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PubMed2005

Autosomal dominant hereditary spastic paraplegia: DHPLC-based mutation analysis of SPG4 reveals eleven novel mutations.

We set up a new denaturing high-performance liquid chromatography (DHPLC)-based protocol to screen patients with autosomal dominant hereditary spastic paraplegia (AD-HSP) for mutations in SPG4. Six patients had a complicated form and 49 a pure HSP phenotype. We also analyzed 19 unrelated patients presenting with an HSP phenotype (pure in 17 and complicated in two subjects) but no clear family history, as such patients may be cases of dominant inheritance with low penetrance. The overall frequency of SPG4 mutations in our study of HSP (in which prior linkage data were unavailable) was 32.4%, rising to 46.9% when only pure AD-HSP patients were considered. This figure falls well within the range reported in different populations. Rather as expected, the clinical data available for the patients did not support an easy genotype-phenotype correlation. Moreover, the clinical picture was not influenced by the length of the predicted residual gene product. As well as identifying novel variants in SPG4, this study constitutes the molecular characterization of the largest cohort of Italian AD-HSP patients studied to date. In addition, it provided an efficient, cost-effective, and reliable detection protocol for mutational screening of SPG4, which might facilitate medical genetic counseling.

Adenosine Triphosphatases↗

PubMed1984

Occupational formaldehyde exposure and increased nasal cancer risk in man.

A comprehensive data linkage system for the detailed investigation of occupational cancer has newly been established in the Danish Cancer Registry, providing employment histories back until 1964. Based on this system a study of 839 cases of cancer of the nasal cavities, sinuses and rhinopharnyx and 2,465 cancer controls diagnosed in Denmark during the period 1970-1982 was conducted. Histories of exposure to formaldehyde, wood-dust and 10 other specified compounds or procedures, were assessed by industrial hygienists unaware of the case-control status of the cancer patients under study. Some 4.2% of the male and 0.1% of the female controls had been exposed to formaldehyde. A statistically significant excess risk (p less than 0.05) for carcinoma of the nasal cavity and sinuses among males with a history of exposure to formaldehyde (RR = 2.8), wood-dust (RR = 2.5) and paint lacquer and glue (RR = 2.1) was found. When adjustment was made for wood-dust exposure the relative risk associated with formaldehyde was reduced to 1.6, which is not significantly in excess of 1.0, although still compatible with a 3- to 4-fold increase in risk using conventional 95% confidence limits. The joint action of exposure to wood-dust and formaldehyde was in accordance with an additive effect. The excess risk of sino-nasal cancer with exposure to paint, lacquer and glue remained statistically elevated after adjustment for contemporary exposure to wood-dust and formaldehyde.

Air Pollutants, Occupational↗

PubMed1994

Intake of fried meat and risk of cancer: a follow-up study in Finland.

It has been suggested that mutagens in fried meat may be involved in the cancer process. Therefore the relationships between intake of fried meat and subsequent risk of cancers at different sites were studied among 9,990 Finnish men and women, 15-99 years of age and initially free of cancer. The baseline study was carried out in 1966-1972, and cases of cancer were identified through data linkage with the Finnish Cancer Registry. During a 24-year follow-up, 853 cancer cases were diagnosed. The intake of fried meat was estimated from a dietary history interview covering the total diet of the participants during the previous year. There was a positive association between fried meat intake and the risk of female-hormone-related cancers, i.e., cancer of the breast, endometrium and ovary combined. The relative risk of these cancers combined between persons in the highest and lowest tertiles of daily intake of fried meat adjusted for age, personal characteristics and intake of other main food groups was 1.77 (95% confidence interval = 1.11-2.84). Pancreatic and nervous system cancers also presented non-significant suggestive associations. No associations were observed with respect to other single cancer sites studied or to all sites of cancer combined. Further epidemiological efforts are needed to ascertain the potential link between fried-food mutagens and cancer risk.

Adolescent↗

PubMed1990

An interspersed repeated sequence specific for human subtelomeric regions.

A family of DNA loci (DNF28) from the pseudoautosomal region of the human sex chromosomes is characterized by a repeated element (STIR: subtelomeric interspersed repeat) which detects homologous sequences in the telomeric regions of human autosomes by in situ hybridization. Several STIR elements from both the pseudoautosomal region and terminal parts of autosomes were cloned and sequenced. A conserved 350 bp sequence and some characteristic structural differences between the autosomal and pseudoautosomal STIRs were observed. Screening of the DNA sequence databases with a consensus sequence revealed the presence of STIRs in several human loci localized in the terminal parts of different chromosomes. We mapped single copy probes flanking the cloned autosomal STIRs to the subtelomeric parts of six different chromosomes by in situ hybridization and genetic linkage analysis. The linkage data show a greatly increased recombination frequency in the subtelomeric regions of the chromosomes, especially in male meiosis. The STIR elements, specifically located in subtelomeric regions, could play a role in the peculiar recombination properties of these chromosomal regions, e.g. by promoting initiation of pairing at meiosis.

Amino Acid Sequence↗

PubMed2001

Structural study on the carbohydrate moiety of calf intestinal alkaline phosphatase.

Surprisingly alkaline phosphatase (AP) (EC 3.1.3.1) of calf intestine is found in large amounts, e.g. 80%, within chyme. Most of the enzyme is present as a mixture of four differently hydrophobic anchor-bearing forms and only the minor part is present as an anchorless enzyme. To investigate whether changes in the N-glycosylation pattern are signals responsible for large-scale liberation from mucosa into chyme, the glycans of the two potential glycosylation sites predicted from cDNA were investigated by matrix-assisted laser desorption/ionization and electrospray ionization mass spectrometry in combination with exoglycosidase treatment after tryptic digestion and reversed-phase chromatography. The glycans linked to Asn249 are at least eight different, mainly non-fucosylated, biantennary or triantennary structures with a bisecting N-acetylglucosamine. For the most abundant glycopeptide (40%) the following glycan structure is proposed: [carbostructure: see text]. The glycans linked to Asn410 are a mixture of at least nine, mainly tetraantennary, fucosylated structures with a bisecting N-acetylglucosamine. For the most abundant glycopeptide (35%) the following glycan structure is proposed: [carbostructure: see text]. For the structures the linkage data were deduced from the reported specificities of the exoglycosidases used and the specificities of the transglycosidases active in biosynthesis. The majority of glycans are capped by alpha-galactose residues at their non-reducing termini. In contrast to the glycans linked to other AP isoenzymes, no sialylation was observed. Glycopeptide 'mass fingerprints' of both glycosylation sites and glycan contents do not differ between AP from mucosa and chyme. These results suggest that the observed large-scale liberation of vesicle-bound glycosylphosphatidylinositol (GPI)-anchored AP from mucosa into chyme is unlikely to be mediated by alteration of glycan structures of the AP investigated. Rather, the exocytotic vesicle formation seems to be mediated by the controlled organization of the raft structures embedding GPI-AP. (c) 2001 John Wiley & Sons, Ltd.

Alkaline Phosphatase↗

PubMed1995

Prenatal and presymptomatic diagnosis of the Marfan syndrome using fluorescence PCR and an automated sequencer.

The Marfan syndrome (MFS) is a heritable connective tissue disorder characterized by skeletal, ocular, and cardiovascular abnormalities. Defects in fibrillin, an elastin-associated microfibrillar protein, are now known to cause MFS. Since the discovery of fibrillin as the gene responsible for MFS, requests for prenatal and presymptomatic diagnosis have become common-place. Here we report the use of the polymerase chain reaction (PCR), using fluorescence labelled primers and an automated sequencer, to establish linkage data for 'molecular diagnosis'. The mistaken clinical diagnosis of MFS based on the appearance of a common cardiovascular manifestation, mitral valve prolapse, and a positive family history is also discussed.

Autoanalysis↗

PubMed1996

YAC/STS map of 9 Mb of Xq26 at 100-kb resolution, localizing 6 ESTs, 6 genes, and 32 genetic markers.

To facilitate functional analysis of the Xq26 region, the physical map has been extended across 9 Mb with 192 YACs and markers including 90 STSs (sequence-tagged sites) and 50 hybridization probes. Six genes and six ESTs are localized. In addition, 32 markers that detect polymorphism permit an integration of physical with genetic linkage data. The localizations of eight uncloned disease genes are thereby delimited on the physical map. The data also suggest a possible gradient of recombination across the cytogenetic band, with little or no recombination reported in the centromeric 3.5-4 Mb.

Base Sequence↗

PubMed1996

A novel human CCAAT/enhancer binding protein gene, C/EBPepsilon, is expressed in cells of lymphoid and myeloid lineages and is localized on chromosome 14q11.2 close to the T-cell receptor alpha/delta locus.

Members of the CsolidusEBP family of transcriptional factors have been implicated in the regulation of genes in a variety of tissues. We report here the isolation and characterization of the human C/EBPepsilon gene (CEBPE). By using low-stringency hybridization conditions and probes derived from the C/EBPalpha and C/EBPdelta genes, we have isolated overlapping genomic clones that cover almost 25 kb of the C/EBPepsilon gene locus and corresponding cDNA clones. DNA sequence analysis reveals that the gene encodes a protein highly homologous to rat CRP1. The gene was assigned to chromosome 14q11.2 by fluorescence in situ hybridization and was physically linked to the genetic marker D14S990. Based on linkage data derived from this marker, we positioned the CEBPE gene between the T-cell receptor alpha/delta locus and a cluster of four serine proteases expressed exclusively in hematopoietic cells. Expression of C/EBPepsilon was detected in Jurkat T-cell and in HL 60 promyelocytic cell lines. From a variety of normal human tissues studied, expression of mRNA was monitored only in peripheral blood mononuclear cells, tissues involved in the immune system, and ovaries. These data demonstrate that the C/EBPepsilon gene shows a restricted pattern of expression, has an intriguing chromosomal location, and suggest a possible role for the regulation of certain genes in cells of myeloid and lymphoid lineages.

Amino Acid Sequence↗

PubMed1996

Chromosomal assignment and tissue expression of CBF-C/NFY-C, the third subunit of the mammalian CCAAT-binding factor.

The mammalian CCAAT-binding factor CBF (NFY) consists of three subunits, CBF-A, CBF-B, and CBF-C. All three subunits are evolutionarily conserved and are essential for DNA binding of CBF. In this study we report the identification of human and plant homologs of CBF-C. Northern analysis revealed that, like the other two subunits, CBF-C was produced at equal levels in all rat tissues that were examined. We assigned the mouse CBF-C gene (designated Nfyc) to chromosome 4 with tight linkage to Lmyc. Our mouse linkage data suggest that the human NFYC homolog will map to 1p32.

Amino Acid Sequence↗

PubMed2001

CTLA-4-/- mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice.

The genes conferring susceptibility to autoimmune (insulin-dependent) diabetes mellitus (IDDM) are, in most cases, not defined. Among the loci so far identified as associated with murine IDDM (Idd1-19), only the nature of Idd1 has been assessed. Here we show that thymocytes and peripheral lymphocytes of the non-obese diabetic (NOD) mouse are relatively resistant to apoptosis induced by gamma-irradiation. By linkage analysis of F2 progeny mice, we map this trait to a locus on chromosome 1 containing the Idd5 diabetes susceptibility region. By the use of congenic mice, we confirm the linkage data and map this locus to a 6 cM region on proximal chromosome 1. Ctla4, being localized in this chromosomal region and mediating crucial functions in T cell biology, is a logical candidate gene in the Idd5 susceptibility region. In line with this, we demonstrate that T cells from Ctla4(-/-)deficient mice show a similar resistance to gamma-irradiation-induced apoptosis as observed in the NOD mice. This reinforces the notion that CTLA-4 contributes to the pathogenesis of autoimmune diabetes.

Abatacept↗

PubMed1992

Multiple myeloma among Danish women: employment history and workplace exposures.

To investigate the role of employment history and workplace exposures as risk factors for multiple myeloma among women, a population-based case-control study using the Danish Cancer Registry data linkage system was conducted. All cases of myeloma diagnosed in Danish women between 1970 and 1984 (1,010 cases) and 4,040 age-matched women alive at the time of case-diagnosis were identified. Industrial histories from 1964 forward were obtained from the nationwide Pension Fund for 363 cases and 1,517 controls, and the most recent occupation on the tax record was available for 607 cases and 2,596 controls. Using industry/occupational-code combinations for the cases and controls who had industry employment, Danish industrial hygienists assessed the likelihood of exposure to 47 workplace substances. An increased myeloma risk (odds ratio [OR] = 1.2, 95 percent confidence interval [CI] = 1.0-1.5) was seen for women not in the Pension Fund, but who had an occupational title coded as 'Mrs/homemaker.' Nonsignificantly elevated risks of 1.3 or greater were observed for employment in: production of agricultural products; orchards/nurseries; spinning/weaving; other textile and plastics manufacturing; hotel, entertainment, and social services industries. Elevated, but nonsignificant risks were observed for possible and probable exposure to exhaust fumes, formaldehyde, wood dust, animals or animal products, and pesticides. The strongest association with myeloma was employment in the agricultural industry (OR = 1.5, CI = 0.8-2.8), however, the number of women who worked on family farms was unknown and could not be included in this risk estimate.

Adult↗

PubMed1992

A 530kb YAC contig tightly linked to the Friedreich ataxia locus contains five CpG clusters and a new highly polymorphic microsatellite.

Friedreich ataxia (FA) is a severe autosomal recessive neurodegenerative disease. The defective gene has been previously assigned to chromosome 9q13-q21 by demonstration of tight linkage to the two independent loci D9S15 and D9S5. Linkage data indicate that FRDA is at less than 1 cM from both markers. Previous physical mapping has shown that probes defining D9S15 (MCT112) and D9S5 (26P) are less than 260 kb apart and are surrounded by at least six CpG clusters within 450 kb, which might indicate the presence of "candidate" genes for FA. We isolated and characterized a 530 kb YAC (yeast artificial chromosome) contig that contains five of the CpG clusters. The YACs were used to search for new polymorphic markers needed to map FRDA precisely with respect to the cloned segment. In particular, we found a (CA)n microsatellite polymorphism, GS4, that detects 13 alleles with a PIC value of 0.83 and allows the definition of haplotypes extending over 310 kb when used in combination with polymorphic markers at D9S5 and D9S15.

Base Sequence↗

PubMed1983

Genetic mapping: X chromosome.

Starting with the male chiasma distribution for chromosome 2, a significantly better fit is obtained to lod scores for the X chromosome if terminalization of distal chiasmata is assumed. The linkage data are not consistent with a uniform distribution of chiasmata, absence of terminalization, or restriction of terminalization to the distal band. As information about the genetic map of the X chromosome increases, the map will be freed from assumptions about chiasma distribution. At present, however, even fragmentary data on the male are useful to construct a genetic map that, by converting physical assignments to equivalent genetic recombinations, has no inconsistencies between genetic and physical map orders.

Chromosome Mapping↗

PubMed1989

Molecular characterization of a ring chromosome 14 showing that the PI locus is centromeric to the D14S1 and IGH loci.

Molecular characterization of a ring chromosome 14 was carried out in a patient with the 46,XX,r(14) karyotype. The breakpoints shown by chromosome banding were within bands p11 and q32. Using molecular probes for the immunoglobulin heavy chain (IGH), D14S1 and PI loci located at 14q32, we showed that the IGH and D14S1 loci, located at 14q32.3 and 14q32.2 respectively, were deleted on the ring chromosome 14, but that the PI locus was not. Therefore, the chromosomal break lies between PI and D14S1. These results show that the order of these chromosome 14 markers is cen-PI-D14S1-IGH, in keeping with multipoint linkage data. Further molecular characterization of ring 14 chromosomes should lead to a detailed understanding of the molecular events and clinical consequences of the gene deletion associated with such chromosomal aberrations.

Blotting, Southern↗

PubMed1992

Genetic mapping of two DNA markers, D16Ros1 and D16Ros2, flanking the mutation site in the chakragati mouse, a transgenic insertional mutant.

We present here the genetic mapping of two novel loci, D16Ros1 and D16Ros2, to mouse Chromosome (Chr) 16. The probes for these loci were genomic fragments isolated from the chakragati mouse, a behavioral mutant resulting from insertional mutagenesis during the course of making transgenic mice. D16Ros1 and D16Ros2 were first mapped by recombinant inbred (RI) strain analysis and subsequently by the analysis of 145 progeny of two interspecific backcrosses between Mus domesticus and Mus spretus. These progeny had been typed for the centromere and this allowed mapping of D16Ros1 and D16Ros2 relative to the centromere. The other markers included in this study were Prm-1, Gap43 and Sod-1. The genetic map generated spanned 47.5 cM from the centromere to Sod-1, the most distal marker mapped here. The linkage data presented here should prove useful in mapping other loci relative to the centromere of Chr 16.

Animals↗

PubMed1994

Changes in external and internal lead load in different working areas of a starter battery production plant in the period 1982 to 1991.

Our investigation was based on routine ambient and biological monitoring data in a starter battery production plant from 1982 to 1991. This retrospective longitudinal study included 134 blue collar workers in seven main production areas (casting, lead oxide production, bunker, pasting, formation, plate stacking, assembly). Over the whole period a statistically significant decrease in blood lead concentration in the whole sample, from 48.92 micrograms/dl (1982) to 22.99 micrograms/dl (1991), could be ascertained. This positive trend could also be proven for the most important production areas. The highest internal lead load was present in employees from the formation and adjoining production areas, followed by pasting, casting and assembly. In comparison to other battery factories our results are in the lower range. Furthermore, we carried out a data linkage between air and blood lead concentrations. We were able to demonstrate a decrease in external lead load in most of the production areas, but this reduction was not so distinct as that in the blood lead concentration. These results indicate the efficiency of preventive efforts in technical work protection and especially in intensive medical supervision of the exposed workers. Influencing personal hygienic behaviour and intervention at blood lead levels of 50 micrograms/dl promises the best success in worker protection.

Air Pollutants, Occupational↗

PubMed1994

Identification and genetic mapping of 151 dispersed members of 16 ribosomal protein multigene families in the mouse.

More than 150 individual members of 16 ribosomal protein multigene families were identified as DNA restriction fragments and genetically mapped. The ribosomal protein gene-related sequences are widely dispersed throughout the mouse genome. Map positions were determined by analysis of 144 progeny mice from both an interspecific (C57BL/6J x SPRET/Ei)F1 x SPRET/Ei and an intersubspecific (C57BL/6J x CAST/Ei)F1 x C57BL/6J backcross. In addition, 30 members of the multigene families encoding PGK1 ODC, and TPI, including five new loci for ODC and one new locus for TPI, were characterized and mapped. Interspecific backcross linkage data for 29 nonecotropic murine leukemia retroviruses endogenous to C57BL/6J mice are also reported. Transmission ratio distortions and recombination frequencies are compared between the two backcrosses.

Animals↗

PubMed1977

Control of anthocyanin synthesis by the C locus in maize.

Alleles at the C locus in maize include C, one of the complementary genes required for anthocyanin pigmentation in the aleurone tissue of the mature kernel; C-I, dominant inhibitor of pigmentation; and c, recessive colorless. The recessive colorless alleles can be differentiated into two distinct forms: c-p (p for positive), conditional colored, develops pigment in the light during germination; c-n (n for negative), colorless, fails to develop pigment at any time. Four-point linkage data support the differentiation of c-p (in the alleles derived from either W22 or K55 inbreds) from c-n. Light and germination conditions are both required for anthocyanin synthesis in c-p tissue, but light "induction" and germination "induction" are two separable events inasmuch as the light stimulus can be stored. The ratio between the two major pigments, cyanidin and pelargonidin, is lowered in c-p tissue relative to that in dominant colored (C) tissue for the W22 allele and background but not for the K55 allele and background. Segregation tests reveal that the difference in the cyanidin-to-pelargonidin ratio in the C and the c-p tissue of W22 background is associated with the C locus. Several properties of the C locus, including anomalous allelic functions, stage- and properties of the C locus, including anomalous allelic functions, stage- and condition-dependent anthocyanin synthesis controlled by its multiple allelic series, and tissue-specific function, suggest that C may be a regulatory locus in the control of anthocyanin synthesis in aleurone tissue.

Alleles↗