with other phenotypic features of GRMD, such as loss of the ability to walk.

Animals↗

PubMed1979

Renal 'salt wasting' despite apparently normal renal, adrenal and central nervous system function.

The inability of the kidney to conserve sodium appropriately in response to a restricted sodium intake is reported in a subject who had entirely normal renal and adrenal function and no evidence of central nervous system disease. Subsequent transplantation of his left kidney to his son afforded a unique opportunity to assess renal sodium conservation in each kidney separately: both the patient and his son were unable to achieve balance in response to dietary sodium restriction after transplantation, indicating that the sodium wasting was due to a process intrinsic to both kidneys. The assessment of intrarenal hemodynamics with xenon-133 washout prior to nephrectomy provided insight into the role of intrarenal hemodynamics in the maintenance of sodium homeostasis in man. The xenon washout curve failed to disclose an identifiable second most rapid exponential (CII). This finding, in concert with previous studies demonstrating that diuretic agents with a primary action in the ascending limb of the loop of Henle caused a marked slowing of CII flow, raises the possibility that limited perfusion in the outer medulla of the kidney may be rate-limiting for sodium conservation in man.

Adrenal Glands↗

PubMed1997

Phosphate transport in renal cell cultures of gy mice: evidence of a single defect in X-linked hypophosphatemia.

Although current theory holds that the murine homologs of X-linked hypophosphatemia represent mutations of two closely linked genes with distinct pathophysiological consequences, insufficient data are available to support this hypothesis. We investigated whether an intrinsic defect in renal sodium (Na+)-dependent Pi cotransport truly distinguishes gy from hyp mice. We compared Pi transport in immortalized cells from S1 and S2 segments of the renal proximal convoluted tubule (PCT) of normal and gy mice. Cells from both murine models exhibit characteristics of differentiated PCT cells including gluconeogenesis, alkaline phosphatase activity, and parathyroid hormone (PTH)- and thyrocalcitonin (TCT)-dependent adenosine 3',5'-cyclic monophosphate production. More importantly, kinetic studies reveal that cells from the PCT of gy mice have intrinsically normal Pi transport and support the hypothesis that, as in hyp mice, a humoral abnormality is likely responsible for the renal Pi wasting in this mouse model. These observations are consistent with the conclusion that gy and hyp mice do not represent mutations of two closely linked genes but rather two separate mutations of the same gene.

Animals↗

PubMed1998

Cloning of human PEX cDNA. Expression, subcellular localization, and endopeptidase activity.

Mutations in the PEX gene are responsible for X-linked hypophosphatemic rickets. To gain insight into the role of PEX in normal physiology we have cloned the human full-length cDNA and studied its tissue expression, subcellular localization, and peptidase activity. We show that the cDNA encodes a 749-amino acid protein structurally related to a family of neutral endopeptidases that include neprilysin as prototype. By Northern blot analysis, the size of the full-length PEX transcript is 6.5 kilobases. PEX expression, as determined by semi-quantitative polymerase chain reaction, is high in bone and in tumor tissue associated with the paraneoplastic syndrome of renal phosphate wasting. PEX is glycosylated in the presence of canine microsomal membranes and partitions exclusively in the detergent phase from Triton X-114 extractions of transiently transfected COS cells. Immunofluorescence studies in A293 cells expressing PEX tagged with a c-myc epitope show a predominant cell-surface location for the protein with its COOH-terminal domain in the extracellular compartment, substantiating the assumption that PEX, like other members of the neutral endopeptidase family, is a type II integral membrane glycoprotein. Cell membranes from cultured COS cells transiently expressing PEX efficiently degrade exogenously added parathyroid hormone-derived peptides, demonstrating for the first time that recombinant PEX can function as an endopeptidase. PEX peptidase activity may provide a convenient target for pharmacological intervention in states of altered phosphate homeostasis and in metabolic bone diseases.

Adult↗

PubMed2000

Identification of Ankrd2, a novel skeletal muscle gene coding for a stretch-responsive ankyrin-repeat protein.

Mechanically induced hypertrophy of skeletal muscles involves shifts in gene expression leading to increases in the synthesis of specific proteins. Full characterization of the regulation of muscle hypertrophy is a prerequisite for the development of novel therapies aimed at treating muscle wasting (atrophy) in human aging and disease. Using suppression subtractive hybridization, cDNAs corresponding to mRNAs that increase in relative abundance in response to mechanical stretch of mouse skeletal muscles in vivo were identified. A novel 1100-bp transcript was detected exclusively in skeletal muscle. This exhibited a fourfold increase in expression after 7 days of stretch. The transcript had an open reading frame of 328 amino acids encoding an ATP/GTP binding domain, a nuclear localization signal, two PEST protein-destabilization motifs, and a 132-amino-acid ankyrin-repeat region. We have named this gene ankyrin-repeat domain 2 (stretch-responsive muscle) (Ankrd2). We hypothesize that Ankrd2 plays an important role in skeletal muscle hypertrophy.

Amino Acid Motifs↗

PubMed1988

Lymphoid cell transfers between adult C57BL/6 mice differing at the LPR locus. Lack of lymphadenopathy transfer and effects on host survival.

"1 pr" is an autosomal recessive locus which determines the lymphoproliferation of an abnormal T cell subset ("T lpr" cell subset). Though a thymus is necessary for the initiation of the lymphadenopathy, adult thymectomy does not interfere with the development of disease. C57BL/6 (B6) mice (either treated with cyclophosphamide or not), lpr heterozygous at the lpr locus, or not), and nu homozygous B6 mice (either homozygous at the lpr locus, or not) are refractory to the growth and massive proliferation of grafted cells of the aberrant T lpr cell subset, which polyclonally expands in lpr homozygous B6 mice. Their lack of expansion in B6 nu, lpr mice is surprising, since such animals may develop the lymphadenopathy under certain circumstances (thymus grafting). While the injection of normal B6 lymphoid cells does not improve the health of the B6 nu, lpr mice, but may even accelerate their wasting, the injection of B6 lpr lymphoid cells into B6 nu, lpr mice causes, after a transient wasting, a remarkable prolongation of survival. B6 nu recipients of B6 lpr lymphoid cells show no sign of wasting and survive like recipients of normal B6 (B6+) cells. Thus the "lpr type" lymphoproliferative potential is neither simply carried by the T lpr subset cells themselves, nor simply determined by the lpr environment of athymic, lpr homozygous mice, and it is also not readily reconstituted by grafting T lpr cells in athymic lpr mice.

Animals↗