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Biomedical subjects

S A Jordan

Publications and source records attributed to S A Jordan.

At least 19 recordsLinked to original sources
PubMed2001

Functional variation of MC1R alleles from red-haired individuals.

Red hair in humans is associated with variant alleles of the alphaMSH receptor gene, MC1R. Loss of MC1R function in other mammals results in red or yellow hair pigmentation. We show that a mouse bacterial artificial chromosome (BAC) which contains Mc1r will efficiently rescue loss of Mc1r in transgenic mice, and that overexpression of the receptor suppresses the effect of the endogenous antagonist, agouti protein. We engineered the BAC to replace the mouse coding region with the human MC1R sequence and used this in the transgenic assay. The human receptor also efficiently rescued Mc1r deficiency, and in addition, appeared to be completely resistant to the effects of agouti, suggesting agouti protein may not play a role in human pigmentary variation. Three human variant alleles account for 60% of all cases of red hair. We engineered each of these in turn into the BAC and find that they have reduced, but not completely absent, function in transgenic mice. Comparison of the phenotypes of alphaMSH-deficient mice and humans in conjunction with this data suggests that red hair may not be the null phenotype of MC1R.

Alleles↗
PubMed2000

MGF (KIT ligand) is a chemokinetic factor for melanoblast migration into hair follicles.

Melanoblasts, the precursors of the pigment-producing cells of the skin and hair, are derived from the neural crest and migrate to the skin around 12 days of gestation in the mouse. In adult mice almost all the melanoblasts are confined to the hair follicles except for the epidermal layers of nonhairy skin. The receptor tyrosine kinase, KIT, is necessary for the survival, proliferation, and migration of melanoblasts. We have utilised an organ culture for embryonic skin taken from Dct-lacZ transgenic mice. The early patterning of the follicles and developing skin layers is retained within the cultures and the lacZ reporter allows visualisation of the melanoblasts within their native tissue environment. Soon after initiation of hair follicle development, melanoblasts localise in the follicles. Inhibition of follicle formation demonstrates that this localisation is an active process; in the absence of follicles, the melanoblasts proliferate but remain associated with the basement membrane. Implantation of beads releasing MGF, the ligand of KIT, does not result in melanoblast migration towards the bead, rather their localisation to the follicles is accelerated. Addition of soluble MGF induces the same effect; KIT therefore promotes melanocyte movement and acts as a chemokinetic, or motogenic, receptor. The melanoblasts must be guided to their correct location by other chemotactic signals or move at random and locate by ceasing movement when the follicle is engaged.

Animals↗
PubMed2000

Melanocortin 1 receptor variation in the domestic dog.

The melanocortin 1 receptor (Mc1r) is encoded by the Extension locus in many different mammals, where a loss-of-function causes exclusive production of red/yellow pheomelanin, and a constitutively activating mutation causes exclusive production of black/brown eumelanin. In the domestic dog, breeds with a wild-type E allele, e. g., the Doberman, can produce either pigment type, whereas breeds with the e allele, e.g., the Golden Retriever, produce exclusively yellow pigment. However, a black coat color in the Newfoundland and similar breeds is thought to be caused by an unusual allele of Agouti, which encodes the physiologic ligand for the Mc1r. Here we report that the predicted dog Mc1r is 317 residues in length and 96% identical to the fox Mc1r. Comparison of the Doberman, Newfoundland, Black Labrador, Yellow Labrador, Flat-coated Retriever, Irish Setter, and Golden Retriever revealed six sequence variants, of which two, S90G and R306ter, partially correlated with a black/brown coat and red/yellow coat, respectively. R306ter was found in the Yellow Labrador, Golden Retriever, and Irish Setter; the latter two had identical haplotypes but differed from the Yellow Labrador at three positions other than R306ter. In a larger survey of 194 dogs and 19 breeds, R306ter and a red/yellow coat were completely concordant except for the Red Chow. These results indicate that the e allele is caused by a common Mc1r loss-of-function mutation that either reoccurred or was subject to gene conversion during recent evolutionary history, and suggest that the allelic and locus relationships for dog coat color genes may be more analogous to those found in other mammals than previously thought.

Alleles↗
PubMed2000

A comparative transcript map and candidates for mutant phenotypes in the Tyrp1 (brown) deletion complex homologous to human 9p21-23.

The mouse Tyrp1 deletion complex is a valuable resource for high-resolution mapping of genes and phenotypes to the central region of Chromosome (Chr) 4. The distal part of the complex is homologous to human Chr 9p21-23, and we have used the available radiation hybrid maps to identify human transcripts in the region. We localize seven genes to a human YAC contig that spans the full extent of the distal deletion complex and show that the mouse homologs of four of these, including Cer1, map within the complex. On the basis of location and/or expression, we exclude genes as candidates for several known phenotypes in the region and identify a candidate transcript for the neonatal lethal phenotype l(4)Rn2.

Animals↗
PubMed2000

A late wave of melanoblast differentiation and rostrocaudal migration revealed in patch and rump-white embryos.

Melanocytes originate from a small number of precursors localized either side of the dorsal midline. The tyrosine kinase receptor Kit and its ligand Mgf (Steel Factor) are essential for melanoblast survival and proliferation during their migration from the neural crest. Inappropriate Kit expression in the dermatome and dermis of patch and rump-white mouse mutants apparently sequester Mgf, inhibiting melanoblast dispersal. Using a reporter transgene Dct-lacZ, extensive regions of the mutant trunks appear devoid of melanoblasts between E12.5 and E15.5, a much larger area than seen in mutant adults. Melanoblast recolonization of the underpopulated lumbar regions occurs very rapidly by E16.5 giving rise to patterns consistent with those observed in adults. The mutations permit observation of aspects of melanoblast development that are not seen, or are obscured, in normal embryos.

Animals↗
PubMed1999

Deficiency of Trp53 rescues the male fertility defects of Kit(W-v) mice but has no effect on the survival of melanocytes and mast cells.

Mutations of the receptor tyrosine kinase, Kit, or its ligand, mast growth factor (Mgf), affect three unrelated cell populations: melanocytes, germ cells, and mast cells. Kit signaling is required initially to prevent cell death in these lineages both in vitro and in vivo. Mgf appears to play a role in the survival of some hematopoietic cells in vitro by modulating the activity of p53. Signaling by Mgf inhibits p53-induced apoptosis of erythroleukemia cell lines and suppresses p53-dependent radiation-induced apoptosis of bone marrow cells. We tested the hypothesis that cell survival in Kit mutant mice would be enhanced by p53 deficiency in vivo. Double-mutant mice, which have greatly reduced Kit receptor tyrosine kinase activity and also lack Trp53, were generated and the affected cell lineages examined. Mast cell, melanoblast, and melanocyte survival in the double Kit(W-v/W-v):Trp53(-/-) mutants was not increased compared to the single Kit(W-v/W-v):Trp53(+/+) mutants. However, double-mutant males showed an increase in sperm viability and could father litters, in contrast to their homozygous Kit mutant, wild-type p53 littermates. This germ cell rescue appears to be male specific, as female ovaries were similar in mice homozygous for the Kit mutant allele with or without p53. We conclude that defective Kit signaling in vivo results in apoptosis by a p53-independent pathway in melanocyte and mast cell lineages but that in male germ cells apoptosis in the absence of Kit is p53-dependent.

Animals↗
PubMed1999

The mouse Cer1 (Cerberus related or homologue) gene is not required for anterior pattern formation.

Cer1 is the mouse homologue of the Xenopus Cerberus gene whose product is able to induce development of head structures during embryonic development. The Cer1 protein is a member of the cysteine knot superfamily and is expressed in anterior regions of the mouse gastrula. A segmental pattern of expression with nascent and newly formed somites is also seen. This suggests an additional role in development of the axial skeleton, musculature, or peripheral nervous system. Xenopus animal cap assays and mouse germ-layer explant recombination experiments indicate that the mouse protein can act as a patterning molecule for anterior development in Xenopus, including induction of Otx2 expression, and suggest it may have a similar role in mouse development. However, we present here genetic data that demonstrate that Cer1 is not necessary for anterior patterning, Otx2 expression, somite formation, or even normal mouse morphogenesis.

Animals↗
PubMed1999

Protection against chronic cadmium toxicity by caloric restriction.

Exposure to cadmium (Cd) can result in nephrotoxicity and osteotoxicity. Because Cd-induced nephrotoxicity involves oxidative stress and caloric restriction decreases oxidative stress, we examined whether reduced caloric intake will protect against Cd-induced nephrotoxicity. In addition, the protection against the osteotoxicity was also examined. Male and female Sprague-Dawley rats were provided drinking water containing 100 mg Cd/l. Since fluid intake relative to the body weight was higher in females as compared to the males, the Cd concentration in their water was reduced to 80 mg/l after 3 months and 65 mg/l after 6.5 months. During the 27 month exposure period the males and females consumed a total of about 5 g Cd/kg body weight. Food was restricted to 20 g/day after the first 3 months. During the unrestricted food intake period Cd exposure reduced the bone density in females by 23%, with a partial recovery and stabilization during the caloric restriction phase. Hepatic and renal Cd accumulation and corresponding metallothionein (MT) levels were very similar in both sexes. The reported critical Cd concentration for nephrotoxicity was reached by 9 months. Renal MT levels were maximum at this time. Despite a 1.5-fold increase in renal Cd concentration over the next 18 months, there was no significant increase in renal MT levels. In spite of high renal Cd levels and lack of availability of sufficient MT, there was no sign of nephrotoxicity, as measured by urinary protein and glucose excretion. It is concluded that caloric restriction prevents Cd-induced nephrotoxicity and also appears to control the osteotoxicity of Cd.

Animals↗
PubMed1999

PCB congener patterns in rats consuming diets containing Great Lakes salmon: analysis of fish, diets, and adipose tissue.

As part of a multidisciplinary toxicological investigation into Great Lakes contaminants, chinook salmon were collected from Lake Huron (LH) and Lake Ontario (LO) and incorporated (as lyophilized fillets) into standard rat diets as 20 or 100% of the protein complement (5 or 20%, w/w diet-LH5, LH20, LO5, and LO20 diets). Final PCB concentrations in the experiment ranged from 3.15 ng/g in the control diet to 1080 ng/g in the high-dose (20%) LO diet, with maximal estimated daily consumption by the rats of 82microg PCBs/kg body wt in the LO20 dietary group. Seventeen PCB congeners, PCB 85, 99, 101, 105, 110, 118, 128, 129, 132, 138, 149, 153, 170, 177, 180, 187, and 199, occurred at >/=3.0% of the total PCBs in the fish with no major site differences. Cumulatively, these 17 congeners accounted for up to 75% of the total PCBs in the fish compared to 44 and 54% in two commercial Aroclors, 1254 and 1260, respectively. PCB 77 was the major "dioxin-like" congener in the fish, followed by PCB 126 and then PCB 169. All major dietary congeners bioaccumulated in the adipose tissue of the rats with the exception of PCB congeners 101, 110, 132, and 149. The group of 17 major congeners accounted for up to 71% of the total PCBs in adipose tissue samples collected from the rats following up to 19 weeks of diet ingestion. Of the coplanar PCB congeners, PCB 77 appeared to bioaccumulate to a lesser extent compared to PCBs 126 and 169. When comparing PCBs in the rat adipose tissue to PCB congeners in Canadian breast milk, PCBs 44, 49, 74, and 137 tended to occur in higher amounts in the human samples (contributing together 18.4 vs. 1.4% of the total PCB concentration), whereas PCB 129 occurred at higher levels in the rats (3.4 vs. 0.3% of the total PCB concentration, respectively). Although adipose tissue from the rats fed diets containing Great Lakes salmon had up to two orders of magnitude higher concentrations of PCBs compared to average human values, with the exception of some lower chlorinated congeners, similar major congeners tended to be present in both the rats in the present study and humans.

Adipose Tissue↗
PubMed1998

Melanocortin receptors and antagonists regulate pigmentation and body weight.

The action two genetic loci--agouti and the melanocortin receptor-1 (Mc1r)-- have opposing effects in the control of mammalian pigmentation and ultimately determine the color of the pigment produced. In a recent paper, Ollmann et al. confirmed that the agouti protein acts via the Mc1r. They show that high-affinity binding of the agouti protein to Mc1r expressed in mammalian cells can be inhibited by the receptor's natural ligand, alpha-melanocyte-stimulating hormone (alpha-MSH). In addition, genetic studies using mice carrying mutations at the Mc1r and agouti loci on a sensitized background of low tyrosinase expression confirm that a functional Mc1r is required for the maximum pigmentary effect of agouti. Thus, the Mc1r appears to be a unique, bifunctionally controlled receptor, activated by alpha-MSH and antagonized by agouti, both of which contribute to the variability seen in mammalian coat color.

Agouti Signaling Protein↗
PubMed1998

Dietary and tissue residue analysis and contaminant intake estimations in rats consuming diets composed of Great Lakes salmon: a multigeneration study.

To further characterize the toxicological risk associated with chemical contaminants in Great Lakes fish, a multigeneration rat reproduction study was designed. Mature chinook salmon (Oncorhynchus tsawytscha), collected during the Fall 1991 spawning runs from Sydenham River, Lake Huron, and Credit River, Lake Ontario, were filleted, lyophilized, and incorporated into standard rat diets at 25% (w/w) or 100% (w/w) of the normal protein compliment [casein, 20% (w/w)]. This resulted in diets composed of 5 or 20% (w/w) lyophilized fish and estimated daily fish intakes by the rats at levels approximately 15- and 60-fold greater, respectively, than the current estimate for the Canadian public for all fish and seafood. Both fresh and lyophilized fish were analyzed for the following groups of contaminants: halogenated aromatic hydrocarbons [polychlorinated biphenyls, dibenzodioxins, and dibenzofurans (PCBs, PCDDs, PCDFs)], polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides, metals, volatile organics, and other extractable organics (chlorinated phenols and benzenes). In general, only minor site differences existed for the specific types of contaminants detected; however, fish from the Credit River contained slightly greater amounts of PCBs (2- to 3-fold), dioxin toxic equivalencies (TCDD TEQs; 1.5- to 2.0-fold), DDT and metabolites (1. 5-fold), and appreciably higher amounts of mirex (15-fold). This general pattern of contaminant differences continued when the various diets were prepared using the lyophilized fish. Tissue samples (adipose, liver) were taken from the animals at various stages of the study and also analyzed for the same groups of contaminants. In general, adipose tissue was the major reservoir for organochlorine (OC) pesticides and PCBs, while "dioxin-like" PCDD/DF congeners and mercury were found preferentially in the liver. Contaminant intake calculations and tissue residue levels are provided.

Adipose Tissue↗
PubMed1998

Neurobehavioral effects of chronic ingestion of Great Lakes chinook salmon.

Cross-generational chronic feeding of either a 5 or a 20% lyophilized Lake Huron (LH) or Lake Ontario (LO) chinook salmon diet to rats caused no observable effects on many behavioral dimensions including activity, exploration, sensorimotor function, and stereotypy. As assessed by the Morris water maze and the radial arm maze, there was no diet-induced impairment of spatial learning or long-term memory. There was no evidence that the fish diets caused an exaggerated response to food reward reduction as had been observed previously for rats fed Oswego area Lake Ontario salmon. Effects of the fish diets with the exception of one statistically significant but probably meaningless effect on the Morris water maze for females were found only for male rats and only for males who ate the 20% diet. F1 male rats were reluctant to traverse a runway for a single pellet reward. Performance of the reference/working memory version of the radial arm maze was affected for the F1 LO-20 rats and for the F2 LH-20 rats. Until further research is conducted it would be unwise to ignore indications that male rats may show some effect of chronic consumption of the highest concentration of these diets, particularly on tasks that require intact frontocortical dopamine function.

Analysis of Variance↗
PubMed1998

The health Canada Great Lakes multigeneration study--summary and regulatory considerations.

The Health Canada Multigeneration Study was initiated to determine the consequences in rodents consuming diets containing Lake Ontario (LO) or Lake Huron (LH) chinook salmon over successive generations. Following lyophilization, the contaminant levels in the salmon used in the formulation of the diets for this study exceeded a number of tolerances or guidelines established for contaminants in commercial fish and seafood products (PCBs, dioxin, mirex, chlordanes, mercury). Consumption of the fish diets by rats of two consecutive generations resulted in a variety of effects that can be described as adaptive responses or of limited biological significance. The two exceptions to this were (1) the suggestion of modification of working and reference memory in males of the high-dose groups 20% fish diets, which may have been related to decreases noted in neurotransmitters in several brain regions in these rats; and (2) an effect on thymus weights noted in the high-dose first generation (F1) reversibility study animals and an overall effect on T-helper/inducer lymphocyte subset numbers in the second generation (F2) male rats fed the LH diets compared to the LO diets. Relatively minor effects were observed in the rats consuming the 5% fish diets from either Great Lakes location (LH-5, LH-5), although their fish intake was approximately 16-fold greater on a daily basis than the average angler consuming Great Lakes sport fish (compared to a 60-fold greater intake in the 20% diet groups: LH-20, LO-20). Based on these study results with rats it would appear that for the average consumer of Great Lakes sports fish, the risk presented by the complex mixture of contaminants in chinook salmon collected from these two locations in the Great Lakes basin could be considered minimal, especially if sport fish consumption advisories are followed.

Animal Feed↗
PubMed1997

Activation of the receptor tyrosine kinase Kit is required for the proliferation of melanoblasts in the mouse embryo.

The development of neural crest-derived melanocytes, as well as haematopoietic and germ cells, is affected by mutations of the Kit and Mgf genes, which lead to dominant spotting (W) or steel (Sl) phenotypes. Mgf codes for the ligand of the receptor tyrosine kinase encoded by the Kit locus. KitW-v, a point mutation exerting a dominant negative effect, causes a substantial reduction in tyrosine kinase activity of the Kit receptor and leads to a characteristic pigmentation phenotype, namely dilute coat colour and a white ventral and head spot with reduced pigmentation of the feet and tail in the heterozygous animal, as well as slight anaemia. Homozygous animals lack coat pigmentation and are severely anaemic and infertile. Dct is a marker for cells of the melanoblast lineage. In order to study these cells in detail we have generated transgenic mouse lines carrying the lacZ reporter under the control of the Dct promoter and have used the embryonic expression of the reporter to identify early melanoblasts before they begin to produce pigment. Our transgenic lines have simplified the study of melanoblasts in the mouse embryo, and by crossing our mice with KitW-v mutants we have been able to identify the midgestation stages at which melanoblasts rely critically on Mgf/Kit interactions. We conclude that the survival of immature melanoblasts depends crucially upon Kit signalling up until E11, and later in development Kit plays a vital role in melanoblast proliferation. Our data do not describe a dependence upon Kit for melanoblast migration or differentiation.

Animals↗
PubMed1996

Three keratin gene mutations account for the majority of dominant simplex epidermolysis bullosa cases within the population of Ireland.

We have located three extended families in Ireland (population 3.5 million) with autosomal dominant simplex forms of Epidermolysis Bullosa (EBS). A mutation within the keratin type I (K14) gene (Met-->272-->Arg) in one family suffering from the generalized simplex (Koebner) form of the disease has been previously described (Humphries et al., Hum Mutat 2:37-42, 1993). Here we report on the identification of mutations within the remaining two families, both of whom suffer from the Weber-Cockayne form of the disease. These mutations, within the type II keratin (K5) gene, are Asn-->193-->Lys and Met-->327-->Thr. They have been shown in each case to co-segregate with the disease and are not present in the normal population. Within the three families, a total of 44 living persons with such mutations have been identified, providing a minimum prevalence estimate for the disease in the Irish population of approximately 1 in 80,000, compared to an overall estimated global incidence at birth for all forms of EB of 1 in 50,000. Therefore, these three mutations probably account for the majority of cases of EBS within this population.

Amino Acid Sequence↗
PubMed1996

Mapping the RP10 locus for autosomal dominant retinitis pigmentosa on 7q: refined genetic positioning and localization within a well-defined YAC contig.

Retinitis pigmentosa is a genetically heterogeneous disease that has autosomal dominant, autosomal recessive and X-linked forms. Autosomal dominant retinitis pigmentosa (adRP) has thus far been associated with eight distinct loci, including the rhodopsin and peripherin/RDS genes as well as unidentified genes on chromosomes 7p, 7q, 8q, 17p, 17q, and 19q. The RP10 locus for adRP on chromosome 7q was first mapped in a Spanish family; later, an unrelated American family was identified that also showed linkage to 7q. By combining the linkage results from both families, we are able to assign the disease gene to a 5-cM interval on 7q. Based on extensive physical mapping of this region, the genetic interval is now fully contained within a approximately 5-Mb segment on a well-defined YAC contig. These studies significantly reduce the size of the RP10 critical region, exclude a number of possible candidate genes, and provide the necessary cloned DNA for the positional cloning of the RP10 gene.

Base Sequence↗
PubMed1994

The human serum amyloid A protein (SAA) superfamily gene cluster: mapping to chromosome 11p15.1 by physical and genetic linkage analysis.

The human serum amyloid A protein (SAA) family comprises a number of small, hepatically produced, differentially expressed apolipoproteins encoded by genes localized on the short arm of chromosome 11.SAA1 and SAA2 are highly related genes that together encode the acute-phase SAAs; SAA3 is a pseudogene; and SAA4 is a low-level constitutively expressed gene encoding constitutive SAA. We have used a combination of physical and genetic mapping techniques to provide evidence that the SAA gene superfamily comprises a cluster of closely linked genes localized to 11p15.1. Pulsed-field gel electrophoresis placed SAA1 to within 350 kb of the previously linked SAA2 and SAA4 genes. SAA locus-specific polymerase chain reaction amplification from a panel of somatic cell hybrids carrying defined regions of chromosome 11p mapped all four loci to 11p15.1-pter. Fluorescence in situ hybridization analysis using a cosmid probe carrying the SAA2 and SAA4 genes refined the localization of these genes (and SAA1) to 11p15.1. To order SAA3 on the genetic map, a highly polymorphic (CA)n dinucleotide repeat within SAA3 was typed through the CEPH reference families. In accordance with the physical localization of SAAs 1, 2, and 4, SAA3 maps to the 11p15.1 region proximal to the parathyroid hormone (PTH) locus (theta = 0.02; lod = 12.020) and distal to D11S455 (theta = 0.058, lod = 8.274). To provide further evidence of an SAA superfamily gene cluster, an NcoI restriction fragment length polymorphism in the SAA2 gene was also typed through the CEPH reference panel.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromosome Mapping↗