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PubMed1986

In vitro cytopathology and pathogenicity to inbred mice shown by five variants of a laboratory strain of type 1 herpes simplex virus.

The in vitro cytopathology and the neurovirulence to inbred mice demonstrated by five variants originally derived from one laboratory strain (Miyama) of type 1 herpes simplex virus (HSV-1) were studied comparatively. Three of the variants are syncytial [+GC (LPV), +GC (SPV), +GC (81)] and two are non-syncytial [-GCr and -GCf]. The size of plaques produced by the five variants was found to be in the order of +GC (LPV) greater than +GC (81) greater than +GC (SPV) greater than -GCf greater than -GCr. The pathogenicity of these variants was compared in three kinds of inbred mice (AKR, C 3 H/He and C 57 BL) after intraperitoneal (IP) or intracerebral (IC) inoculation. The +GC (LPV) variant was the most virulent as shown by the highest mortality of mice by either route of inoculation. The other four variants caused death of mice only after IC inoculation, and among these variants, +GC (81) was shown to be the most virulent. These data indicate that so far as these five variants of the Miyama strain of HSV-1 are concerned, neurovirulence is positively correlated with their cell fusion activity or the size of plaques which they produce. Pre-IP-inoculation with any of the less virulent variants [-GCr, +GC (SPV) and +GC (81)] protected mice from subsequent lethal infection with +GC (LPV) by the same route of inoculation.

Animals↗
PubMed2001

Prototheca zopfii mastitis in dairy herds under continental climatic conditions.

In the last 2 years 223 cases of bovine mastitis caused by Prototheca zopfii infection were identified in 32 large-scale dairy herds. All of these farms were in Hungary, which has a continental type, temperate zone climate. Both the sporadic and epidemic forms of P. zopfii mastitis were observed. All the herds affected by the epidemic form had poor hygienic conditions and suffered from several managerial faults, but no specific predisposing factors could be identified. In almost all of the cases, the type II variant of this pathogen was isolated; however, the type III variant was isolated from three cows. The cows had a higher chance of new infection in the early weeks of lactation and in the summer. The P. zopfii infection usually resulted in a chronic subclinical, or mild clinical, inflammatory process in the udder, and was followed by a dramatic loss in milk production and a permanent increase in somatic cell count. The histopathological findings could be characterized as a progressive interstitial mastitis associated with alveolar atrophy. The self-recovery rate was very low.

Animals↗
PubMed2025

Exome sequencing identifies a homozygous splice site variant in RP1 as the underlying cause of autosomal recessive retinitis pigmentosa in a Pakistani family.

BACKGROUND: Mutations in RP1 gene are the third leading cause of inherited retinal dystrophies (IRDs) in Pakistani families. PATIENTS: A two-generation consanguineous Pakistani family underwent both clinical and genetic analyses. Clinical examinations included visual acuity test, visual field, fundoscopy, and ocular coherence tomography (OCT). Whole exome sequencing (WES) was performed on the proband's DNA, and Sanger sequencing was performed to validate the WES findings. Splicing prediction tools such as Human Splicing Finder (HSF), NNSplice predictor, SpliceAI, MaxENTScan, and SpliceRover were used. RESULTS: A nuclear family of seven children, comprising five affected individuals (four males and one female) and two healthy siblings, was recruited from northwestern Pakistan. The proband was a 49-years old male who was presented with complaints of decreased visual acuity and night blindness since early childhood. Upon clinical evaluation, the proband appeared to have severely reduced visual acuity of hand movement (HM), bilateral visual field constriction, a waxy pale disc with vascular attenuation, pigmentary bone spicules at the periphery associated with chorioretinal degeneration, diffuse macular atrophy, and horizontal nystagmus in both of his eyes. Exome sequencing (ES) in the proband identified a homozygous splice site variant (NM_006269.2: c.615 + 1G > A) in RP1 gene. In-silico analysis, genotype-phenotype co-segregation study, and literature survey strongly supported the causality of the detected variant. CONCLUSIONS: We report a previously known pathogenic splice site variant of RP1 as the underlying cause of early-onset autosomal recessive retinitis pigmentosa (arRP) in a Pakistani family. We contemplate that the detected allele might constitute a mutational hotspot in RP1.

Humans↗
PubMed1998

Evolution of a simian immunodeficiency virus pathogen.

Analysis of disease induction by simian immunodeficiency viruses (SIV) in macaques was initially hampered by a lack of molecularly defined pathogenic strains. The first molecularly cloned SIV strains inoculated into macaques, SIVmacBK28 and SIVmacBK44 (hereafter designated BK28 and BK44, respectively), were cases in point, since they failed to induce disease within 1 year postinoculation in any inoculated animal. Here we report the natural history of infection with BK28 and BK44 in inoculated rhesus macaques and efforts to increase the pathogenicity of BK28 through genetic manipulation and in vivo passage. BK44 infection resulted in no disease in four animals infected for more than 7 years, whereas BK28 induced disease in less than half of animals monitored for up to 7 years. Elongation of the BK28 transmembrane protein (TM) coding sequence truncated by prior passage in human cells marginally increased pathogenicity, with two of four animals dying in the third year and one dying in the seventh year of infection. Modification of the BK28 long terminal repeat to include four consensus nuclear factor SP1 and two consensus NF-kappaB binding sites enhanced early virus replication without augmenting pathogenicity. In contrast, in vivo passage of BK28 from the first animal to die from immunodeficiency disease (1.5 years after infection) resulted in a consistently pathogenic strain and a 50% survival time of about 1.3 years, thus corresponding to one of the most pathogenic SIV strains identified to date. To determine whether the diverse viral quasispecies that evolved during in vivo passage was required for pathogenicity or whether a more virulent virus variant had evolved, we generated a molecular clone composed of the 3' half of the viral genome derived from the in vivo-passaged virus (H824) fused with the 5' half of the BK28 genome. Kinetics of disease induction with this cloned virus (BK28/H824) were similar to those with the in vivo-passaged virus, with four of five animals surviving less than 1.7 years. Thus, evolution of variants with enhanced pathogenicity can account for the increased pathogenicity of this SIV strain. The genetic changes responsible for this virulent transformation included at most 59 point mutations and 3 length-change mutations. The critical mutations were likely to have been multiple and dispersed, including elongation of the TM and Nef coding sequences; changes in RNA splice donor and acceptor sites, TATA box sites, and Sp1 sites; multiple changes in the V2 region of SU, including a consensus neutralization epitope; and five new N-linked glycosylation sites in SU.

Amino Acid Sequence↗
PubMed2003

Production of cytolethal distending toxins by pathogenic Escherichia coli strains isolated from human and animal sources: establishment of the existence of a new cdt variant (Type IV).

Three types of cytolethal distending toxin (CDT), namely, CDT-I, CDT-II, and CDT-III, have been described in Escherichia coli. Using primers designed for the detection of sequences common to the cdtB genes, we analyzed by PCR a set of 21 CDT-producing E. coli strains of intestinal and extraintestinal origins isolated from human and different animal species in several European countries and in the United States. On the basis of the existing differences in the cdtB genes, cdt-I-, cdt-II-, and cdt-III-specific primer pairs were designed and used for cdt typing. These new primers successfully differentiated all of the previously described cdt genes. Six strains proved to be cdt-I; eight strains proved to be cdt-III. However, none of the type I-, II-, and III-specific primers generated amplicons from six CDT(+) strains, suggesting the existence of a new cdt variant. Sequence analysis of the amplicons from two untypeable genes confirmed the existence of a new cdt variant that we called cdt-IV. Using the new specific primers, cdt-IV was detected in human, porcine, and poultry strains of intestinal and extraintestinal origins. To validate all sets of cdt specific primers, a group of 353 human E. coli strains isolated in Hungary was then investigated for the presence of cdt genes. This included 190 strains isolated from patients with urinary tract infections (UTI), 51 strains isolated from other (nonurinary) extraintestinal infections, and 112 intestinal strains isolated from healthy individuals. Of 190 UTI strains, 15 (7.9%) had cdt genes. Of 51 non-UTI extraintestinal strains 3 (5.9%) contained the cdt gene, and 1 (0.9%) of 112 healthy intestinal strains was PCR positive. Five strains proved to be cdt-I, and fourteen strains proved to be cdt-IV. The CDT-producing extraintestinal strains belonged to a wide variety of serogroups, including O2, O6, O75, and O170. In conclusion, we have developed a new PCR typing system for CDT able to detect a new CDT variant present in pathogenic E. coli strains obtained from animals and humans.

Animals↗
PubMed1993

Geographic and temporal distribution and molecular characterization of two highly pathogenic clones of Streptococcus pyogenes expressing allelic variants of pyrogenic exotoxin A (Scarlet fever toxin).

The molecular population genetics and pathogenic potential of North American and European invasive strains of Streptococcus pyogenes were assessed. Isolates from recent invasive infections and from infections in the 1920s and 1930s were characterized for multilocus enzyme genotype and allelic variation in the gene (speA) that encodes streptococcal pyrogenic exotoxin (SPE) A (scarlet fever toxin). A subset of strains was studied for allelic variation in genes that encode SPE B and streptokinase. All contemporary strains assigned to electrophoretic types (ETs) 1 and 2 that synthesize SPE A have the speA2 and speA3 allelic variants, respectively, and their relative virulence in two mouse models is similar to that of strains of the same ET and M protein types recovered earlier. In contrast, ET 1 and 2 isolates from disease episodes in the 1920s and 1930s contain the speA1 allele. The data suggest there may be temporal and geographic variation in the occurrence of clone--virulence factor allele combinations, an observation that may in part explain fluctuations in disease frequency, severity, and character.

Alleles↗
PubMed2026

Identification of novel HUWE1 variants in Turner-type X-linked intellectual disability.

OBJECTIVE: To characterize the clinical phenotypes and identify the genetic etiology in four unrelated families affected by Turner-type X-linked intellectual disability (XLID). METHODS: Peripheral blood samples were collected from four probands and their parents. Genomic DNA was extracted, and a comprehensive genetic analysis was performed using trio-based Whole Exome Sequencing (WES) combined with low-pass Copy Number Variation sequencing (CNV-seq). Candidate variants were subsequently validated via Sanger sequencing. RESULTS: Genetic analysis identified distinct variants in the HUWE1 across the four families. Specifically, four distinct HUWE1 variants were identified across the families: a hemizygous c.10034 > T (p.Lys3345Met) in Family 1; a heterozygous c.9209G > A (p.Arg3070His) in Family 2; a heterozygous c.12688T > C (p.Phe4230Leu) in Family 3; and a hemizygous c.9070G > A (p.Ala3024Thr) in Family 4. In accordance with ACMG guidelines, the novel variants in Families 1, 3, and 4 were classified as "Likely Pathogenic" (PS2 + PM2_Supporting + PP2 + PP3). In contrast, the previously reported variant in Family 2 was categorized as "Pathogenic" based on the criteria PS2 + PM2_Supporting + PM5 + PP2 + PP3_Moderate. All probands were clinically diagnosed with Turner-type XLID. CONCLUSIONS: This study expands the pathogenic variant spectrum of HUWE1 and provides novel molecular evidence for the clinical diagnosis of Turner-type XLID. These findings are of significant value for genetic counseling, carrier screening, and prenatal diagnosis for the affected families.

Humans↗
PubMed2025

Exome sequencing revealed a novel homozygous variant in TRMT61 A in a multiplex family with atypical Cornelia de Lange Syndrome from Rwanda.

BACKGROUND: In 30% of patients who exhibit the clinical profile of Cornelia de Lange Syndrome (CdLS), the genetic cause remains undetermined. This proportion tends to be higher in low-resource settings including Africa. We performed a molecular characterization of CdLS in a multiplex Rwandan family. METHODS: After a clinical evaluation of two affected siblings, DNA isolated from peripheral whole blood of the affected patients and their parents underwent Exome Sequencing (ES). Sanger sequencing validated the variant segregating with CdLS. In silico predictive tools, protein modelling, and cell-based experiments using HEK293T cells were used to investigate the pathogenicity of the variant found. RESULTS: We identified a family with two parents and their two offspring (male and female), who were referred for hearing impairment. The 17-year-old female presented bilateral profound hearing impairment with moderate hypertelorism, progressive visual impairment, and secondary amenorrhea. The 14-year-old male displayed intellectual disability and a bilateral profound hearing impairment with no noticeable facial dysmorphism. Following exome sequencing (ES) of DNA samples obtained from the four family members, we found that the siblings harbored a novel likely pathogenic homozygous missense variant in the TRMT61 A gene [NM_152307.3:c.665C > T p.(Ala222Val)] inherited from both heterozygous parents. In silico analysis suggested that the variant substitutes a highly conserved amino acid, and 2-D structure modelling revealed a significant decrease in the stability of the protein. Cell-based experiment in HEK293T showed that the variant significantly affected the TRMT61 A protein localization which is thought to impact the mitochondrial and cytosolic functions. CONCLUSION: We reported a novel biallelic variant in TRMT61 A, [NM_152307.3:c.665C > T p.(Ala222Val)], which is associated with autosomal recessive atypical CdLS in a multiplex Rwandan family, the first report from Africa, and the second globally. The study emphasizes the need to expand the availability of ES for molecular characterization of rare diseases for the understudied genetically diverse population of Africa.

Humans↗
PubMed1992

Characterization of form variants of Xenorhabdus luminescens.

From Xenorhabdus luminescens XE-87.3 four variants were isolated. One, which produced a red pigment and antibiotics, was luminescent, and could take up dye from culture media, was considered the primary form (XE-red). A pink-pigmented variant (XE-pink) differed from the primary form only in pigmentation and uptake of dye. Of the two other variants, one produced a yellow pigment and fewer antibiotics (XE-yellow), while the other did not produce a pigment or antibiotics (XE-white). Both were less luminescent, did not take up dye, and had small cell and colony sizes. These two variants were very unstable and shifted to the primary form after 3 to 5 days. It was not possible to separate the primary form and the white variant completely; subcultures of one colony always contained a few colonies of the other variant. The white variant was also found in several other X. luminescens strains. DNA fingerprints showed that all four variants are genetically identical and are therefore derivatives of the same parent. Protein patterns revealed a few differences among the four variants. None of the variants could be considered the secondary form. The pathogenicity of the variants decreased in the following order: XE-red, XE-pink, XE-yellow, and XE-white. The mechanism and function of this variability are discussed.

Animals↗
PubMed2000

Mitochondrial DNA sequence diversity in bipolar affective disorder.

OBJECTIVE: Point mutations in mitochondrial DNA (mtDNA) are one mechanism that could explain the apparent excess maternal transmission of bipolar affective disorder observed in some families. The authors sequenced the mtDNA from probands with bipolar disorder and tested nucleotide variants for association with the disorder. METHOD: The entire 16.5 kilobase mitochondrial genome was sequenced in nine unrelated probands selected from large pedigrees with exclusively maternal transmission of bipolar affective disorder. Compared to a reference sequence, variants were detected at 107 nucleotide positions. Fifteen variants of possible pathogenic significance were selected for further study. These variants were assayed in 93 unrelated probands with bipolar I, bipolar II, or schizoaffective-manic disorder and 63 comparison subjects, all of whom were classified into the major groups comprising the European mtDNA haplotype structure (haplogroups). RESULTS: The major European haplogroups were represented at the expected frequencies among both probands and comparison subjects. There was no significant difference between probands and comparison subjects in the frequency of any variant, although odds ratios >2 or <0.5 were observed for four variants. Frequencies of these four variants were similar in probands and haplogroup-matched comparison subjects. The results of all comparisons were essentially unchanged when probands from families with an apparently paternal transmission pattern were excluded. CONCLUSIONS: The results demonstrate that bipolar affective disorder occurs across all of the major European mtDNA haplogroups but do not reveal any point mutations that explain excess maternal transmission of the disorder.

Adolescent↗
PubMed2006

A model to infer the pathogenic significance of CDH1 germline missense variants.

Germline mutations of the E-cadherin gene (CDH1) are involved in the tumorigenesis of hereditary diffuse gastric cancer (HDGC). Recent studies have highlighted the lifesaving potential of total prophylactic gastrectomy for CDH1 germline mutation carriers. In this regard, CDH1 germline mutations of the missense type represent a clinical burden in genetic counseling, as their pathogenic relevance is not straightforward. In this work, we have outlined a possible multivariate approach to infer the significance of such variants. We reviewed all HDGC-associated E-cadherin germline missense mutations reported to date. The information collected included: co-segregation of the mutation within pedigrees, frequency in healthy population control, recurrence in independent families, and functional in vitro and in silico data. We used the neighbor-joining method to group mutations according to the collected information and assessed the robustness of mutation clusters with a bootstrap test. CDH1 germline missense variants were classified according to the parameters defined in the multivariate analysis. This analysis allowed the distribution of the variants into two distinct groups: neutral variants vs mutations. The model described in this study provides an important tool that can ultimately improve the genetic counseling offered to the carriers of the germline CDH1 missense variants.

Alleles↗
PubMed2026

Bipolar disorder-associated variants in RAB5A disrupt its function in endolysosomal trafficking in fruit fly and mammalian systems.

Bipolar disorder is a severe neuropsychiatric disorder associated with significant morbidity and mortality. Although the heritability of bipolar disorder is among the highest of all neuropsychiatric disorders, the specific genetic etiologies for most affected individuals have remained elusive. This is due, in part, to difficulty confirming pathogenicity of genomic variants identified in bipolar disorder populations. From the Bipolar Exomes Browser (BipEX) project, we identified three missense variants in RAB5A in four individuals with bipolar disorder not found in controls. We used a Drosophila overexpression system to evaluate these bipolar disorder-associated variants in RAB5A. We determined that when bipolar disorder-associated RAB5A variants are expressed in fruit flies, synaptic neurotransmission, endolysosomal trafficking, viability, survival and wing morphology are all disrupted. We confirmed that certain bipolar disorder-associated RAB5A variants also disrupt early endosomal trafficking in mammalian cells. This confirms bipolar disorder-associated variants in RAB5A disrupt its normal function. Moreover, Drosophila melanogaster is a viable experimental system to test the pathogenicity of genomic variants associated with psychiatric disorders.

Journal Article↗
PubMedDate not supplied

The Amazonia variant of Vibrio cholerae: molecular identification and study of virulence genes.

The pathogenic O1 Amazonia variant of Vibrio cholerae has been shown previously to have a cytotoxin acting on cultured Vero and Y-1 cells, and to lack important virulence factors such as the cholera toxin (Coelho et al. 1995a). This study extends the molecular analysis of the Amazonia strains, detecting the presence of the toxR gene, with a very similar sequence to that of the E1 Tor and classical biotypes. The outer membrane proteins are analyzed, detecting a variation among the group of Amazonia strains, with three different patterns found. As a by-product of this work a polymerase chain reaction fragment was sequenced, reading part of the sequence of the Lon protease of the Amazonia strains. This gene was not previously described in V. cholerae, but its sequence is present in the TIGR database specific for this species.

ATP-Dependent Proteases↗
PubMed2025

DHX37 variants in patients with 46,XY disorders or differences of sex development.

Here, using whole-exome sequencing of a cohort of 17 Japanese patients with 46,XY disorders or differences of sex development, we identified two pathogenic DEAH-box helicase 37 (DHX37) variants in three patients. We also identified a patient with a likely pathogenic variant in SOX9 and a rare likely benign variant in DHX37. This Data Report highlights the genetic and phenotypic diversity of DXH37 variants.

Journal Article↗
PubMed2002

Amino acid deletions are introduced into the V2 region of gp120 during independent pathogenic simian immunodeficiency virus/HIV chimeric virus (SHIV) infections of rhesus monkeys generating variants that are macrophage tropic.

Highly pathogenic simian immunodeficiency virus/HIV chimeric viruses (SHIVs) cause extremely rapid, irreversible, and systemic depletions of CD4(+) T lymphocytes in inoculated rhesus monkeys. In the absence of this T cell subset, virus production can be sustained for several months by tissue macrophage. During independent infections of seven animals with uncloned virus stocks, SHIV variants emerged bearing amino acid deletions that affected specific residues of the gp120 V2 loop. Some of these macrophage-phase SHIVs replicated to high levels in alveolar macrophage.

Amino Acid Sequence↗
PubMed2005

A model for pathogen population structure with cross-protection depending on the extent of overlap in antigenic variant repertoires.

The persistence of discrete antigenic types among pathogens with multiple immunogenic loci can be explained by the action of immune-mediated competition. It has previously been shown that pathogen populations will self-organize into non-overlapping subsets of antigenic variants if cross-protection between pathogen types sharing any variants is high. Here, we examine the critical question of whether such strain structure will emerge if the degree of immune-mediated competition is dependent on the number of variants shared between pathogen types, rather than in an all-or-nothing manner. Our analysis uncovers a progression from no strain structure through to discrete stable strain structure through intermediate partially structured states. This suggests that the number of loci or epitope regions required to detect linkage disequilibrium (as a manifestation of stable discrete strain structure) in pathogen populations correlates inversely with the strength of immune selection.

Antigenic Variation↗
PubMed2002

HIV disease progression: is the Brazilian variant subtype B' (GWGR motif) less pathogenic than US/European subtype B (GPGR)?

BACKGROUND: The aim of this study was to investigate differences in HIV disease progression in patients infected with HIV subtype B with a GPGR motif in the V3 loop region (B-GPGR) versus the Brazilian subtype B variant with a GWGR motif (B'-GWGR). MATERIALS AND METHODS: Patients were enrolled in an ongoing cohort study at the University of São Paulo Dermatology Clinic in Sao Paulo, Brazil. V3 serology was performed by enzyme immunoassay with peptides representing two HIV subtype B strains, MN and SF2, and two Brazilian variant B'-GWGR strains. The incidence of AIDS-defining events was calculated, and Cox proportional hazards regression was used to estimate adjusted risk ratios. RESULTS: Of the samples from 114 patients studied, 23 (20%) were classified as B'-GWGR motif, and 91 (80%) as B-GPGR motif. Patients with T CD4+ cell counts less than 200 cells/mm3 or 200-400 cells/mm3 experienced an increased incidence of AIDS-defining events compared with patients who entered the cohort with T CD4+ cell counts greater than 400 cells/mm3. In a proportional hazard model including age, gender, T CD4+ cell count at entry into the cohort, and V3 serology, GWGR reactivity was associated with a decreased hazard rate for presenting an AIDS-defining condition during follow-up. Three patients in the group with GPGR serology died after experiencing an AIDS-defining event. None of the patients with GWGR serology died during follow-up. DISCUSSION: Survival analysis showed that patients infected with the Brazilian subtype B variant with a GWGR motif in the V3 loop had lower risk, adjusted for initial CD4+ cell count, of AIDS-defining events than patients infected with subtype B-GPGR strains.

Adult↗
PubMed2003

Mutations in the COL4A4 gene in thin basement membrane disease.

BACKGROUND: Patients with thin basement membrane disease (TBMD) are often from families where hematuria segregates with the COL4A3 and COL4A4 genes. These genes also are affected in autosomal recessive Alport syndrome. The aim of this study was to demonstrate COL4A4 mutations in TBMD. METHODS: Forty-eight unrelated individuals with TBMD who had no family members with autosomal recessive Alport syndrome were examined for COL4A4 mutations. The diagnosis of TBMD had been confirmed by renal biopsy (43/48, 90%) or by a family history of hematuria but without a renal biopsy (5/48, 10%). The 47 coding exons of COL4A4 were screened for mutations with the methods of enzyme mismatch cleavage or single stranded conformational polymorphism (SSCP) analysis, and exons that demonstrated electrophoretic abnormalities were sequenced. RESULTS: Nine variants that altered the coding sequences were identified. These were nonsense and frameshift mutations that resulted in stop codons (N = 3), and glycine (N = 3) and non-glycine missense variants (N = 3). Four intronic variants and three neutral polymorphisms were also detected. In total, four variants were considered 'pathogenic' principally because they resulted in stop codons or were not present in non-hematuric normal subjects. Three variants were considered 'possibly pathogenic' but two of these were each present in one of 46 non-hematuric normal subjects. CONCLUSIONS: Pathogenic COL4A4 mutations were demonstrated in three of the nine (33%) families in whom hematuria segregated with the COL4A3/COL4A4 locus. Two stop codons (R1377X and 2788/91delG) and a glycine substitution (G960R) resulted in hematuria in all 16 members who were tested from these three families. The S969X mutation described here in TBMD for the first time, as well as the R1377X mutation, also occur in autosomal recessive Alport syndrome.

Adolescent↗