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G Sirugo

Publications and source records attributed to G Sirugo.

At least 19 recordsLinked to original sources
PubMed2006

Global distribution of a novel trinucleotide microsatellite polymorphism (ATA)n in intron 8 of the SLC11A1 gene and susceptibility to pulmonary tuberculosis.

We identified a novel trinucleotide (ATA)n repeat polymorphism in intron 8 of SLC11AI, a candidate gene for susceptibility to tuberculosis (TB) infection. We characterized the frequency of this polymorphism in 485 individuals originating from eight globally diverse human populations and compared the distribution of (ATA)n alleles in 146 adults and in 80 cord blood samples from newborns in the Gambian population. Lastly, we tested for association of this microsatellite with pulmonary TB in 318 TB cases and 146 controls in the Gambian population. We found no significant difference in frequency or distribution of alleles in adult and cord blood samples, and we found no significant association between this marker and pulmonary TB.

Case-Control Studies↗
PubMed2004

The toll-like receptor 4 Asp299Gly variant: no influence on LPS responsiveness or susceptibility to pulmonary tuberculosis in The Gambia.

SETTING: Tuberculosis (TB) remains a major cause of morbidity and mortality worldwide. Studies in a murine model of pulmonary TB have identified a role for Toll-like receptor 4 (TLR4) in the development of chronic lung infection with Mycobacterium tuberculosis. The Asp299Gly polymorphism in the human TLR4 gene is associated with in vivo hyporesponsiveness to lipopolysaccharide (LPS) in Caucasians. OBJECTIVE: To determine whether TLR4 Asp299Gly influences LPS responses or susceptibility to pulmonary TB in humans in a Gambian population sample. DESIGN: We compared whole blood monokine responses to LPS in 245 healthy blood donors stratified by TLR4 Asp299Gly genotype to assess whether this polymorphism was functional in this population. A case-control study of 640 subjects was conducted to investigate whether TLR4 Asp299Gly was associated with TB. RESULTS: LPS-induced tumour necrosis factor, interleukin-1 beta and interleukin-10 production was not influenced by TLR4 Asp299Gly genotype. There was no association between TLR4 Asp299Gly and TB. CONCLUSION: Our data suggest that TLR4 Asp299Gly has no influence on monocyte LPS responses or susceptibility to TB in Gambians and could be an ancient neutral polymorphism.

Adolescent↗
PubMed2003

A Gambian TNF haplotype matches the European HLA-A1,B8,DR3 and Chinese HLA-A33,B58,DR3 haplotypes.

Caucasians carry TNFA-308*2 in the 8.1 ancestral haplotype (AH) (HLA-A1,B8,DR3). In Gambians, TNFA-308*2 occurs without HLA-B8 or -DR3, suggesting an independent effect of TNFA-308 on disease. Hence we sought a segment of the 8.1 AH in Gambians. BAT1 (intron 10)*2 was selected as a specific marker of the haplotype and was found with TNFA-308*2 in Gambians. Samples homozygous at TNFA-308 and BAT1 (intron 10) demonstrated identity between the African TNFA-308*2 haplotype, the 8.1AH and the Asian diabetogenic 58.1AH (HLA-A33,B58,DR3) across a region spanning BAT1, ATP6G, IKBL, LTA, TNFA, LTB, LST-1 and AIF-1. Conservation of this block in geographically distinct populations suggests a common evolutionary origin and challenges current views of the role of TNFA-308*2 in disease.

Asian People↗
PubMed2000

Short tandem-repeat polymorphism/alu haplotype variation at the PLAT locus: implications for modern human origins.

Two dinucleotide short tandem-repeat polymorphisms (STRPs) and a polymorphic Alu element spanning a 22-kb region of the PLAT locus on chromosome 8p12-q11.2 were typed in 1,287-1,420 individuals originating from 30 geographically diverse human populations, as well as in 29 great apes. These data were analyzed as haplotypes consisting of each of the dinucleotide repeats and the flanking Alu insertion/deletion polymorphism. The global pattern of STRP/Alu haplotype variation and linkage disequilibrium (LD) is informative for the reconstruction of human evolutionary history. Sub-Saharan African populations have high levels of haplotype diversity within and between populations, relative to non-Africans, and have highly divergent patterns of LD. Non-African populations have both a subset of the haplotype diversity present in Africa and a distinct pattern of LD. The pattern of haplotype variation and LD observed at the PLAT locus suggests a recent common ancestry of non-African populations, from a small population originating in eastern Africa. These data indicate that, throughout much of modern human history, sub-Saharan Africa has maintained both a large effective population size and a high level of population substructure. Additionally, Papua New Guinean and Micronesian populations have rare haplotypes observed otherwise only in African populations, suggesting ancient gene flow from Africa into Papua New Guinea, as well as gene flow between Melanesian and Micronesian populations.

Africa South of the Sahara↗
PubMed2000

Functional and genomic analysis of the human mitochondrial intermediate peptidase, a putative protein partner of frataxin.

We showed recently that the yeast mitochondrial intermediate peptidase (YMIP polypeptide; gene symbol, OCT1) promotes mitochondrial iron uptake by catalyzing the maturation of iron-utilizing proteins and exacerbates the mitochondrial iron accumulation that results from loss of yeast frataxin, a mitochondrial protein required for mitochondrial iron efflux. This suggests that the human MIP (HMIP polypeptide; gene symbol MIPEP) may be one of the loci predicted to influence the clinical manifestations of Friedreich's ataxia (FRDA), an autosomal recessive neurodegenerative disease caused by lack of human frataxin. To begin to test this hypothesis, we have characterized HMIP at the functional and genomic levels. We show that HMIP can complement a yeast knock-out mutant lacking YMIP, demonstrating that HMIP and YMIP are functional homologues. The MIPEP gene spans 57 kb and consists of 19 exons that correlate with the functional domains of HMIP. Primer extension analysis has identified a major transcript of the MIPEP gene expressed differentially and predominantly in tissues with high oxygen consumption, while sequence analysis of approximately 2 kb of 5'-flanking DNA has revealed putative Mt1/3/4, NF-kappaB, and AP-1 elements that may regulate MIPEP expression in these tissues. Using a new polymorphic (CA)(n) repeat in intron 4, MIPEP has been genetically mapped within a 7-cM interval between markers D13S283 and D13S217 on 13q12. This work provides the basis for molecular analysis of MIPEP in FRDA and possibly other neurodegenerative diseases.

Base Sequence↗
PubMed1999

Genetic anticipation in Portuguese kindreds with familial amyloidotic polyneuropathy is unlikely to be caused by triplet repeat expansions.

Familial amyloidotic polyneuropathy (FAP) is a lethal autosomal dominant type of amyloidosis resulting from the deposition of transthyretin (ATTR) variants in the peripheral and autonomic nervous systems. ATTR V30M-associated FAP exhibits marked genetic anticipation in some families, with clinical symptoms developing at an earlier age in successive generations. The genetic basis of this phenomenon in FAP is unknown. Anticipation has been associated with the dynamic expansion of trinucleotide repeats in several neurodegenerative disorders, such as Huntington disease, myotonic dystrophy, and fragile X syndrome. We have used the repeat expansion detection (RED) assay to screen affected members of Portuguese FAP kindreds for expansion of any of the ten possible trinucleotide repeats. Nine generational pairs with differences in their age of onset greater than 12 years and a control pair with identical ages of onset were tested. No major differences were found in the lengths of the ten trinucleotide repeats analyzed. The distribution of the maximal repeat sizes was consistent with reported studies in unrelated individuals with no known genetic disease. The present data do not support a role for trinucleotide repeat expansions as the molecular mechanism underlying anticipation in Portuguese FAP.

Adolescent↗
PubMed1998

Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting.

Survivin is a new IAP apoptosis inhibitor expressed during development and in human cancer in vivo. The coding strand of the survivin gene was extensively complementary to that of effector cell protease receptor-1 (EPR-1), prompting the present investigation on the origin and functional relationship of these two transcripts. Southern blots of genomic DNA were consistent with the presence of multiple, evolutionarily conserved, EPR-1/Survivin-related genes. By pulsed field gel electrophoresis and single- and two-color fluorescence in situ hybridization, these were contained within a contiguous physical interval of 75-130 kilobases (kb) on chromosome 17q25. In Northern blots, a single strand-specific probe identified a 1.3-kb EPR-1 mRNA broadly distributed in normal adult and fetal tissues, structurally distinct from the 1.9-kb Survivin transcript expressed in transformed cell lines. Transient co-transfection of an EPR-1 cDNA potentially acting as a Survivin antisense with a lacZ reporter plasmid resulted in loss of viability of HeLa cells. In contrast, co-transfection of an antisense cDNA of intercellular adhesion molecule-1 or a sense-oriented Survivin cDNA was without effect. In stably transfected HeLa cells, ZnSO4 induction of an EPR-1 mRNA under the control of a metallothionein promoter suppressed the expression of endogenous survivin. This resulted in (i) increased apoptosis as detected by analysis of DNA content and in situ internucleosomal DNA fragmentation and (ii) inhibition of cell proliferation as compared with induced vector control transfectants. These findings suggest the existence of a potential EPR-1/survivin gene cluster and identify survivin as a new target for disrupting cell viability pathways in cancer.

Apoptosis↗
PubMed1998

Analyses of cross species polymerase chain reaction products to infer the ancestral state of human polymorphisms.

In numerous population genetic and disease association studies decisions about the ancestry of polymorphic alleles are often made based on the relative frequency of the alleles in the extant populations with the most frequent allele being deemed as ancestral. However, the frequency of an allele in a population is generally not a perfect indicator of its ancestral status. A more accurate method to assess ancestral/derived status of polymorphic alleles involves identification of shared alleles between species. We used this strategy to examine genomic regions homologous to several human polymorphisms in four species of non-human primates. Cross species polymerase chain reaction (CS-PCR), with primers designed from human sequence, was used to investigate regions of interest. Nineteen polymorphisms at six loci (DRD2, HOXB@, PAH, D4S10, RBP3, and RET) were examined either by restriction fragment length analysis of PCR products (PCR-RFLP) or by direct sequencing. At seventeen of the eighteen PCR-RFLPs, non-human primates were monomorphic and identical to each other for either lack of restriction enzyme site or presence of the site. Thus, at these seventeen polymorphic sites the shared alleles are most likely to be the ancestral ones in humans. In several cases we have used sequence data to further demonstrate that the nucleotide at the site of the polymorphism is conserved between species confirming the hypothesis of a single ancestral allele. However, not all human alleles can be simply resolved into ancestral and derived; sequence data from one PCR-RFLP (in an intron of the PAH locus) and a single strand conformational polymorphism (SSCP) in the 3' untranslated region (UTR) of the DRD2 gene illustrate this point.

Alleles↗
PubMed1997

Cloning, expression, and chromosomal assignment of the human mitochondrial intermediate peptidase gene (MIPEP).

The mitochondrial intermediate peptidase of Saccharomyces cerevisiae (YMIP) is a component of the yeast mitochondrial protein import machinery critically involved in the biogenesis of the oxidative phosphorylation (OXPHOS) system. This leader peptidase removes specific octapeptides from the amino terminus of nuclear-encoded OXPHOS subunits and components of the mitochondrial genetic apparatus. To address the biologic role of the human peptidase [MIPEP gene, HMIP polypeptide], we have initiated its molecular and functional characterization. A full-length cDNA was isolated by screening a human liver library using a rat MIP (RMIP) cDNA as a probe. The encoded protein contained a typical mitochondrial leader peptide and showed 92 and 54% homology to RMIP and YMIP, respectively. A survey of human mitochondrial protein precursors revealed that, similar to YMIP, HMIP is primarily involved in the maturation of OXPHOS-related proteins. Northern analysis showed that the MIPEP gene is differentially expressed in human tissues, with the highest levels of expression in the heart, skeletal muscle, and pancreas, three organ systems that are frequently affected in OXPHOS disorders. Using fluorescence in situ hybridization, the MIPEP locus was assigned to 13q12. This information offers the possibility of testing the potential involvement of HMIP in the pathophysiology of nuclear-driven OXPHOS disorders.

Amino Acid Sequence↗
PubMed1997

A novel, heritable, expanding CTG repeat in an intron of the SEF2-1 gene on chromosome 18q21.1.

There are currently 13 diseases known to be caused by unstable triplet repeat mutations; however, there are some instances (as with FRAXF and FRA16) when these mutations appear to be asymptomatic. In a search for polymorphic CTG repeats as candidate genes for bipolar disorder, we screened a genomic human chromosome 18-specific library and identified a 1.6 kb clone (7,6A) with a CTG24 repeat that maps to 18q21.1. The CTG repeat locus, termed CTG18.1, is located within an intron of human SEF2-1, a gene encoding a basic hellx-loop-hellx DNA binding protein involved in transcriptional regulation. The CTGn repeat is highly polymorphic and very enlarged alleles, consistent with expansions of up to CTG2100, were identified. PCR and Southern blot analysis in pedigrees ascertained for a Johns Hopkins University bipolar disorder linkage study and in CEPH reference pedigrees revealed a tripartite distribution of CTG18.1 alleles with stable alleles (CTG10-CTG37), moderately enlarged and unstable alleles (CTG53-CTG250), and very enlarged, unstable alleles (CTG800-CTG2100). Moderately enlarged alleles were not associated with an abnormal phenotype and have a combined enlarged allele frequency of 3% in the CEPH and bipolar populations. Very enlarged alleles, detectable only by Southern blot analysis of genomic digests, have thus far been found in only three individuals from our bipolar pedigrees, and to date, have not been found in any of the CEPH reference pedigrees. These enlarged alleles may arise, at least in part, via somatic mutation.

Alleles↗
PubMed1997

Survey of maximum CTG/CAG repeat lengths in humans and non-human primates: total genome scan in populations using the Repeat Expansion Detection method.

Repeat Expansion Detection (RED) is an efficient and simple method for detecting repeat expansions in the human genome, including expansion mutations resulting in disease. Here we report the first population survey of CTG/CAG repeat lengths in humans using the RED method; we have determined maximum CTG/CAG repeat length in 244 individuals from six human populations: Danes, Chinese, Japanese, Rondonian Surui, Maya and Mbuti/Biaka Pygmies. We have also sampled a number of non-human primates including eight orang-utans (Pongo pygmaeus), seven gorillas (Gorilla gorilla), seven pygmy chimpanzees (Pan paniscus), 13 common chimpanzees (Pan troglodytes) and three Hylobatidae (one Hylobates lar, one H.klossii, and one H.syndactylus). Our results demonstrate the existence of significant variation in the sizes and frequencies of the longest CTG/CAG repeat length seen per individual both within and between human populations. The population differences argue that overall mutation rates at CTG/CAG repeat loci are sufficiently low that mutation does not obliterate the effect of random genetic drift and clearly indicate that population stratification could occur in disease association studies using the RED method. No significant differences were detected among the non-human primates sampled. Our results also show that both common chimpanzees and pygmy chimpanzees (bonobos) are polymorphic for maximum length of any CTG/CAG repeats while no variation was found for gorillas and orang-utans.

Animals↗
PubMed1996

Chromosomal localization of long trinucleotide repeats in the human genome by fluorescence in situ hybridization.

Trinucleotide microsatellites are widespread in the human and other mammalian genomes. Expansions of unstable trinucleotide repeats have been associated so far with a number of different genetic diseases including fragile X, myotonic dystrophy (DM) and Huntington disease. While ten possible trinucleotides can occur at the DNA level, only CTG and CCG repeats are involved in the disorders described so far. However, the repeat expansion detection (RED) technique has identified additional large repeats of ATG, CCT, CTT, and TGG of potentially pathological significance in the human genome. We now show that conclusive information about the chromosomal localization of long trinucleotide repeats can be achieved in a relatively short time using fluorescence in situ hybridization (FISH) with biotin-labelled trinucleotide polymers. Large CTG expansions (> 1 kb) in DM and an unstable (CTG)306 repeat in a patient with schizophrenia were detected by eye through the microscope without electronic enhancement. Digital imaging was used to analyse the chromosomal distribution of long CCA and AGG repeats. Our results suggest that long trinucleotide repeats occur in the normal human genome and that the size of individual repeat loci may be polymorphic.

Base Sequence↗
PubMed1996

Frequency analysis of large CAG/CTG trinucleotide repeats in schizophrenia and bipolar affective disorder.

Much interest has recently been focussed on the possibility of the involvement of unstable DNA in the etiology of schizophrenia and bipolar affective disorder (BPAD), following several publications that report increases in frequency of large CAG/CTG repeats in affected individuals. Using the Repeat Expansion Detection (RED) technique, we have performed a matched control pair analysis for both disorders. No significant differences in CAG/CTG repeat sizes were observed for 52 bipolar affecteds and matched controls (P = 0.15), and borderline significance was observed for 54 schizophrenia affecteds and matched controls (P = 0.05), using a (CTG)10 oligonucleotide (one-tailed t-tests for paired samples). Furthermore, using a (CTG)17 oligonucleotide, no significant differences were observed for 58 bipolar affecteds and 55 schizophrenia affecteds compared to 81 unmatched controls. No significant sex effect was observed for either group, and no significant differences in repeat size were found for responders and non-responders to drug treatments. More importantly, there was no significant correlation (either positive or negative) between age of onset of disease and size of repeat. We thus cannot conclude that CAG/CTG trinucleotides are involved in psychotic disorders and that either the differences observed in similar studies may be the result of population stratification, or that the increased frequency of larger repeats amongst affected individuals is a much smaller effect than previously thought.

Adult↗