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PubMed2004

Evaluation of the role of the SQSTM1 gene in sporadic Belgian patients with Paget's disease.

A positional cloning effort in French Canadian families with Paget's disease of bone (PDB) resulted in the identification of a mutation in the sequestosome1 (SQSTM1) gene in a subset of both familial and sporadic PDB cases. This was confirmed in samples of mainly United Kingdom (UK) origin. In this study, we performed both mutation analysis and association studies in order to evaluate the role of this gene in a collection of isolated Belgian PDB patients. A mutation in the SQSTM1 gene was found in only 6 of 111 patients (5.4%). In all cases it involves the P392L mutation, previously shown to be common in both familial and sporadic cases. To perform association studies, we selected 8 single nucleotide polymorphisms (SNPs) and looked for linkage disequilibrium (LD) between these. Haplotype analysis indicated that typing of 3 Tag SNPs (IVS1 + 633A/C, IVS5 - 23A/G, and 976A/G) enables us to identify the most common haplotypes. Association studies for the 3 selected SNPs, based on 105 PDB cases without a SQSTM1 mutation and 159 control individuals, did not support a possible influence of natural variants in the SQSTM1 gene either on the pathogenesis of PDB or on the disease severity. In conclusion, our study confirms that the P392L mutation is a recurrent mutation causing PDB in different populations. We were not able to show an association between SQSTM1 polymorphisms and PDB in our population but this clearly needs to be extended to other populations. The presented identification of haplotype Tag SNPs will be of major help for such studies.

Adaptor Proteins, Signal Transducing↗

PubMed1989

Helper T-cell determinants in vaccine design.

Mice belonging to the H-2d haplotype do not respond to the 141-160 peptide of foot-and-mouth disease virus protein VP1. However, when defined 'foreign' helper T-cell determinants from ovalbumin or sperm whale myoglobin are added they do respond. These observations are likely to have important implications for the design of peptide vaccines.

Animals↗

PubMed2005

Promoter haplotype of a new ABCA1 mutant influences expression of familial hypoalphalipoproteinemia.

Mutations in the ATP-binding cassette A1 (ABCA1) transporter cause the high-density lipoprotein (HDL) deficiency syndromes of Tangier disease and familial hypoalphalipoproteinemia (FHA). Between individuals carrying ABCA1 mutations, the expression of FHA can be highly variable. Using denaturing HPLC (dHPLC) and direct promoter sequencing we screened the ABCA1 gene of a family with Tangier disease and variable expression of FHA. A new mutation (R1068H) within the first ATP-binding domain was identified in homozygous form in the Tangier disease individual and was present in several family members. Haplotyping of both 1068H alleles in the proband showed homozygosity in the coding region, however, the maternal 1068H allele had three single nucleotide polymorphisms (SNPs) in the promoter previously reported to be associated with reduced ABCA1 expression and HDL levels. An analysis of HDL levels based on 1068H allele haplotype showed the paternal 1068H heterozygotes to have the expected low HDL levels (0.67+/-0.16mmol/L), while maternal 1068H heterozygotes showed normal HDL levels (1.18+/-0.14mmol/L). Haplotype analysis of the wildtype allele amongst heterozygotes showed no haplotype that was common to the paternal or maternal side. We propose that the paternal 1068H ABCA1 allele causes a negative effect on the function of the wildtype allele and is associated with low HDL levels. In contrast, the maternal 1068H allele has less effect and is associated with a relatively normal HDL level. We conclude that haplotypes of mutant ABCA1 alleles may contribute to the phenotypic variance shown between FHA individuals.

ATP Binding Cassette Transporter 1↗

PubMed1999

Human leukocyte antigens influence the immune response to a pre-S/S hepatitis B vaccine.

In this study we investigated the effects of a single pre-S/S (Hepagene) revaccination in a large population of multiple 'S' vaccinated anti-HBs antibody nonresponder individuals (< 3 IU/l). We investigate the influence of vaccine dose (5, 10, 20 and 40 micrograms/ml), number of previous 'S' containing vaccinations and the individuals HLA genotype on both B- and T-cell responses. We show that 76% of persistently nonresponder individuals produce anti-HBs antibody (> 3 IU/l) following a single revaccination with Hepagene. This anti-HBs antibody response was dose dependent. The group that received 5 micrograms/ml of Hepagene vaccine produced significantly less anti-HBs antibody than those receiving 10, 20 and 40 micrograms/ml doses (p < 0.05 in all cases). Individuals homozygous for HLA-DRB1*0701; DQB1*0202 failed to produce > 100 IU/l of anti-HBs antibody, whereas, heterozygous individuals required > 10 micrograms/ml Hepagene vaccine. The T-cell responses to Hepagene were exclusive of the dose and magnitude of anti-HBs antibody responses. There was a trend towards increased stimulation indices in those individuals who received repeated 'S' containing vaccines. We have clearly shown that the immune response to Hepagene is influenced by the HLA genotype of the individual. However, further investigation is required to determine the specific role of these molecules in hepatitis B vaccine nonresponse. Hepagene is a registered trademark of Hedeva Pharma Ltd.

Adult↗

PubMed2001

Genetic differentiation of Glossina morsitans centralis populations.

Variation at mitochondrial and microsatellite loci was used to study the breeding and dispersal structure of Glossina morsitans centralis, in six natural populations from Botswana, the Caprivi Strip (Namibia), Zambia, and in a laboratory culture derived from Singida, Tanzania. Only seven mitochondrial haplotypes were found. Mean diversity averaged over the six natural populations was 0.216 +/- 0.085. The fixation index FST = 0.866 indicated a high degree of genetic differentiation among populations. Fifty-three alleles were detected among six microsatellite loci and six natural populations. Mean microsatellite diversity was 0.702 +/- 0.091. Depending on the estimating model used, fixation indices varied from 0.15 to 0.225 confirming that G. m. centralis populations are strongly subdivided. For all FST estimates, positive correlations were detected between pair-wise genetic distance measures and geographical distances. The difference in fixation indices estimated from mitochondrial or nuclear loci was explained by the greater sensitivity of mitochondrial genomes to genetic drift. Population differentiation can be explained by genetic drift and the subsequent recovery of extant populations from small, discontinuous populations. These data confirm genetically the collapse and retreat of G. m. centralis populations caused by the rinderpest epizootic of the late 19th and early 20th centuries.

Animals↗

PubMed1999

Genetic structure of fragmented populations of red squirrel (Sciurus vulgaris) in the UK.

The relationships among 207 squirrels from 12 locations in the UK and three in mainland Europe were examined using mitochondrial DNA (mtDNA) control region sequence. Twenty-six haplotypes were detected, many of which were population specific. Eighty per cent of the populations analysed contained two or more haplotypes. Hierarchical analysis of molecular variance showed the majority of genetic variation to be partitioned among populations. Genetic diversity varied considerably within the UK, and conformed to no obvious geographical trend. The populations in Argyll and Spadeadam Forest showed the highest levels of variation in the UK. However, the greatest genetic diversity was seen in Bavaria, southern Germany where six unique alleles were detected in a sample of 10 individuals. Phylogenetic analysis revealed no evolutionary divergence between UK and mainland European haplotypes. We conclude that, within the UK, the genetic patterns observed are most likely to be explained by the effects of genetic drift which has occurred since the isolation of populations during the past few hundred years, hence we cannot detect any underlying phylogeographic pattern. Therefore, the use of larger, geographically distinct populations within the UK for augmentation of small isolated populations is unlikely to pose problems of genetic incompatibility. Further, the role that demographic factors may have in complicating the application of current genetically based management unit criteria is likely to need further attention.

Animals↗

PubMed2003

Molecular phylogeography of the Amazonian Chagas disease vectors Rhodnius prolixus and R. robustus.

The phylogeographical structure of the closely related species Rhodnius prolixus and R. robustus is presented based on a 663-base pair (bp) fragment of the mitochondrial cytochrome b gene. Twenty haplotypes were recovered from 84 samples examined, representing 26 populations from seven Latin American countries. The resulting phylogenetic tree is composed of five major reciprocally monophyletic clades, one representing R. prolixus and four representing R. robustus. While R. prolixus is a very homogeneous assemblage, R. robustus has deeper clades and is paraphyletic, with the clade comprising R. robustus from Venezuela (Orinoco region) more closely related to the R. prolixus clade than to the other R. robustus populations from the Amazon region. The R. robustus paraphyly was supported further by the analysis of a nuclear gene (D2 region of the 28S RNA) for a subset of specimens. The data support the view that R. robustus represents a species complex. Levels of sequence divergence between clades within each region are compatible with a Pleistocene origin. Nucleotide diversity (pi) for all R. prolixus populations was extremely low (0.0008), suggesting that this species went through a recent bottleneck, and was subsequently dispersed by man.

Animals↗

PubMed2001

Haplotype analysis of the human alpha2-HS glycoprotein (fetuin) gene.

Alpha2-HS glycoprotein (AHSG), which is equivalent to fetuin in other species, is a protein found in human plasma. AHSG is polymorphic with two common alleles and many variants. To examine the intragenic haplotypes and their diversity at this locus, a contiguous genomic DNA sequence (10.3 kb) was analyzed in 20 samples (40 chromosomes), and haplotypes were determined for 309 subjects. Judging from the aligned nucleotide sequences and the conserved amino acid residues comparing human and chimpanzee AHSG, it was concluded that the type 1 allele is probably older and has evolved into four major suballeles. The type 2 allele was generated from one branch of the type 1 allele. AHSG*3 and *5 variants were each found to have a single nucleotide change in exon 7, resulting in the change of an amino acid residue from Arg299 to Cys and from Asp258 to Asn, respectively. It was noted that the AHSG*3 mutation gives rise to an additional cysteine residue, which possibly affects the conformation of the protein. The AHSG gene was found to have a low mutation rate and no apparent recombination events. Furthermore, the detected substitutions were nonhomogeneously distributed at this locus. In particular, four nonsynonymous substitutions were concentrated in the carboxyl-terminal domain.

Alleles↗

PubMed2004

Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.

The hypomyelinating leukodystrophies X-linked Pelizaeus-Merzbacher disease (PMD) and Pelizaeus-Merzbacher-like disease (PMLD) are characterized by nystagmus, progressive spasticity, and ataxia. In a consanguineous family with PMLD, we performed a genomewide linkage scan using the GeneChip Mapping EA 10K Array (Affymetrix) and detected a single gene locus on chromosome 1q41-q42. This region harbors the GJA12 gene, which encodes gap junction protein alpha 12 (or connexin 46.6). Gap junction proteins assemble into intercellular channels through which signaling ions and small molecules are exchanged. GJA12 is highly expressed in oligodendrocytes, and, therefore, it serves as an excellent candidate for hypomyelination in PMLD. In three of six families with PMLD, we detected five different GJA12 mutations, including missense, nonsense, and frameshift mutations. We thereby confirm previous assumptions that PMLD is genetically heterogeneous. Although the murine Gja12 ortholog is not expressed in sciatic nerve, we did detect GJA12 transcripts in human sciatic and sural nerve tissue by reverse-transcriptase polymerase chain reaction. These results are in accordance with the electrophysiological finding of reduced motor and sensory nerve conduction velocities in patients with PMLD, which argues for a demyelinating neuropathy. In this study, we demonstrate that GJA12 plays a key role in central myelination and is involved in peripheral myelination in humans.

Amino Acid Sequence↗

PubMed2006

Genetic polymorphism of the binding domain of surfactant protein-A2 increases susceptibility to meningococcal disease.

BACKGROUND: Meningococcal disease occurs after colonization of the nasopharynx with Neisseria meningitidis. Surfactant protein (SP)-A and SP-D are pattern-recognition molecules of the respiratory tract that activate inflammatory and phagocytic defences after binding to microbial sugars. Variation in the genes of the surfactant proteins affects the expression and function of these molecules. METHODS: Allele frequencies of SP-A1, SP-A2, and SP-D were determined by polymerase chain reaction in 303 patients with microbiologically proven meningococcal disease, including 18 patients who died, and 222 healthy control subjects. RESULTS: Homozygosity of allele 1A1 of SP-A2 increased the risk of meningococcal disease (odds ratio [OR], 7.4; 95% confidence interval [CI], 1.3-42.4); carriage of 1A5 reduced the risk (OR, 0.3; 95% CI, 0.1-0.97). An analysis of the multiple single-nucleotide polymorphisms in SP-A demonstrated that homozygosity for alleles encoding lysine (in 1A1) rather than glutamine (in 1A5) at amino acid 223 in the carbohydrate recognition domain was associated with an increased risk of meningococcal disease (OR, 6.7; 95% CI, 1.4-31.5). Carriage of alleles encoding lysine at residue 223 was found in 61% of patients who died, compared with 35% of those who survived (OR adjusted for age, 2.9; 95% CI, 1.1-7.7). Genetic variation of SP-A1 and SP-D was not associated with meningococcal disease. CONCLUSIONS: Gene polymorphism resulting in the substitution of glutamine with lysine at residue 223 in the carbohydrate recognition domain of SP-A2 increases susceptibility to meningococcal disease, as well as the risk of death.

Adult↗

PubMed2005

Examination of the clock gene Cryptochrome 1 in bipolar disorder: mutational analysis and absence of evidence for linkage or association.

Bipolar disorder is associated with malfunctions of the circadian system, which regulates individual circadian rhythms and which enables the adaptation to a daily 24-h cycle and seasonal change. One of the human circadian clock genes, cryptochrome 1 (Cry1) (located on 12q23-q24.1) was analyzed because of its close correspondence to a linkage hotspot for bipolar disorder. We found no evidence for linkage of 52 bipolar families to two Cry1 flanking microsatellites under several parametric and non-parametric models. In order to employ association for a more sensitive test, 25 affected subjects selected from families with positive LOD scores were screened for mutations by sequencing 9.5% of the Cry1 gene. A total of 16 single nucleotide polymorphisms (SNPs) and a 3 base pair insertion were identified. However, no mutations with probable functional impact were found. These novel SNPs and data on allele frequency and linkage disequilibrium structure will be useful for future association analyses. Nine SNPs have been analyzed in a set of 159 parent proband triads. Linkage disequilibrium analyses using single SNPs and haplotypes showed no association to bipolar disease.Additional, more powerful, studies involving Cry1 and other circadian clock genes need to be tested before an association of circadian abnormalities with bipolar disorder can be excluded.

Base Sequence↗

PubMed1998

Characterization and distribution of HLA-B*5002 in a Spanish population sample.

HLA-B45, in contrast to B44, does not show molecular polymorphism. We have found a group of Caucasian Spanish individuals, serologically typed as B45, showing an unexpected HLA-B12 PCR-SSO subtyping pattern. Complete coding region sequencing and B45 subtyping by PCR-SSO demonstrated that the B45 serologic specificity is constituted by two molecular alleles: B*4501 and B*5002. B*5002 is recognized by polyclonal and monoclonal allosera against B12 and B45, whereas it is not detected by B21, B49, or B50 reagents, providing a new example of poor correlation between serology and structure. B*5002 explains an important subset (18%) of the B45-positive individuals of the Spanish population studied, and almost half are included in a very infrequent haplotypic association, Cw6-B*5002-DRB1*0406-DQA1*03-DQB1*0402.

Amino Acid Sequence↗

PubMed1998

Molecular pathology of familial hypertrophic cardiomyopathy caused by mutations in the cardiac myosin binding protein C gene.

DNA studies in familial hypertrophic cardiomyopathy (FHC) have shown that it is caused by mutations in genes coding for proteins which make up the muscle sarcomere. The majority of mutations in the FHC genes result from missense changes, although one of the most recent genes to be identified (cardiac myosin binding protein C gene, MYBPC3) has predominantly DNA mutations which produce truncated proteins. Both dominant negative and haploinsufficiency models have been proposed to explain the molecular changes in FHC. This study describes two Australian families with FHC caused by different mutations in MYBPC3. The first produces a de novo Asn755Lys change in a cardiac specific domain of MYBPC3. The second is a Gln969X nonsense mutation which results in a truncated protein. Neither mutation has previously been found in the MYBPC3 gene. The consequences of DNA changes on the function of cardiac myosin binding protein C are discussed in relation to current molecular models for this disorder.

Amino Acid Sequence↗

PubMed2006

Comparative phylogeography of two bitterlings, Tanakia lanceolata and T. limbata (Teleostei, Cyprinidae), in Kyushu and adjacent districts of western Japan, based on mitochondrial DNA analysis.

To understand the geographical patterns of genetic variation in freshwater fishes in western Japan, the genetic structures of populations of Tanakia lanceolata and T. limbata (Teleostei, Cyprinidae) in this area were investigated using mitochondrial DNA (mtDNA) cytb sequences. Neighbor-joining trees of mtDNA haplotypes revealed four and three genetically divergent groups in T. lanceolata and T. limbata, respectively. Each group was restricted to one or the other of the geographical regions in the area studied. The patterns of geographical divergence in the two species showed some similarities, which seem to reflect common historical events experienced by freshwater fishes distributed in western Japan. On the other hand, dissimilarities were also found in the patterns, indicating that species-specific historical processes also occurred. Within one region, T. lanceolata was less differentiated than T. limbata, suggesting a difference in the dispersal abilities of the two bitterlings. In addition, several individuals in Kunichika River on Shikoku island were morphologically identified as T. lanceolata but had mtDNA haplotypes of T. limbata. We tentatively suggest that these individuals are hybrids of the two species, but further studies employing nuclear markers are necessary to validate this hypothesis.

Animals↗

PubMed2000

Molecular genetics of RH.

BACKGROUND AND OBJECTIVES: The two Rhesus proteins, RhD and RhCE, constitute one of the clinically most relevant blood group antigen system. In the last two years, the understanding of RH molecular genetics has increased considerably. The state of the current knowledge was briefly summarised. MATERIALS AND METHODS: Recent reviews, original work since 1999 and own results were utilised. RESULTS: The structure of the RH gene locus comprising RHD, RHCE and SMP1 was presented. True RHD genotyping became feasible by establishing the molecular basis of the most prevalent RH haplotype in whites harbouring the RHD gene deletion and of the RHD pseudogene RHD psi in Africans. Molecular and serologic characteristics of weak D and partial D alleles were compared. Closely related alleles for both, weak D and partial D, were collated as examples contributing to the understanding of RH phylogeny. CONCLUSION: The RH gene locus is a model system for molecular polymorphism in clustered genes and suitable for studying molecular evolution in humans. It lends itself for developing molecular diagnostics because its genetics is appropriately complex and challenging; yet the expressed phenotypes have been studied for decades and are well understood. Legal and ethical issues that are rightfully of public concern would not be infringed if RH genotyping will be attempted on a massive scale.

Alleles↗

PubMed1989

Beta+-thalassemia in cis of a sickle cell gene: occurrence of a promoter mutation on a beta s chromosome.

An atypical sickle cell trait with a very low level of hemoglobin S and features of heterozygous beta-thalassemia was recently described. In vitro globin chain synthesis strongly suggested the presence of the two abnormalities on the same chromosome. We report the corresponding beta S-thal gene. DNA sequence revealed a C----T base substitution in the distal promoter element CACCC, at position-88 from the cap site, in addition to the expected GAG----GTG mutation responsible for the structural variant (beta 6 Glu----Val). Reticulocyte mRNA titration and transient assay of the mutant gene in COS cells showed a defect in beta-mRNA production. Restriction haplotype and DNA sequence analyses revealed that the doubly mutated gene is associated with haplotype 19 (or Benin/Algeria haplotype). In particular, we found the (AT)9(T)4 repeated sequences specifically encountered 5' to the beta S gene of Benin Algeria type. These results support the view that the beta S-thal gene resulted from an independent thalassemic mutation having occurred on a beta S chromosome rather than (a) from a beta S mutation having altered a beta-thalassemic gene or (b) from a recombination event between two chromosomes, each carrying one of the mutations.

Anemia, Sickle Cell↗

PubMed1993

Cross-reactive T cell clones from unrelated individuals reveal similarities in peptide presentation between HLA-B27 and HLA-DR2.

HLA-B27- responder cells were stimulated in vitro with B*2705+ lymphoblastoid cell lines and alloreactive CTL clones were obtained by limiting dilution. Of the CD3+ CD4-CD8+ HLA-B27-specific CTL clones obtained, two of them, possessing the same TCR, cross-reacted with HLA-DR2. The fine specificity of these CTL was established with HLA-B27 and HLA-DR2 subtypes. They recognized the B*2701 to B*2706 subtypes, but only DR2Dw2. Lysis of DR2+ target cells was specifically inhibited by anti-CD3, anti-class II, and anti-DR mAb, but not with an anti-CD8 antibody. The monoclonal nature of the cross-reaction was established by the mutual inhibition of HLA-B27 and DR2Dw2 cells in cold target competition experiments. The DR2 protein involved in the cross-reaction was the heterodimer carrying the B5*0101 product, as shown by using L cell transfectants expressing each of the two molecules encoded in the DR2Dw2 haplotype. A correlation between the fine specificity of these CTL clones and the amino acid sequences of HLA-B27 and HLA-DR2 subtypes revealed a shared structural motif between HLA-B27 and the DR2 B5*0101 chain, which could be related to the observed cross-reaction. This motif was contributed for by several residues located in adjacent beta strands, at the floor of the peptide-binding site. The contribution of two of these residues, as well as other beta-pleated sheet residues to HLA-B27 allorecognition by the cross-reactive CTL clones was directly demonstrated with site-directed mutants. These results suggest that the dual reactivity pattern reflects presentation of identical or structurally related peptide by HLA-B27 and HLA-DR2Dw2. As T cell cross-reactivity between HLA-B27 and HLA-DR2 was previously found in cells from an unrelated individual the results reported here are likely to reflect an intrinsic property of HLA-B27, rather than the fortuitous finding of a rare clonal reaction pattern. We speculate on the potential implications of these results for the pathogeny of HLA-B27-associated spondyloarthropathies.

Amino Acid Sequence↗

PubMed1996

Phylogeography and population structure of the Atlantic and Mediterranean green turtle Chelonia mydas: a mitochondrial DNA control region sequence assessment.

Mitochondrial (mt) DNA sequences were analysed to resolve the phylogeography and population genetic structure of Atlantic and Mediterranean populations of green turtles (Chelonia mydas). Analysis of sequence variation over 487 base pairs of the control (D-loop) region identified 18 haplotypes among 147 individuals from nine nesting populations. Pairwise comparisons of haplotype frequencies distinguished most nesting colonies, indicating significant genetic differentiation among rookeries and a strong propensity for natal homing behaviour by nesting females. Comparison of control region sequence data to earlier restriction fragment length polymorphism (RFLP) data for the same individuals demonstrates approximately a sixfold higher substitution rate in the 5' end of the control region. The sequence data provide higher resolution both in terms of the number of mtDNA genotype variants and the phylogeographic relationships detected within the Atlantic region, and reveal a gene genealogy that distinguishes two groups of haplotypes corresponding to (i) the western Caribbean and Mediterranean, and (ii) eastern Caribbean, South Atlantic and West Africa. The data suggest that phylogeographic patterns in the Atlantic Ocean may be interpreted in terms of female nest site fidelity and episodic dispersal events. The distribution of mtDNA haplotypes within the region is thus explained by the geological and climatic alternations (glacial and interglacial) over the last million years.

Animals↗