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PubMed2004

Mutation screening of the phosducin gene PDC in patients with retinitis pigmentosa and allied diseases.

PURPOSE: To search for a phenotype associated with mutations in the phosducin gene PDC. METHODS: We screened 853 patients with retinitis pigmentosa or an allied disease diseases, including groups of 61 to 212 patients, each with dominant retinitis pigmentosa (RP), recessive RP, Leber congenital amaurosis, or cone-rod degeneration, for mutations in the PDC gene using direct genomic sequencing of the three coding exons and their flanking intron splice sites. RESULTS: We found one polymorphism in the 5' untranslated region (minor allele frequency of 0.149) and three rare single-base sequence variants (one missense change, one isocoding change, and one in the 3' untranslated region). The rare variants were found in one heterozygous patient each and none was interpreted as pathogenic. CONCLUSIONS: Phosducin mutations are not a major cause of dominant or recessive RP, Leber congenital amaurosis, or cone-rod degeneration. The human phenotype associated with phosducin defects remains unknown.

DNA Mutational Analysis↗
PubMed1992

Structure and function of murine TIMP gene.

Specific inhibitors of metalloproteinases, such as TIMP, are potential regulators of tissue integrity. In order to understand their exact role in both normal and pathological processes we have initiated molecular studies on the TIMP gene and its product(s). We have used cDNA and genomic clones corresponding to the murine TIMP gene to define the intron-exon structure of the gene and to map multiple clustered sites where transcription is initiated; we have also partially characterized the cis-acting DNA sequences required for transcriptional activity. The murine TIMP cDNA has also been used in transcription/translation experiments to produce polypeptides which can be processed by endoplasmic reticulum membranes and which are biochemically active in inhibition of fibroblast interstitial collagenase. As a result of our analysis of the expression of the TIMP gene in different cell types and under varied conditions, we have observed an important increase of TIMP mRNA levels in mouse fibroblasts in response to physiological modulators (whole serum and double-stranded RNA) as well as a pathogen (NewCastle Disease Virus). In addition, an analysis of TIMP mRNA in several variants of a cell line derived from a spontaneous mammary adenocarcinoma, which possess different levels of metastatic potential indicated that the serum dependence of TIMP mRNA accumulation is different in metastatic as compared to nonmetastatic cells. The significance of these results in view of the role of TIMP in matrix maintenance is discussed.

Adenocarcinoma↗
PubMed1988

[Clinical characteristics of unipolar depressive psychosis].

Clinico-catamnestic investigation was performed in 100 patients with endogenous affective psychosis with phasic depression. Two variants of the unipolar depression were identified characteristically differing in major clinical and pathogenic parameters. This fact allowed regarding unipolar depression as a distinct pathogenic entity. A series of its clinical traits (premanifest period features, clinical type and course of the manifest depression) can be used for prognosing further development of the disease.

Adolescent↗
PubMed1997

Rationale for development of immunotherapies that target mucoid Pseudomonas aeruginosa infection in cystic fibrosis patients.

Despite a complex sputum bacteriology, the progressive decline in pulmonary function that is the hallmark of the genetic disease cystic fibrosis (CF) is attributable to a single infecting pathogen, mucoid Pseudomonas aeruginosa. Therefore, active and passive immunotherapies that target this particular variant of the bacterium should be of value in attenuating infection and interfering with the decline in pulmonary function. The major surface antigen of mucoid P. aeruginosa is referred to as either mucoid exopolysaccharide (MEP) or alginate, a random polymer of D-mannuronic and L-guluronic acid residues linked beta 1-4. During chronic infection CF patients make antibodies to MEP that fail to mediate opsonic killing of bacteria in vitro. These antibodies can be elicited by vaccination in 35-40% of plasma donors given a preparation of MEP comprised of only the highest molecular-weight polymers; inclusion in human vaccines of smaller polymers normally produced by the bacterium fails to elicit opsonic antibodies, just like in infected CF patients. Opsonic, but not non-opsonic, antibodies to MEP protect animals against chronic endobronchial infection. CF patients do produce opsonic antibodies to mucoid P. aeruginosa that are in a planktonic or suspended state, but these antibodies are not directed at the MEP antigen and they fail to kill P. aeruginosa growing in a biofilm. This is the state that the bacteria grow in the lung. Therefore immunoglobulin G preparations with opsonic antibodies to MEP could provide CF patients with antibodies that they normally do not produce during chronic lung infection and may improve their clinical course.

Animals↗
PubMed2026

Whole-exome sequencing-centered genetic evaluation for early-onset obesity in Chinese children: a retrospective single-center cohort.

BACKGROUND: Genetic causes of early-onset obesity remain undercharacterized in East Asian children. This study evaluated a whole-exome sequencing (WES)-centered diagnostic workflow in Chinese children with obesity onset before 5 years. METHODS: Consecutive children with body mass index above the 95th percentile and obesity onset before 5 years who completed structured inpatient assessment at a single center between February 2022 and December 2023 were retrospectively analyzed. Phenotyping included clinical, biochemical, oral glucose tolerance, cortisol rhythm, and liver assessments. Genetic testing combined WES, mitochondrial DNA analysis, multiplex ligation-dependent probe amplification (MLPA) for obesity-related imprinting loci, WES-based copy-number variant and runs-of-homozygosity analyses, and Sanger validation. Variants were interpreted according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria. RESULTS: Among 23 children, clinically relevant genetic findings were identified in 6 (26.1%): melanocortin-4 receptor (MC4R) c.831T>A (p.C277*), maternal uniparental disomy of 15q11-13, and four phenotype-correlated variants of uncertain significance in UCP3, BBS1, NCOA1, and SH2B1. The definitive/likely diagnostic yield, restricted to pathogenic or confirmed imprinting findings, was 8.7% (2/23). Findings involved leptin-MC4R signaling, BBSome function, fatty-acid oxidation, and chromosomal imprinting. Genetically positive children showed numerically higher alanine aminotransferase (ALT) and aspartate aminotransferase (AST), but differences were not statistically significant. BBS1 p.T374S was relatively enriched in East Asian reference data. CONCLUSIONS: A WES-centered integrated workflow detected heterogeneous genetic mechanisms in Chinese children with early-onset obesity, but variant of uncertain significance (VUS)-associated findings should be distinguished from confirmed diagnoses. Orthogonal methylation/MLPA and runs of homozygosity (ROH) analyses were necessary for imprinting diagnosis. Larger multicenter studies and functional validation are needed.

Chinese children↗
PubMed2024

A novel mutation in SORD gene associated with distal hereditary motor neuropathies.

BACKGROUND: Distal hereditary motor neuropathy (dHMN) is a heterogeneous group of hereditary diseases caused by the gradual degeneration of the lower motor neuron. More than 30 genes associated with dHMN have been reported, while 70-80% of those with the condition are still unable to receive a genetic diagnosis. METHODS: A 26-year-old man experiencing gradual weakness in his lower limbs was referred to our hospital, and data on clinical features, laboratory tests, and electrophysiological tests were collected. To identify the disease-causing mutation, we conducted whole exome sequencing (WES) and then validated it through Sanger sequencing for the proband and his parents. Silico analysis was performed to predict the pathogenesis of the identified mutations. A literature review of all reported mutations of the related gene for the disease was performed. RESULTS: The patient presented with dHMN phenotype harboring a novel homozygous variant c.361G > C (p.Ala121Pro) in SORD, inherited from his parents, respectively. A121 is a highly conserved site and the mutation was categorized as "likely pathogenic" according to the criteria and guidelines of the American College of Medical Genetics and Genomics (ACMG). A total of 13 published articles including 101 patients reported 18 SORD variants. Almost all described cases have the homozygous deletion variant c.757delG (p.A253Qfs*27) or compound heterozygous state of a combination of c.757delG (p.A253Qfs*27) with another variant. The variant c.361G > C (p.Ala121Pro) detected in our patient was the second homozygous variant in SORD-associated hereditary neuropathy. CONCLUSION: One novel homozygous variant c.361G > C (p.Ala121Pro) in SORD was identified in a Chinese patient with dHMN phenotype, which expands the mutation spectrum of SORD-associated hereditary neuropathy and underscores the significance of screening for SORD variants in patients with undiagnosed hereditary neuropathy patients.

Humans↗
PubMed2005

ClpV, a unique Hsp100/Clp member of pathogenic proteobacteria.

Hsp100/Clp proteins are key players in the protein quality control network of prokaryotic cells and function in the degradation and refolding of misfolded or aggregated proteins. Here we report the identification of a new class of Hsp100/Clp proteins, termed ClpV (virulent strain), that are present in bacteria interacting with eukaryotic cells, including human pathogens. The ClpV proteins are most similar to ClpB proteins within the Hsp100/Clp family, but cluster in a separate phylogenetic tree with a remarkable distance to ClpB. ClpV representatives from Salmonella typhimurium and enteropathogenic Escherichia coli form oligomeric assemblies and display ATP hydrolysis rates comparable to ClpB. However, unlike ClpB, both ClpV proteins failed to solubilize aggregated proteins. This lack of disaggregation activity correlated with the inability of ClpB model substrates to stimulate the ATPase activity of ClpV proteins, indicating differences in substrate selection. Furthermore, we show that clpV genes are generally organized in a conserved gene cluster, encoding a potential secretion system, and we demonstrate that increased levels of a dominant negative variant of either S. typhimurium or Yersinia pseudotuberculosis ClpV strongly reduce the ability of these pathogenic bacteria to invade epithelial cells. We propose a role of this novel and unique class of AAA+ proteins in bacteria-host cell interactions.

Amino Acid Sequence↗
PubMed1992

A rapid and versatile method for cloning viroids or other circular plant pathogenic RNAs.

We surveyed the occurrence of unique restriction sites on the cDNAs of viroids, virusoids, and plant viral satellite RNAs that have a circular RNA as an intermediate of replication and found that four such sites would linearize their circular cDNAs. A rapid and simple method was then developed for cloning a naturally occurring viroid from Nematanthus wettsteinii plants. First-strand cDNA was synthesized using random hexanucleotide DNA primers and M-MuLV reverse transcriptase (Superscript RT). Second-strand DNA was synthesized by employing the replacement synthesis method using Escherichia coli RNase H, E. coli DNA polymerase I, E. coli DNA ligase, and beta-NAD+. The circular double-stranded DNA was analyzed for the presence of commonly available, unique restriction sites and subsequently linearized with a selected restriction enzyme. The linear cDNA was ligated to dephosphorylated plasmid vector pGEM 3Z f(+) and cloned in E. coli strain DH5 alpha. This cDNA cloning procedure is suitable for cloning sequence variants of well-characterized viroids, virusoids, certain plant viral satellite RNAs, and new such pathogens of unknown sequence.

Autoradiography↗
PubMed1989

[A fermenter dialysis cultivation technic for encapsulated pathogenic bacteria. II. Group B streptococci].

For mass cultivation of group B streptococci (B-III and B-variant streptococci), a fermenter dialysis culture technique is described and compared to conventional shaking culture and fermenter batch culture techniques. The influence of two kinds of cultivation media on the bacterial yield is demonstrated. The growth rate of the bacteria and the yield of the microbes is higher in modified POPE medium than that observed with Nährbouillon I. The type-specific polysaccharide of B-III-streptococci prepared by phenol-water extraction followed by gel-chromatography can be used as a screening antigen for the production of monoclonal antibodies against B-III-streptococci.

Antigens, Bacterial↗
PubMed2006

Identification of a 4-mer peptide inhibitor that effectively blocks the polymerization of pathogenic Z alpha1-antitrypsin.

alpha(1)-Antitrypsin (AT) is a major proteinase inhibitor within the lung. The Z variant of AT (E342K) polymerizes within the liver and lung, resulting in hepatic aggregation of AT and tissue deficiency, predisposing to early onset of cirrhosis and emphysema, respectively. Polymerization of the aberrant protein can be prevented in vitro by specific peptides such as FLEAIG. This peptide serves as a lead molecule to design a shorter peptide that may be effective as a therapeutic agent. In this study we employed a systematic chemical approach using alanine scanning of Ac-FLEAIG-OH and subsequent peptide shortening to study the binding of shorter peptides to Z-AT. While two additional 6-mer peptides Ac-FLAAIG-OH and Ac-FLEAAG-OH were found to bind to Z-AT, their daughter peptides Ac-FLEAA-NH(2) and Ac-FLAA-NH(2) also bound avidly to Z-AT and prevented polymerization of the protein. Further comparative studies revealed that the binding of Ac-FLAA-NH(2) was more specific for Z-AT. The peptide-AT complex formation was enhanced by the presence of C-terminal amide group on the peptide, and circular dichroism analysis demonstrated that a random coil rather than a beta-helical conformation favored binding of the peptide to AT. In summary, this study has identified novel small peptides that inhibit Z-AT polymerization, and are a significant advance towards the treatment of Z-AT-related cirrhosis and emphysema.

Amino Acid Sequence↗
PubMed2004

Genomic interrogation of the dassie bacillus reveals it as a unique RD1 mutant within the Mycobacterium tuberculosis complex.

Despite their remarkable genetic homology, members of the Mycobacterium tuberculosis complex express very different phenotypes, most notably in their spectra of clinical presentation. For example, M. tuberculosis is regarded as pathogenic to humans, whereas members having deleted RD1, such as Mycobacterium microti and Mycobacterium bovis BCG, are not. The dassie bacillus, an infrequent variant of the M. tuberculosis complex characterized as being most similar to M. microti, is the causative agent of tuberculosis (TB) in the dassie (Procavia capensis). Intriguingly, the dassie bacillus is not pathogenic to rabbits or guinea pigs and has never been documented to infect humans. Although it was identified more than a half-century ago, the reasons behind its attenuation are unknown. Because large sequence polymorphisms have presented themselves as the most obvious genomic distinction among members of the M. tuberculosis complex, the DNA content of the dassie bacillus was interrogated by Affymetrix GeneChip to identify regions that are absent from it but present in M. tuberculosis H37Rv. Comparison has led to the identification of nine regions of difference (RD), five of which are shared with M. microti (RDs 3, 7, 8, 9, and 10). Although the dassie bacillus does not share the other documented deletions in M. microti (RD1(mic), RD5(mic), MID1, MID2, and MID3), it has endured unique deletions in the regions of RD1, RD5, N-RD25, and Rv3081-Rv3082c (virS). RD1(das), affecting only Rv3874-Rv3877, is the smallest natural deletion of the RD1 region uncovered and points to genes within this region that are likely implicated in virulence. Newfound deletions from the dassie bacillus are discussed in relation to their evolutionary and biological significance.

Animals↗
PubMed1986

Highly pathogenic strains of Escherichia coli revealed by the distinct electrophoretic patterns of carboxylesterase B.

One hundred and ninety one strains of Escherichia coli isolated from extra-intestinal infections and 85 strains isolated from the stools of healthy human beings were compared for electrophoretic mobility and isoelectric point of carboxylesterase B, and for production of alpha-haemolysin and the presence of mannose resistant haemagglutinin. Fast and slow electrophoretic mobilities were distinguished among the strains. The frequency of strains showing slow mobilities was considerably higher when they originated from extra-intestinal infections (40%) than when they were obtained from the stools of healthy individuals (7%). In a two-dimensional electrophoretic profile, the fast and slow mobility variants of carboxylesterase B were resolved into two patterns, B1 and B2, respectively. The frequency of pathogenic strains that concomitantly produced alpha-haemolysin and mannose resistant haemagglutinin was 48.7% for strains of pattern B2 but only 2.8% for strains of pattern B1. Thus, the electrophoretic pattern B2 of carboxylesterase B appears to be a molecular marker for a group of highly pathogenic E. coli strains which are frequently implicated in extra-intestinal infections.

Bacterial Proteins↗
PubMed1989

Migraine headache variants.

Migraine headache variants consist of the complicated migraine headache subtypes such as basilar artery migraine, migraine equivalents, and late-life migraine accompanients. Although these disorders occur infrequently, diagnosis may be more difficult. Generally, comprehensive diagnostic studies are required to rule out underlying pathogenic conditions that may present with similar symptom complexes. Standard migraine treatment is often useful in these disorders; however, migrainous variants deserve special therapeutic considerations.

Humans↗
PubMed1998

Outer-membrane antigen expression by Moraxella (Branhamella) catarrhalis influences pulmonary clearance.

Moraxella (Branhamella) catarrhalis is a common respiratory tract pathogen in man. The bacterium shows a strong tendency to form aggregates in vitro. A variant strain of M. catarrhalis that showed a reduced tendency to form aggregates was selected by successive in-vitro passage in broth culture from which aggregates had settled. The non-clumping variant strain showed alteration in expression of outer-membrane antigens, including the HMW-OMP, an outer-membrane protein of c. 200 kDa, outer-membrane protein CD and lipo-oligosaccharide. A mouse model for pulmonary challenge with M. catarrhalis revealed significant differences in the rate of clearance of the isogenic variant strains from the lung. The parent strain caused enhanced recruitment of neutrophils to the lung and more rapid clearance of bacteria from the lungs in comparison to the non-clumping variant. It is concluded that alteration of expression of surface molecules by M. catarrhalis has a significant impact in an in-vivo model of pulmonary clearance.

Adult↗
PubMed2005

Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk.

BACKGROUND: Chronic inflammation plays an important role in several human cancers and may be involved in the etiology of prostate cancer. Toll-like receptors (TLRs) are important in the innate immune response to pathogens and in cross-talk between innate immunity and adaptive immunity. Our previous finding of an association of TLR4 gene sequence variants and prostate cancer risk provides evidence for a role of TLRs in prostate cancer. In this study, we investigated whether sequence variants in the TLR6-TLR1-TLR10 gene cluster, residing within a 54-kb region on 4p14, were associated with prostate cancer risk. METHODS: We selected 32 single-nucleotide polymorphisms (SNPs) covering these three genes and genotyped these SNPs in 96 control subjects from the Cancer Prostate in Sweden (CAPS) population-based prostate cancer case-control study. Five distinct haplotype blocks were inferred at this region, and we identified 17 haplotype-tagging SNPs (htSNPs) that could uniquely describe >95% of the haplotypes. These 17 htSNPs were then genotyped in the entire CAPS study population (1383 case subjects and 780 control subjects). Odds ratios of prostate cancer for the carriers of a variant allele versus those with the wild-type allele were estimated using unconditional logistic regression. RESULTS: The allele frequencies of 11 of the 17 SNPs were statistically significantly different between case and control subjects (P = .04-.001), with odds ratios for variant allele carriers (homozygous or heterozygous) compared with wild-type allele carriers ranging from 1.20 (95% confidence interval [CI] = 1.00 to 1.43) to 1.38 (95% CI = 1.12 to 1.70). Phylogenetic tree analyses of common haplotypes identified a clade of two evolutionarily related haplotypes that are statistically significantly associated with prostate cancer risk. These two haplotypes contain all the risk alleles of these 11 associated SNPs. CONCLUSION: The observed multiple associated SNPs at the TLR6-TLR1-TLR10 gene cluster were dependent and suggest the presence of a founder prostate cancer risk variant on this haplotype background. The TLR6-TLR1-TLR10 gene cluster may play a role in prostate cancer risk, although further functional studies are needed to pinpoint the disease-associated variants in this gene cluster.

Case-Control Studies↗
PubMed2003

A hexA homologue from Photorhabdus regulates pathogenicity, symbiosis and phenotypic variation.

Photorhabdus is a genus of entomopathogenic Gram-negative bacteria that belong to the family Enterobactericeae. Remarkably, at the same time as being pathogenic to insect larvae, Photorhabdus also have a mutualistic relationship with entomophagous nematodes of the family Heterorhabditiae. Photorhabdus can be isolated in two phenotypically distinct forms, termed the primary and secondary variant. Both variants grow equally well and are equally virulent when injected into insect larvae. However, only the primary variant can colonize the intestinal tract of the IJ stage of the nematode and support nematode growth and development. The primary variant expresses several phenotypes that are absent from the secondary variant, including the production of extracellular enzymes, pigments, antibiotics and light. In this study, we use Photorhabdus temperata strain K122 to show that these primary-specific products are symbiosis factors, i.e. factors that are required for nematode growth and development. We also show that, in P. temperata K122, the production of these symbiosis factors is repressed in the secondary variant by the protein encoded by a gene with homology to hexA from Erwinia. Moreover, the derepression of the symbiosis factors in the secondary variant results in a significant attenuation of virulence to larvae of the greater wax moth, Galleria mellonella. This suggests that, during a normal infection, pathogenicity and symbiosis must be temporally separated and that HexA is involved in the regulation of this pathogen-symbiont transition.

Animals↗
PubMed1992

Hemagglutinin activation of pathogenic avian influenza viruses of serotype H7 requires the protease recognition motif R-X-K/R-R.

The hemagglutinin of influenza virus A/FPV/Rostock/34 (H7) was altered at its multibasic cleavage site by site-directed mutagenesis and assayed for proteolytic activation after expression in CV-1 cells. The results indicated that the cellular protease responsible for activation recognizes the tetrapeptide motif R-X-K/R-R that must be presented in the correct sequence position. Studies on plaque variants of influenza virus A/fowl/Victoria/75 (H7N7) showed that alteration of the consensus sequence resulted in a loss of pathogenicity for chickens.

Amino Acid Sequence↗
PubMed2004

Dermatology for the practicing allergist: Tinea pedis and its complications.

Tinea pedis is a chronic fungal infection of the feet, very often observed in patients who are immuno-suppressed or have diabetes mellitus. The practicing allergist may be called upon to treat this disease for various reasons. Sometimes tinea infection may be mistaken for atopic dermatitis or allergic eczema. In other patients, tinea pedis may complicate allergy and asthma and may contribute to refractory atopic disease. Patients with recurrent cellulitis may be referred to the allergist/immunologist for an immune evaluation and discovered to have tinea pedis as a predisposing factor. From a molecular standpoint, superficial fungal infections may induce a type2 T helper cell response (Th2) that can aggravate atopy. Th2 cytokines may induce eosinophil recruitment and immunoglobulin E (IgE) class switching by B cells, thereby leading to exacerbation of atopic conditions. Three groups of fungal pathogens, referred to as dermatophytes, have been shown to cause tinea pedis: Trychophyton sp, Epidermophyton sp, and Microsporum sp. The disease manifests as a pruritic, erythematous, scaly eruption on the foot and depending on its location, three variants have been described: interdigital type, moccasin type, and vesiculobullous type. Tinea pedis may be associated with recurrent cellulitis, as the fungal pathogens provide a portal for bacterial invasion of subcutaneous tissues. In some cases of refractory asthma, treatment of the associated tinea pedis infection may induce remission in airway disease. Very often, protracted topical and/or oral antifungal agents are required to treat this often frustrating and morbid disease. An evaluation for underlying immuno-suppression or diabetes may be indicated in patients with refractory disease.

Journal Article↗