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PubMed1997

Transglutaminase 1 mutations in autosomal recessive congenital ichthyosis: private and recurrent mutations in an isolated population.

Autosomal recessive congenital ichthyosis (ARCI) is a rare, heterogenous keratinization disorder of the skin, classically divided into two clinical subtypes, lamellar ichthyosis (LI) and nonbullous congenital ichthyosiformis erythroderma (CIE). Recently, strong evidence for the involvement of the transglutaminase 1 gene (TGM1) in LI has evolved. We have studied ARCI in the isolated Finnish population, in which recessive disorders are often caused by single mutations enriched by a founder effect. Surprisingly, five different mutations of TGM1 (Arg141His, Arg142Cys, Gly217Ser, Val378Leu, and Arg395Leu) were found in Finnish ARCI patients. In addition to affected LI patients, we also identified TGM1 mutations in CIE patients. Moreover, haplotype analysis of the chromosomes carrying the most common mutation, a C-->T transition changing Arg142 to Cys, revealed that the same mutation has been introduced twice in the Finnish population. In addition to this Arg142Cys mutation, three other mutations, in Arg141 and Arg142, have been described elsewhere, in other populations. These findings suggest that this region of TGM1 is more susceptible to mutation. The corresponding amino acid sequence is conserved in other transglutaminases, but, for example, coagulation factor XIII (FXIII) mutations do not cluster in this region. Protein modeling of the Arg142Cys mutation suggested disruption or destabilization of the protein. In transfection studies, the closely related transglutaminase FXIII protein with the corresponding mutation was shown to be susceptible to degradation in COS cells, further supporting evidence of the destabilizing effect of the Arg142Cys mutation in TGM1.

Adolescent↗

PubMed2003

An intragenic suppressor in the cytochrome c oxidase I gene of mouse mitochondrial DNA.

We report here the identification of a cell line containing single and double missense mutations in cytochrome c oxidase (COX) subunit I gene of mouse mitochondrial DNA. When present in homoplasmy, the single mutant displays a normal complex IV assembly but a significantly reduced COX activity, while the double mutant almost completely compensates the functional defect of the first mutation. We discuss the potential structural consequences of those mutations based on the modeled structure of mouse complex IV. Based on genetic, biochemical and molecular analyses of cultured mouse cells we infer that: (i) deleterious mutations can arise and become predominant; (ii) cultured cells can maintain several mtDNA haplotypes at stable frequencies; (iii) the respiratory chain has little spare COX capacity; and (iv) the size of a cavity in the vicinity of Val421 in CO I of animal COX may affect the function of the enzyme.

Animals↗

PubMed1992

Geographic mitochondrial DNA variation in the rock hyrax, Procavia capensis.

Restriction-fragment-length polymorphisms in mitochondrial DNA (mtDNA) were used to evaluate geographic population genetic structure in the rock hyrax, Procavia capensis, a species which occurs widely, though restricted to rocky habitat, throughout South Africa. Ten restriction endonucleases were employed to assay mtDNAs from 55 specimens representing 10 localities. Haplotypes showed strong geographic patterning, and estimates of nucleotide sequence divergence indicate two major clades thought to be dispersing along separate routes. The divergence time of approximately 2 Myr between clades is relatively high for intraspecific variation. We speculate that the marked genetic break distinguishing the northwestern populations from those constituting the south/central clade may be indicative of two species in what has conventionally been regarded as P. capensis.

Animals↗

PubMed2004

Polymorphic segmental duplications at 8p23.1 challenge the determination of individual defensin gene repertoires and the assembly of a contiguous human reference sequence.

BACKGROUND: Defensins are important components of innate immunity to combat bacterial and viral infections, and can even elicit antitumor responses. Clusters of defensin (DEF) genes are located in a 2 Mb range of the human chromosome 8p23.1. This DEF locus, however, represents one of the regions in the euchromatic part of the final human genome sequence which contains segmental duplications, and recalcitrant gaps indicating high structural dynamics. RESULTS: We find that inter- and intraindividual genetic variations within this locus prevent a correct automatic assembly of the human reference genome (NCBI Build 34) which currently even contains misassemblies. Manual clone-by-clone alignment and gene annotation as well as repeat and SNP/haplotype analyses result in an alternative alignment significantly improving the DEF locus representation. Our assembly better reflects the experimentally verified variability of DEF gene and DEF cluster copy numbers. It contains an additional DEF cluster which we propose to reside between two already known clusters. Furthermore, manual annotation revealed a novel DEF gene and several pseudogenes expanding the hitherto known DEF repertoire. Analyses of BAC and working draft sequences of the chimpanzee indicates that its DEF region is also complex as in humans and DEF genes and a cluster are multiplied. Comparative analysis of human and chimpanzee DEF genes identified differences affecting the protein structure. Whether this might contribute to differences in disease susceptibility between man and ape remains to be solved. For the determination of individual DEF gene repertoires we provide a molecular approach based on DEF haplotypes. CONCLUSIONS: Complexity and variability seem to be essential genomic features of the human DEF locus at 8p23.1 and provides an ongoing challenge for the best possible representation in the human reference sequence. Dissection of paralogous sequence variations, duplicon SNPs ans multisite variations as well as haplotypes by sequencing based methods is the way for future studies of interindividual DEF locus variability and its disease association.

Chromosome Mapping↗

PubMed1999

Mutations in von Willebrand factor multimerization domains are not a common cause of classical type 1 von Willebrand disease.

Type 1 von Willebrand disease (vWD) is an autosomal dominant bleeding disorder of variable penetrance. It is characterised by a mild to moderate bleeding tendency and a quantitative deficiency of von Willebrand factor (vWF) with the full range of vWF multimers. Few mutations have been described which account for the mode of inheritance in dominant vWD type 1. We screened the vWF multimerization domains (regions D1-D3 of the vWF gene) of 12 unrelated patients with dominant vWD type 1 to investigate the hypothesis that multimerization of vWF sub-units may be inhibited or reduced by a "dominant negative" mechanism. Platelet-derived RNA was reverse transcribed and the resulting vWF cDNA amplified by the polymerase chain reaction (PCR) in a series of overlapping fragments. These were subjected to a combination of single-strand conformation polymorphism (SSCP) and heteroduplex analysis. This approach identified mobility shifts on acrylamide gels that represented 12 distinct SSCP and/or heteroduplex patterns in our patient group. DNA sequencing of the region encompassing each mobility shift showed these variants to represent previously described polymorphisms within the vWF coding sequence. Examination in all 12 patients for the previously described G3389T and T3445C mutations proved negative. The molecular pathology of classical type 1 vWD remains enigmatic, mutations having been identified in only a small minority of patients. A common mechanism underlying this disease state has still to be elucidated.

Amino Acid Substitution↗

PubMed2001

[Human histocompatibility HLA system. Considerations in the light of current concepts. VIII. Polymorphism of HLA-related MIC system].

The recent advances about a new distinct family of polymorphic genes MIC (PERB11) "mapped" in the region of the major histocompatibility complex of antigens MHC were presented. Some aspects connected with their molecular organisation, degree of polymorphism, expression, and immunogenetical function were discussed. Special attention sacrificed to results of investigations over existence of particular MICA allele association with some diseases. Many relating problems, especially functional MICA and MICB genes are still in interests both clinicians, and immunogenetists.

Genotype↗

PubMed2006

The congenital "ant-egg" cataract phenotype is caused by a missense mutation in connexin46.

PURPOSE: "Ant-egg" cataract is a rare, distinct variety of congenital/infantile cataract that was reported in a large Danish family in 1967. This cataract phenotype is characterized by ant-egg-like bodies embedded in the lens in a laminar configuration and is inherited as an autosomal dominant trait. We retrieved the family and performed linkage analysis to determine the disease locus and identify the mutated gene. METHODS: The family (CC00103) was identified in a National Register of Hereditary Eye Diseases and updated based on The Danish Civil Register System. Genome wide linkage analysis and haplotyping using STS marker systems were carried out to achieve a LOD score above 3. The disease-causing candidate gene was sequenced and the mutation was identified and verified by restriction enzyme digestion of genomic DNA from all individuals in family CC00103 and 60 healthy controls. RESULTS: Linkage analysis resulted in a LOD score of 3.91 for marker D13S1275 located close to the known cataract gene GJA3. A novel missense mutation c.32T > C (L11S), was found by sequencing DNA from two affected members. The mutation was present in all affected individuals and was neither found in unaffected family members nor in 60 healthy individuals by restriction enzyme digests. CONCLUSIONS: The congenital "ant-egg" cataract phenotype is caused by a L11S mutation in connexin46 (Cx46) located in the signal peptide domain. Further studies are needed to unravel the mechanism leading to the formation of the "ant-eggs".

Amino Acid Sequence↗

PubMed2006

In silico structure-based design of a potent and selective small peptide inhibitor of protein tyrosine phosphatase 1B, a novel therapeutic target for obesity and type 2 diabetes mellitus: a computer modeling approach.

Protein Tyrosine Phosphatase 1B (PTP1B) has been shown to be a negative regulator of insulin signaling by dephosphorylating key tyrosine residues within the regulatory domain of the beta-subunit of the insulin receptor. Recent gene knockout studies in mice have shown the mice to have increased insulin sensitivity and improved glucose tolerance. Furthermore, these mice also exhibited a resistance to diet induced obesity. Inhibitors of PTP1B would have the potential of enhancing insulin action by prolonging the phosphorylated state of the insulin receptor. In addition, recent clinical studies have shown that the haplotype ACTTCAG0 of the PTPN1 gene, which encodes PTP1B, is a major risk contributor to type 2 diabetes mellitus (T2DM). Thus, there is compelling evidence that small molecule inhibitors of PTP1B may be effective in treating insulin resistance at an early stage, thereby leading to a prevention strategy for T2DM and obesity. Based on the crystal structure of the complex of PTP1B with a known inhibitor, we have identified a tetrapeptide inhibitor with the sequence WKPD. Docking calculations indicate that this peptide is as potent as the existing inhibitors. Moreover, the peptide is also found to be selective for PTP1B with a greatly reduced potency against other biologically important protein tyrosine phosphatases such as PTP-LAR, Calcineurin, and the highly homologous T-Cell Protein Tyrosine Phosphatase (TCPTP). Thus the designed tetrapeptide is a suitable lead compound for the development of new drugs against type 2 diabetes and obesity.

Amino Acid Sequence↗

PubMed2004

Haplotype sharing correlation analysis using family data: a comparison with family-based association test in the presence of allelic heterogeneity.

The haplotype-sharing correlation (HSC) method for association analysis using family data is revisited by introducing a permutation procedure for estimating region-wise significance at each marker on a study segment. In simulation studies, the HSC method has a correct type 1 error rate in both unstructured and structured populations. The HSC signals on disease segments occur in the vicinity of a true disease locus on a restricted region without recombination hotspots. However, the peak signal may not pinpoint the true disease location in a small region with dense markers. The HSC method is shown to have higher power than single- and multilocus family-based association test (FBAT) methods when the true disease locus is unobserved among the study markers, and especially under conditions of weak linkage disequilibrium and multiple ancestral disease alleles. These simulation results suggest that the HSC method has the capacity to identify true disease-associated segments under allelic heterogeneity that go undetected by the FBAT method that compares allelic or haplotypic frequencies.

Alleles↗

PubMed1985

Structural analysis of TL genes of the mouse.

Three Tla region-specific probes have been generated from the BALB/c genomic cosmid clone C6.3. One probe, pTL1, corresponds to 3' sequences of a thymus leukemia (TL)-encoding gene, whereas pTL2 and pTL3 detect noncoding flanking sequences. The TL specificity of pTL1 was demonstrated by studies of RNA from thymocytes of TL+ and TL- mouse strains and from TL+ and TL- leukemias; presence/absence of pTL1+ transcripts correlated with presence/absence of TL antigens detected serologically. Nine Tla haplotypes were defined by restriction fragment polymorphism with pTL1, and the number of TL genes has been estimated to be greater than or equal to 4 in Tlaa, Tlac and Tlae mice, greater than or equal to 3 in Tlad mice, and greater than or equal to 2 in Tlab and Tlaf mice. A TL-encoding gene (C25.1) from the C57BL/6TL+ leukemia ERLD has been cloned and sequenced, and the exon/intron organization of C25.1 has been deduced from the structure of pTL1+ cDNA clones and from the known organization of H-2 genes. The major structural differences between TL and H-2 genes are in exons coding for the cytoplasmic domain.

Alleles↗

PubMed2000

Genetic evidence for the effect of a postglacial population expansion on the phylogeography of a North American songbird.

Phylogeographical studies of Nearctic songbirds conducted to date have yielded unexpectedly low levels of genetic differentiation and weak phylogeographical structure in mitochondrial DNA lineages as compared with species studied in Neotropical areas. Factors leading to this pattern may include (i) gene flow, (ii) population expansions from bottlenecked populations, and (iii) selective sweeps. Here we provide evidence for the role played by Pleistocene postglacial population expansions on the phylogeography of MacGillivray's warbler (Oporornis tolmiei), a long-distance migratory bird. Samples from 12 breeding localities in the temperate USA were compared with those from two localities in north-eastern Mexico. The former showed evidence of a Late Pleistocene population expansion as indicated by low haplotype and nucleotide diversity, a star-like phylogeny of alleles, and a mismatch distribution indicating a sudden increase in effective population size. By contrast, the Mexican population showed high levels of genetic diversity and a mismatch distribution as expected for a population unaffected by sudden demographic change. Haplotypes from the two regions formed two distinct phylogroups which separated roughly one million years ago according to a conventional molecular clock for songbirds. This study provides support for the Pleistocene expansion hypothesis in MacGillivray's warbler and suggests that postglacial expansion of bottlenecked populations is responsible for the lack of variation and structure reported for most North American songbird species.

Animals↗

PubMed2005

Restriction fragment length polymorphisms of different DNA regions as genetic markers in the hoverfly Episyrphus balteatus (Diptera: Syrphidae).

A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis using mitochondrial (A+T-rich region; mtDNA) and genomic (zen-region; nDNA) DNA was performed on 182 female individuals of Episyrphus balteatus (DeGeer), a widespread aphidophagous hoverfly with supposed migratory behaviour. Specimens originated from 13 sampling sites in six European countries. The analyses revealed 12 and 18 haplotypes, respectively, for the two DNA types, several of them with a wide distribution, although seven and eight haplotypes, respectively, occurred only in one location. In contrast to other studies on mobile insects, the genetic diversity was relatively high. However, lack of population subdivision, low genetic distances between populations, the very high gene flow rates, and the complete lack of isolation by distance suggest that E. balteatus populations are largely connected and that there is an absence of large-scale geographic structuring. These results support the hypothesis that E. balteatus is a migratory hoverfly species, capable of moving over large distances. These findings related to the seasonal migrations of this species are discussed.

Animals↗

PubMed1988

DQw3 variants defined by cloned alloreactive T cells.

The polymorphism of HLA class II molecules expressing the serologically defined alloantigen DQw3 was studied using cloned proliferative T lymphocytes. Two clones, IG9 and IC3, were selectively primed against DQw3-associated determinants and tested against a panel of 92 HLA-D homozygous cells. Both clones were specific for DQw3, but each showed a distinct response pattern. Clone IG9 recognized a DQw3-associated determinant expressed on a subset of DR4 and DR5 haplotypes and on all DRw6, 7, w8, and w9 haplotypes tested. In contrast, clone IC3 recognized a distinct DQw3-associated determinant expressed only on a subset of DR4 haplotypes. In monoclonal antibody inhibition experiments, anti-DQ, but not anti-DR or anti-DP antibodies, blocked reactivity of both clones IG9 and IC3, further demonstrating that the determinants defined by these clones are associated with DQ molecules. In DNA hybridization studies using a DQ beta probe, a correlation was observed between restriction site polymorphisms in the DQ beta gene, designated DQw"3.1" and "3.2," and the expression of the T-cell-defined IG9 and IC3 determinants. It is, thus, possible to demonstrate by cloned T-cell reactivity functionally relevant recognition sites on DQw3+ molecules that are associated with structural polymorphisms defined by molecular and genomic analysis.

Antibodies, Monoclonal↗

PubMed1981

Biochemical evidence for structurally distinct H-2Dd antigens differing in serological properties.

H-2Dd antigens, as defined by the private H-2.4 determinant, exist as two immunochemically distinct populations in H-2a and H-2dm2 splenocytes and in the transformed cell line, RADA1 (H-2a). The two populations are distinguishable by the anti-H-2.28 serum, k/r anti-h2, which is directed, in part, against the H-2.28 family of public determinants encoded by the D end of the b haplotype. Sequential precipitates of lentil-lectin-purified glycoprotein extracts metabolically labeled with radioactive amino acids reveal that approximately one-quarter to one-third of the H-2Dd antigens, designated H-2Dd (b28+), react with this antiserum, whereas two-thirds to three-quarters, designated H-2Dd (b28-), do not. Paired-label tryptic peptide maps in this and a previous study indicate that H-2Dd (b28+) and H-2Dd (b28-) are closely related structurally and are more likely to represent modified forms of the same gene product rather than products of different genes, although the existence of closely related genetic loci is not rigorously excluded. Together, H-2Dd (b28+) and H-2Dd (b28-) have a radioactivity level seven times higher than H-2Ld, which also reacts with the anti-H-2.28 serum but which lacks the H-2.4 determinant. As yet unresolved, however, is the question of whether the observed quantitative differences between these three antigens reflect actual molar differences at the cellular level, or whether the variation is the result of metabolic or compositional factors. In any case, a complex serological and structural relationship is found to exist between antigens encoded by the D/L end of the MHC.

Amino Acids↗

PubMed2007

Two pedigrees segregating Duane's retraction syndrome as a dominant trait map to the DURS2 genetic locus.

PURPOSE: The genetic bases of Duane's retraction syndrome (DRS) were investigated to determine its molecular etiologies. In prior studies, the transcription factors SALL4 and HOXA1 were identified as the genes mutated in DRS with radial anomalies, and in DRS with deafness, vascular anomalies, and cognitive deficits, respectively. Less is known, however, about the genetic etiology of DRS when it occurs in isolation, and only one genetic locus for isolated DRS, the DURS2 locus on chromosome 2, has been mapped to date. Toward the goal of identifying the DURS2 gene, two pedigrees have been ascertained that segregate DRS as a dominant trait. METHODS: Members of two large dominant DRS pedigrees were enrolled in an ongoing study of the genetic basis of the congenital cranial dysinnervation disorders, and linkage analysis was conducted to determine whether their DRS phenotype maps to the DURS2 locus. RESULTS: By haplotype analysis, the DRS phenotype in each family cosegregates with markers spanning the DURS2 region. Linkage analysis reveals maximum lod scores >2, establishing that the DRS phenotype in these two pedigrees maps to the DURS2 locus. CONCLUSIONS: These two pedigrees double the published pedigrees known to map to the DURS2 locus and can thus contribute toward the search for the DURS2 gene. The affected members represent a genetically defined population of DURS2-linked DRS individuals, and hence studies of their clinical and structural features can enhance understanding of the DURS2 phenotype, as described in the companion paper.

Chromosome Mapping↗

PubMed1990

Structural model for T-cell recognition of HLA class II-associated alloepitopes.

In an effort to investigate the structure-function relationship of HLA class II molecules vis-à-vis alloepitope expression, cloned T-cell reagents were used to define polymorphic epitopes associated with DR and DQ molecules. DNA sequences of genes encoding allelic or isotypic DR or DQ molecules that appear to express the same T-cell-defined epitopes were compared in an attempt to identify association of shared sequences with shared epitopes. When sequence sharing is associated with shared epitope expression, we suggest that it is the shared sequence that encodes the epitope in question. Based on the hypothetical three-dimensional structure of the class II molecule, an approximation is made as to which parts of the HLA class II molecule are involved in alloepitope expression. T-cell clones were generated from cells primed against HLA-DR2 haplotypes representing the cellularly defined subgroups Dw2 or Dw21 (previously designated MN2, FJ0, or Tb24). Those clones determined to be DR- or DQ-directed based on monoclonal antibody inhibition assays were tested by panel cell analysis utilizing DR2-positive and DR2-negative target cells. The data support the concept that amino acids 67, 70, 71, and 74 for DR molecules and amino acids 57, 70, and 71 for DQ molecules, which appear to comprise one face of the alpha helix, are of primary importance in T-cell recognition. In other cases, sharing of both the second hypervariable region (amino acids 25-33) and the third hypervariable region (amino acids 67-74) appears necessary to explain epitope sharing for DR molecules. We emphasize that the involvement of these two hypervariable regions may indicate that alloepitope expression involves the complex of class II molecule plus peptide, with the second HVR primarily involved in determining which peptides are bound and the third in T-cell receptor (TcR) recognition and/or peptide binding; we do not rule out that conformational changes of the second HVR can induce conformational changes in the third HVR. Finally, shared alloepitopes detected by some clones could not be explained based on shared primary sequences.

Amino Acid Sequence↗

PubMed2006

Association of common haplotypes of surfactant protein A1 and A2 (SFTPA1 and SFTPA2) genes with severity of lung disease in cystic fibrosis.

Most individual cystic fibrosis transmembrane conductance regulator (CFTR) mutations appear not to correlate directly with severity of lung damage in cystic fibrosis (CF). Components of innate immunity, namely, mannose-binding lectin (MBL2), and surfactant protein A1 and A2 genes (SFTPA1 and SFTPA2), were shown to be critical in pulmonary host defenses. A pilot association study was conducted to identify genetic modifiers of lung disease in adult patients with CF. The structural and promoter (-221x/y) variants of MBL2, variants at codons 19, 50, 62, and 219 of SFTPA1, and at codons 9, 91, and 223 for SFTPA2, were studied in 135 adults with CF and compared to their forced expired volume in 1 sec (FEV1), diffusion of CO (DLCO), and other pulmonary scores. Predicted FEV1 was significantly lower in adults with the SFTPA1 6A3 allele and SFTPA2 1A1) allele (P = 0.01 and 0.009, respectively). The extended haplotype 6A3/1A1, which includes SFTPA1 and SFTPA2, was associated with lower pulmonary function, using FEV1 (P = 0.005) and poor pulmonary scores which were determined by American Medical Association, American Thoracic Society, and modified Shwachman-Kulczycki scores. Lower FEV1 and DLCO values were associated with MBL2 coding variants in those who had the DeltaF508 CFTR mutation (P = 0.03 and 0.004, respectively). These results support the current hypothesis that variants in pulmonary host defense molecules are potentially genetic modifiers of pulmonary disease in CF. Further work in larger populations is required to provide important new insights into the pathogenesis of CF.

Adult↗

PubMed2005

Low levels of linkage disequilibrium in wild barley (Hordeum vulgare ssp. spontaneum) despite high rates of self-fertilization.

High levels of inbreeding cause populations to become composed of homozygous, inbred lines. High levels of homozygosity limit the effectiveness of recombination, and therefore, retard the rate of decay of linkage (gametic phase) disequilibrium (LD) among mutations. Inbreeding and recombination interact to shape the expected pattern of LD. The actual extent of nucleotide sequence level LD within inbreeding species has only been studied in Arabidopsis, a weedy species whose global range has recently expanded. In the present study, we examine the levels of LD within and between 18 nuclear genes in 25 accessions from across the geographic range of wild barley, a species with a selfing rate of approximately 98%. In addition to examination of intralocus LD, we employ a resampling method to determine whether interlocus LD exceeds expectations. We demonstrate that, for the majority of wild barley loci, intralocus LD decays rapidly, i.e., at a rate similar to that observed in the outcrossing species, Zea mays (maize). Excess interlocus LD is observed at 15% of two-locus combinations; almost all interlocus LD involves loci with significant geographic structuring of mutational variation.

DNA, Plant↗