We examined the prevalence, genotype-phenotype correlation, and natural history of lamin A/C gene (LMNA) mutations in subjects with dilated cardiomyopathy (DCM).
Mutations in LMNAhave been found in ...patients with DCM with familial conduction defects and muscular dystrophy, but the clinical spectrum, prognosis, and clinical relevance of laminopathiesin DCM are unknown.
A cohort of 49 nuclear families, 40 with familial DCM and 9 with sporadic DCM (269 subjects, 105 affected), was screened for mutations in LMNAusing denaturing high-performance liquid chromatography and sequence analysis. Bivariate analysis of clinical predictors of LMNAmutation carrier status and Kaplan-Meier survival analysis were performed.
Mutations in LMNAwere detected in four families (8%), three with familial (R89L, 959delT, R377H) and one with sporadic DCM (S573L). There was significant phenotypic variability, but the presence of skeletal muscle involvement (p < 0.001), supraventricular arrhythmia (p = 0.003), conduction defects (p = 0.01), and “mildly” DCM (p = 0.006) were predictors of LMNAmutations. The LMNAmutation carriers had a significantly poorer cumulative survival compared with non-carrier DCM patients: event-free survival at the age of 45 years was 31% versus 75% in non-carriers.
Mutations in LMNAcause a severe and progressive DCM in a relevant proportion of patients. Mutation screening should be considered in patients with DCM, in particular when clinical predictors of LMNAmutation are present, regardless of family history.
Microbial diversity was characterized in mining-impacted soils collected from two abandoned uranium mine sites, the Edgemont and the North Cave Hills, South Dakota, using a high-density 16S ...microarray (PhyloChip) and clone libraries. Characterization of the elemental compositions of soils by X-ray fluorescence spectroscopy revealed higher metal contamination including uranium at the Edgemont than at the North Cave Hills mine site. Microarray data demonstrated extensive phylogenetic diversity in soils and confirmed nearly all clone-detected taxonomic levels. Additionally, the microarray exhibited greater diversity than clone libraries at each taxonomic level at both the mine sites. Interestingly, the PhyloChip detected the largest number of taxa in Proteobacteria phylum for both the mine sites. However, clone libraries detected Acidobacteria and Bacteroidetes as the most numerically abundant phyla in the Edgemont and North Cave Hills mine sites, respectively. Several 16S rDNA signatures found in both the microarrays and clone libraries displayed sequence similarities with yet-uncultured bacteria representing a hitherto unidentified diversity. Results from this study demonstrated that highly diverse microbial populations were present in these uranium mine sites. Diversity indices indicated that microbial communities at the North Cave Hills mine site were much more diverse than those at the Edgemont mine site.
Simple sequence repeats (SSRs) are one of the earliest available forms of genetic variation available for analysis and have been utilized in studies of neurological, behavioral, and health ...phenotypes. Although findings from these studies have been suggestive, their interpretation has been complicated by a variety of factors including, among others, limited power due to small sample sizes. The current report details the availability, diversity, and allele and genotype frequencies of six commonly examined SSRs in the ethnically diverse, population-based National Longitudinal Study of Adolescent Health. A total of 106,743 genotypes were generated across 15,140 participants that included four microsatellites and two di-nucleotide repeats in three dopamine genes (
DAT1
,
DRD4
,
DRD5
), the serotonin transporter, and monoamine oxidase A. Allele and genotype frequencies showed a complex pattern and differed significantly between populations. For both di-nucleotide repeats we observed a greater allelic diversity than previously reported. The availability of these six SSRs in a large, ethnically diverse sample with extensive environmental measures assessed longitudinally offers a unique resource for researchers interested in health and behavior.
Generalized vitiligo is a common autoimmune disorder in which patchy loss of skin and hair pigmentation results from loss of pigment-forming melanocytes from the involved regions. Vitiligo occurs ...with a frequency of about 1% in most populations, and is highly associated with other autoimmune disorders, particularly Hashimoto thyroiditis. Most cases of vitiligo are sporadic, although some cases cluster in families, and the disorder is thought to be oligogenic in origin. We have studied a large family cluster in which vitiligo and Hashimoto thyroiditis occur in numerous individuals. A whole-genome scan of 24 family members, including 14 affected with autoimmune disease, showed significant linkage of an oligogenic autoimmune susceptibility locus, termed AIS1, to a 14.4 cM interval in 1p31.3–p32.2. A two-locus analysis of Hashimoto thyroiditis in family members segregating an AIS1 susceptibility allele showed suggestive linkage to markers in chromosome 6p22.3–q14.1, in a region spanning both the major histocompatibility complex and AITD1, a susceptibility locus for autoimmune thyroid disease. Our results indicate that the 1p AIS1 locus is associated with susceptibility to autoimmunity, particularly vitiligo, in this family, and that a chromosome 6 locus, most likely AITD1, may mediate the occurrence of Hashimoto’s thyroiditis in AIS1-susceptible family members.
Generalized vitiligo is a common autoimmune disorder characterized by the development of white patches of skin and overlying hair due to loss of pigment-forming melanocytes from the involved areas. ...Family clustering of cases is not uncommon, in a pattern suggestive of multifactorial, polygenic inheritance, and there is strong association between vitiligo and other autoimmune diseases. To map genetic loci that confer susceptibility to generalized vitiligo and perhaps other autoimmune diseases, we performed a genomewide linkage scan in 71 white multiplex families with vitiligo from North America and the United Kingdom. Linkage was assessed by multipoint nonparametric linkage analyses. One linkage signal,
AIS1, located at 1p31, met genomewide criteria for highly significant linkage (nonparametric LOD 5.56;
P=.000000282), establishing its importance as a major vitiligo susceptibility locus. An additional seven signals, on chromosomes 1, 7, 8, 11, 19, and 22, met genomewide criteria for “suggestive linkage,” and will thus be of particular importance for follow-up studies.
The need to develop a blood substitute is now urgent because of the increasing concern over blood-transmitted viral and bacterial pathogens. Cell-free haemoglobin solutions and human haemoglobin ...synthesized in Escherichia coli and Saccharomyces cerevisiae have been investigated as potential oxygen-carrying substitutes for red blood cells. But these haemoglobins cannot be used as a blood substitute because (1) the oxygen affinity in the absence of 2,3-bisphosphoglycerate is too high to allow unloading of enough oxygen in the tissues, and (2) they dissociate into alpha beta dimers that are cleared rapidly by renal filtration, which can result in long-term kidney damage. We have produced a human haemoglobin using an expression vector containing one gene encoding a mutant beta-globin with decreased oxygen affinity and one duplicated, tandemly fused alpha-globin gene. Fusion of the two alpha-globin subunits increases the half-life of this haemoglobin molecule in vivo by preventing its dissociation into alpha beta dimers and therefore also eliminates renal toxicity.
Conduct disorder (CD) is characterized by a persistent pattern of violating age-appropriate norms and the rights of others, and is one of the most frequently diagnosed disorders among children. CD is ...moderately heritable, but we know of no reliable associations with specific genes. Evidence suggests that a variable number tandem repeat polymorphism of the dopamine transporter (DAT1) gene may be associated with externalizing behavior in children.
To test for an association between the DAT1 gene and CD.
Case-control analyses and a transmission disequilibrium test (TDT) were conducted.
Cases were (n=210) adolescents enrolled in a Colorado treatment program for conduct and substance use problems. Controls included adolescents matched to the probands in the treatment program and their siblings (n=162). The TDT was conducted using case families in which DNA from both parents was available (95 trios).
The case-control analysis of the full sample did not result in a significant association chi2 (2,372)=0.13, P=0.94. Cases with early-onset conduct problems had slightly more 10-repeat alleles than controls, although this difference was not significant chi2 (2,264)=2.19, P=0.33, 9/10 odds ratio (OR)=1.58, 10/10 OR=2.14. The TDT also did not result in a significant association chi2(1)=0.12, P=0.94.
Results did not support an association between this polymorphism of the DAT1 gene and CD in adolescents.
Synthetic genes encoding the human α- and β-globin polypeptides have been expressed from a single operon in Escherichia coli. The α- and β-globin polypeptides associate into soluble tetramers, ...incorporate heme, and accumulate to >5% of the total cellular protein. Purified recombinant hemoglobin has the correct stoichiometry of α- and β-globin chains and contains a full complement of heme. Each globin chain also contains an additional methionine as an extension to the amino terminus. The recombinant hemoglobin has a C4reversed-phase HPLC profile essentially identical to that of human hemoglobin A0and comigrates with hemoglobin A0on SDS/PAGE. The visible spectrum and oxygen affinity are similar to that of native human hemoglobin A0. The recombinant protein shows a reduction in Bohr and phosphate effects, which may be attributed to the presence of methionine at the amino termini of the α and β chains. We have also expressed the α- and β-globin genes separately and found that the expression of the α-globin gene alone results in a marked decrease in the accumulation of α-globin in the cell. Separate expression of the β-globin gene results in high levels of insoluble β-globin. These observations suggest that the presence of α- and β-globin in the same cell stabilizes α-globin and aids the correct folding of β-globin. This system provides a simple method for expressing large quantities of recombinant hemoglobin and allows facile manipulation of the genes encoding hemoglobin to produce functionally altered forms of this protein.
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