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PubMed2004

Preliminary data suggest that mutations in the CgRP pathway are not involved in human sporadic cryptorchidism.

In testicular descent to the scrotum, a multistep process, many anatomical and hormonal factors play a role. Cryptorchidism occurs in about 1-2% of males and may cause secondary degeneration of the testes. Animal models have shown that abnormalities, in the calcitonin gene-related peptide (CgRP) activity, could be relevant in the pathogenesis of cryptorchidism. We performed a mutation screening by PCR exon amplification, single-strand conformation polymorphism (SSCP) and sequencing in four candidate genes, CgRPs (alphaCgRP, betaCgRP), their receptor (CgRPR) and the receptor component protein (CgRP-RCP), in 90 selected cases of idiopathic unilateral or bilateral cryptorchidism. Mutation screening of the coding regions and intron-exon boundaries revealed some polymorphic variants but no pathogenic sequence changes. These preliminary data suggest that these genes are not major factors for cryptorchidism in humans.

Adult↗

PubMed2003

Average age-specific cumulative risk of breast cancer according to type and site of germline mutations in BRCA1 and BRCA2 estimated from multiple-case breast cancer families attending Australian family cancer clinics.

If the risk of disease is not the same for all germline mutations in a given gene, or if there are other familial modifiers of risk in carriers, then family-history-based estimates of average risk for detected mutations in that gene will depend on how carriers are sampled. Risk may also depend on the site or type of mutation. We studied 51 families with strong histories of breast cancer who attended Australian family cancer clinics and in which a germline mutation in BRCA1 or BRCA2 had been identified (28 and 23 families, respectively). Breast cancer risk in carriers was estimated under maximum likelihood theory, using information from all family members including those not tested, with adjustment for ascertainment by conditioning on genotype of the proband and family phenotype. The average cumulative risk of breast cancer for mutations in either BRCA1 or BRCA2 was 27% (95% confidence interval 16-43%) to age 50 and 64% (44-83%) to age 70. When grouped, the incidence in carriers was on average 17 (10-30) times that in non-carriers, independent of gene or mutation type (hazard ratios: 11 (4-29) for BRCA1, 23 (12-43) for BRCA2 (P for difference = 0.23); 13 (6-29) for protein-truncating mutations, 30 (9-104) for missense mutations and 30 (10-90) for splice-site mutations). For missense mutations, this was equivalent to a cumulative risk to age 70 of 83% (40-100%) and was due in part, but not totally, to the missense mutations 300 T>G in BRCA1 and 4486 G>T in BRCA2, which were individually found to be associated with high risk (P<0.001). Mutations in the central region of BRCA1 may be associated with a lower risk. The issue of the pathogenicity of specific variants may be addressed analytically providing there are one or more suitably informative families with that mutation.

Age Factors↗

PubMed2003

Inherited BRCA2 mutations in African Americans with breast and/or ovarian cancer: a study of familial and early onset cases.

In order to identify the spectrum of BRCA2 mutations in African Americans, breast or ovarian cancer patients from 74 independent families at elevated risk of germline mutations were investigated. The entire coding regions and flanking introns of BRCA2 were screened for germline mutations by single-stranded conformation polymorphism, protein truncation test, or denaturing high performance liquid chromatography followed by DNA sequencing. Eight distinct protein-truncating mutations were detected in six female patients (average age of onset of breast cancer: 37.6 years) and two male patients, but not in 163 unrelated disease-free controls. Two (1993delAA, 8643delAT) of the eight pathogenic mutations observed in African Americans have not been previously described. The other six pathogenic mutations (1882delT, 1991delATAA, 2001delTTAT, 2816insA, 4075delGT, 4088delA) have been detected in Caucasians; only the 2816insA mutation has been reported previously in African Americans. There were no significant differences in the frequency of deleterious BRCA2 mutations in African Americans compared with Caucasians. Six rare variations, not previously reported, were identified in five breast cancer patients but not in 163 disease-free control subjects. Of 11 different polymorphisms identified in high-risk African-American breast cancer patients, four may be unique to African Americans. An intron 10 polymorphism observed in patients was not detected in 163 disease-free African-American control subjects; this difference is statistically significant. Since many different pathogenic mutations and variants of unknown significance are observed in African Americans, BRCA2 genetic testing in high-risk African-American families must include the entire coding and flanking non-coding regions of the gene.

Adult↗

PubMed2025

Small RNAs derived from avocado sunblotch viroid and their association with bleaching symptoms: implications for pathogenesis in avocado sunblotch disease.

Avocado sunblotch viroid (ASBVd) is a structured RNA molecule responsible for sunblotch disease of avocado, characterised by distinct chloroses of fruit, leaves, and stems. Despite its impact on avocado, the mechanism by which ASBVd elicits sunblotch symptoms remains unknown. Previous studies on other avsunviroids have shown that viroid-derived small RNAs (vd-sRNAs) with specific sequence mutations can trigger leaf chlorosis via RNA silencing of host genes. Building on this knowledge, we aimed to shed light on the molecular basis of ASBVd pathogenesis by analysing ASBVd sequence variants and ASBVd-sRNAs from bleached and asymptomatic leaf tissues of sunblotch-affected avocado trees. Sequencing of ASBVd clones revealed that variants carrying the pathogenic determinant for bleaching were present in both green and yellow leaf tissues. Next-generation sequencing (NGS) identified ASBVd-sRNAs that varied in abundance between symptomatic and asymptomatic leaf tissues, correlating with viroid titre. We discovered 64 vd-sRNAs spanning the pathogenic region of the ASBVd genome, which were almost exclusively found in yellow tissues. The ASBVd-sRNAs containing the bleaching-associated mutation were predicted to target numerous avocado transcripts for degradation, with 25 of these transcripts significantly downregulated in bleached tissues. Notably, one of these genes, encoding a chloroplastic protein, demonstrated strong evidence of ASBVd-sRNA-guided RNA silencing, presenting a promising candidate for future research into the molecular trigger for ASBVd-induced bleaching symptoms. This study is the first to investigate ASBVd-sRNAs in bleached leaves using NGS. Our findings support the role of RNA silencing in sunblotch symptom development and reveal a unique silencing trigger compared to other avsunviroids.

Persea↗

PubMed2005

Introducing a novel human mtDNA mutation into the Paracoccus denitrificans COX I gene explains functional deficits in a patient.

We identified a novel mutation (S142F) in the human mtDNA CO I gene in a patient with a clinical phenotype resembling mitochondrial cardioencephalomyopathy. To substantiate pathogenicity, we modeled the identified mutation in the homologous gene in Paracoccus denitrificans and analyzed the biochemical consequences. We observed a deleterious effect on enzyme activity, with a lack of heme a3. Taking advantage of the extensive structural homology between the bacterial enzyme and the mammalian core complex, we conclude that the novel S142F mutation is disease-related. This approach can be used in other cases to support the pathogenicity of novel variants in the mitochondrial genome.

Adult↗

PubMed2025

The functional study of novel KLHL3 missense mutations associated with pseudohypoaldosteronism type II.

BACKGROUND: Pseudohypoaldosteronism type II (PHA II) is an inherited tubulopathy, clinically defined by three hallmark features, including secondary hypertension, hyperchloremic metabolic acidosis, and persistent hyperkalemia occurring despite maintained glomerular filtration function. Herein, we aim to investigate the association of kelch like family member 3 (KLHL3) gene mutations with PHA II. METHODS: Compound heterozygous KLHL3 mutations were identified through whole-exome sequencing and Sanger validation. AlphaFold-based structural modeling, site-directed mutagenesis of Flag-tagged plasmids, and co-immunoprecipitation (Co-IP)/immunoblotting in vivo were combined to analyze mutant protein interactions and ubiquitination effects. RESULTS: A Chinese patient was identified with two previously unreported KLHL3 variants (c.131G > A [p.R44Q] and c.744 C > G [p.Y248*]), exhibiting a biochemical triad of asymptomatic hyperkalemia, mild metabolic acidosis, and borderline hypertension. Administration of thiazide diuretics effectively normalized the patient’s hyperkalemia and hypertension. A p.R44Q missense mutation predicted as variants of uncertain significance (VOUS) by American College of Medical Genetics and Genomics (ACMG) guidelines, and a p.Y248* nonsense mutation predicted as variants of likely pathogenic. Functional study revealed that the two KLHL3 mutations impair its ubiquitination of with-no-lysine kinase 1 (WNK1) and with-no-lysine kinase 4 (WNK4), and further increase phosphorylation of both SPAK (sterile20/sporulation-specific protein-1 related proline/alanine-rich kinase)/OSR1 (oxidative stress response kinase-1) and Na-Cl-cotransporter (NCC). CONCLUSIONS: Our study characterized two previously unreported KLHL3 mutations, followed by comprehensive in vitro functional analyses to elucidate their pathophysiological contributions at the molecular level.

Humans↗

PubMed1994

Role of Shiga-like toxin I in bacterial enteritis: comparison between isogenic Escherichia coli strains induced in rabbits.

BACKGROUND/AIMS: Enteroadherent Escherichia coli that produce Shiga-like toxins are important causes of human disease, including enterohemorrhagic E. coli-induced colitis (EHEC). The role of Shiga-like toxins in these illnesses is unclear. The aim of this study was to establish an animal model for human EHEC and to determine the role of Shiga-like toxin I (SLT-I) in this model. METHODS: E. coli strain RDEC-1 is an enteroadherent rabbit diarrheal pathogen. An isogenic variant of RDEC-1 (termed RDEC-H19A) producing high levels of SLT-I was obtained by infecting RDEC-1 with an SLT-I-converting bacteriophage. The effects of in vivo enteric infection produced in rabbits by RDEC-H19A were compared with those in uninfected and RDEC-1-infected animals. RESULTS: SLT-I-producing RDEC-H19A induced a severe, noninvasive, enteroadherent infection in rabbits. Clinically, infection with RDEC-H19A was more severe than infection with RDEC-1 and caused more serious histological lesions including vascular changes, edema, and more severe inflammation. Interleukin 1 and platelet-activating factor appear to be important inflammatory mediators to this infection. CONCLUSIONS: The illness induced by RDEC-H19A in rabbits resembled enterohemorrhagic E. coli-induced colitis of humans. SLT-I is an important virulence factor in the pathogenesis of EHEC.

Animals↗

PubMed1993

Characterisation of isolates and strains of citrus tristeza closterovirus using restriction analysis of the coat protein gene amplified by the polymerase chain reaction.

Citrus Tristeza Virus (CTV) exists as a large number of distinct strains differing in biological properties and with different distributions in citrus producing countries. Strategies such as eradication or cross protection, aimed at controlling severe variants of the pathogen, require procedures to identify virus strains accurately and reliably. To fill the need for a rapid, reproducible assay, we have investigated the use of restriction analysis of the CTV coat protein gene amplified using the polymerase chain reaction (PCR). The primers 5' ATG GAC GAC GAA ACA AAG 3' and 5' TCA ACG TGT GTT GAA TTT 3' amplified a DNA copy of the CTV coat protein gene (approx. 670 base pairs) when used in a reverse transcriptase PCR assay. Amplifications were carried out using dsRNA prepared from field and indicator plants, or from single-stranded RNA prepared from crude PEG precipitates of intact virions. All 51 CTV isolates tested produced an amplified product of the same size, regardless of country of origin or biological properties. Digestion of the amplified coat protein genes with the restriction enzymes Hinf1 or Rsa1 revealed sequence variation in the PCR products. Hinf1 provided the best discrimination between strains, defining seven Restriction Fragment Length Polymorphism (RFLP) groups, some of which circumscribed sets of isolates with similar biological properties. Limited analysis of field isolates using this method showed that individual trees could contain mixtures of CTV strains, as assessed by the recovery of several RFLP types from individual reactions. Single aphid transmissions of isolates usually, but not always, generated apparently pure single strains judged by the recovery of single RFLP groups.

Animals↗

PubMed2026

Management of complex lipid disorders in a community lipid clinic setting: Implementing a multidisciplinary model.

BACKGROUND: Large treatment gaps exist in the management of lipid disorders, and many high-risk patients have factors that complicate management efforts. While lipid clinics exist within academic medical centers, most of these patients are cared for in community settings. OBJECTIVE: To report our experience and results managing challenging and complex lipid disorders in a community-based lipid clinic. METHODS: We established a specialized lipid clinic in a community medical setting, with a focus on patients with management challenges and/or suspicion of a genetic lipid disorder, employing a multidisciplinary approach to optimize patient outcomes, emphasizing appropriate medical therapies and lipid genetic testing in selected patients. Retrospective electronic health record data were collected to analyze patient characteristics, treatment patterns, and lipid results. RESULTS: Over the period 2022 through 2024, 183 patients were seen (mean 63 years, 62% female). The challenging nature of the patient population was highlighted by high rates of statin intolerance (50%), no lipid medical therapy at baseline (50%), and comorbidities (atherosclerotic cardiovascular disease [ASCVD], diabetes, and/or hypertension-61%). Despite this, over a mean follow-up of 9.4 ± 7.3 months, we observed a mean low-density lipoprotein cholesterol decrease of 49 mg/dL (-24.5%, P < .001), along with significant decreases in total cholesterol and triglycerides. Pathogenic dyslipidemia genetic variants were discovered in 21 patients (of 105 tested). Significant lipid improvements in the whole cohort, as well as multiple subgroups, were associated with greater utilization of combination therapies. CONCLUSION: Patients with complex lipid disorders can be successfully managed within a specialized lipid clinic in community medical settings. Applying such a multidisciplinary model outside of traditional academic medical centers offers the potential to raise the level of lipid management and ASCVD prevention more broadly in larger populations.

Combination medical therapy↗

PubMed2004

Identification of the role of presenilins beyond Alzheimer's disease.

Mutations in the genes encoding presenilin 1 (PS1) and presenilin 2 (PS2) account for the majority of the cases of familial early-onset Alzheimer's disease (FAD). Presenilins (PSs) facilitate the intramembraneous cleavage of amyloid precursor protein (APP), coined gamma-secretase cleavage, which generates beta-amyloid peptides (A beta). Considerable evidence suggests that FAD-linked PS variants exert their pathogenic influence by selectively elevating the levels of highly fibrillogenic A beta 42 peptides. In addition, numerous other functions have been ascribed to PSs based on subcellular localization, protein interactions, loss of function studies, and intramembraneous gamma-secretase cleavage of growing number of substrates. This review summarizes the diverse physiological functions that are regulated by PSs beyond APP metabolism.

Alzheimer Disease↗

PubMed2003

Tick-borne encephalitis.

Tick-borne encephalitis (TBE) is one of the most dangerous human infections occurring in Europe and many parts of Asia. The etiological agent Tick-borne encephalitis virus (TBEV), is a member of the virus genus Flavivirus, of the family Flaviviridae. TBEV is believed to cause at least 11,000 human cases of encephalitis in Russia and about 3000 cases in the rest of Europe annually. Related viruses within the same group, Louping ill virus (LIV), Langat virus (LGTV) and Powassan virus (POWV), also cause human encephalitis but rarely on an epidemic scale. Three other viruses within the same group, Omsk hemorrhagic fever virus (OHFV), Kyasanur Forest disease virus (KFDV) and Alkhurma virus (ALKV), are closely related to the TBEV complex viruses and tend to cause fatal hemorrhagic fevers rather than encephalitis. This review describes the clinical manifestations associated with TBEV infections, the main molecular-biological properties of these viruses, and the different factors that define the incidence and severity of disease. The role of ticks and their local hosts in the emergence of new virus variants with different pathogenic characteristics is also discussed. This review also contains a brief history of vaccination against TBE including trials with live attenuated vaccine and modern tendencies in developing of vaccine virus strains.

Animals↗

PubMed1999

Heterogeneity observed in the components of hemolysin BL, an enterotoxin produced by Bacillus cereus.

Hemolysin BL (HBL), a diarrheal enterotoxin originally isolated from Bacillus cereus strain F837/76, is composed of three antigenically distinct proteins designated B, L1, and L2. All three components are required for biological activity. Here, we report antigenic and physical variations in HBL components produced by other B. cereus isolates. Reactions of partial identity were observed in double gel immunodiffusion assays using antibodies to highly purified B, L1, and L2 components of F837/76 and culture supernatants of strains F837/76 and S1C. Western blot analysis showed that F837/76 produced one 38-kDa B protein, one 38-kDa L1, and one 43-kDa L1 protein. In strain S1C, two B (38 and 42 kDa), two L1 (38 and 41 kDa), and one L1 (43 kDa) proteins were detected. Further Western blot analysis of 127 B. cereus isolates showed that 90 produced one or more of the three HBL components. Approximately half of these 90 isolates (43/90; 48%) produced protein profiles which differed from that of F837/76. A total of four B, two L1, and three L2 component profiles with proteins of different sizes were observed. Individual strains produced various combinations of single or multiple bands of each component. In addition, some strains produced only one or two of the three HBL components. The public health significance of these strains is unknown, as all three components are required for biological activity. The data presented here demonstrates a high degree of heterogeneity in HBL and provide the basis for further studies to characterize the variations in HBL and to determine the role of the variant components in pathogenicity.

Antibodies, Bacterial↗

PubMed2006

Species identification of non-tuberculous mycobacteria from humans and cattle of Chad.

In Chad, during a study on tuberculosis in humans and cattle, 52 non-tuberculous mycobacteria (NTM) strains were isolated. By means of INNO-LiPA, PRA-hsp65 amplification and sequencing of 16S rDNA, NTM species of 25/52 isolates were identified. M. fortuitum complex (8) was the most frequent species, followed by M. nonchromogenicum (4) and M. avium complex (4). PRA method could identify M. fortuitum 3rd variant among isolates derived from cattle specimens. This finding could confirm the existence of farcy in the Chadian cattle population as M. fortuitum 3rd variant and putitative pathogen M. farcinogenes can't be distinguished by the methods used in this study. Half of the NTM isolates could not be specified and we considered them as contaminants from the environment.

Animals↗

PubMed1999

Emerging cytopathic and antigenic simian immunodeficiency virus variants influence AIDS progression.

Genetic variants of human and simian immunodeficiency virus (HIV and SIV) that evolve during the course of infection and progression to AIDS are phenotypically and antigenically distinct from their progenitor viruses present at early stages of infection. However, it has been unclear how these late variants, which are typically T-cell tropic, cytopathic and resistant to neutralizing antibodies, influence the development of clinical AIDS. To address this, we infected macaques with cloned SIVs representing prototype variants from early-, intermediate- and late-stage infection having biological characteristics typical of viruses found at similar stages of HIV infection in humans. These studies demonstrate that sequential, phenotypic and antigenic variants represent viruses that have become increasingly fit for replication in the host, and our data support the hypothesis that emerging variants have increased pathogenicity and drive disease progression in SIV and HIV infection.

Animals↗

PubMed2002

COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome.

UNLABELLED: COL4A3/COL4A4 mutations: From familial hematuria to autosomal-dominant or recessive Alport syndrome. BACKGROUND: Mutations of the type IV collagen COL4A5 gene cause X-linked Alport syndrome (ATS). Mutations of COL4A3 and COL4A4 have been reported both in autosomal-recessive and autosomal-dominant ATS, as well as in benign familial hematuria (BFH). In the latter conditions, however, clinical features are less defined, few mutations have been reported, and other genes and non-genetic factors may be involved. METHODS: We analyzed 36 ATS patients for COL4A3 and COL4A4 mutations by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and direct sequencing. Sporadic patients who had tested negative for COL4A5 mutations were included with typical cases of autosomal recessive ATS to secure a better definition of the phenotype spectrum. RESULTS: We identified seven previously undescribed COL4A3 mutations: in two genetic compounds and three heterozygotes, and one in COL4A4. In agreement with the literature, some of the mutations of compound heterozygotes were associated with microhematuria in healthy heterozygous relatives. The mutations of heterozygous patients are likely dominant, since no change was identified in the second allele even by sequencing, and they are predicted to result in shortened or abnormal chains with a possible dominant-negative effect. In addition, both genes showed rare variants of unclear pathogenicity, and common polymorphisms that are shared in part with other populations. CONCLUSIONS: This study extends the mutation spectrum of COL4A3 and COL4A4 genes, and suggests a possible relationship between production of abnormal COL IV chains and dominant expression of a continuous spectrum of phenotypes, from ATS to BFH.

Adult↗

PubMed2003

Emergence and evolution of Vibrio cholerae O139.

The emergence of Vibrio cholerae O139 Bengal during 1992-1993 was associated with large epidemics of cholera in India and Bangladesh and, initially, with a total displacement of the existing V. cholerae O1 strains. However, the O1 strains reemerged in 1994 and initiated a series of disappearance and reemergence of either of the two serogroups that was associated with temporal genetic and phenotypic changes sustained by the strains. Since the initial emergence of the O139 vibrios, new variants of the pathogen derived from multiple progenitors have been isolated and characterized. The clinical and epidemiological characteristics of these strains have been studied. Rapid genetic reassortment in O139 strains appears to be a response to the changing epidemiology of V. cholerae O1 and also a strategy for persistence in competition with strains of the O1 serogroup. The emergence of V. cholerae O139 has provided a unique opportunity to witness genetic changes in V. cholerae that may be associated with displacement of an existing serogroup by a newly emerging one and, thus, provide new insights into the epidemiology of cholera. The genetic changes and natural selection involving both environmental and host factors are likely to influence profoundly the genetics, epidemiology, and evolution of toxigenic V. cholerae, not only in the Ganges Delta region of India and Bangladesh, but also in other areas of endemic and epidemic cholera.

Bangladesh↗

PubMed2002

Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production.

The Alzheimer's disease (AD)-associated presenilin (PS) proteins are required for the gamma-secretase cleavages of the beta-amyloid precursor protein and the site 3 (S3) protease cleavage of Notch. These intramembrane cleavages release amyloid-beta peptide (Abeta), including the pathogenic 42-aa variant (Abeta(42)), as well as the beta-amyloid precursor protein and the Notch intracellular domains (AICD, NICD). Whereas Abeta is generated by endoproteolysis in the middle of the transmembrane domain, AICD and NICD are generated by cleavages at analogous positions close to the cytoplasmic border of the transmembrane domain. Numerous mutations causing familial AD (FAD) that all cause increased production of Abeta(42) have been found in the PS1 gene. Here we have investigated the previously uncharacterized, very aggressive FAD mutation L166P that causes onset of AD in adolescence. Strikingly, the PS1 L166P mutation not only induces an exceptionally high increase of Abeta(42) production but also impairs NICD production and Notch signaling, as well as AICD generation. Thus, FAD-associated PS mutants cannot only affect the generation of NICD, but also that of AICD. Moreover, further analysis with artificial L166 mutants revealed that the gamma-secretase cleavage at position 40/42 and the S3-like gamma-secretase cleavage at position 49 of the Abeta domain are both differentially affected by PS1 L166 mutants. Finally, we show that PS1 L166 mutants affect the generation of NICD and AICD in a similar manner, supporting the concept that S3 protease and S3-like gamma-secretase cleavages are mediated by identical proteolytic activities.

Alzheimer Disease↗

PubMed2004

Genetic association studies in mood disorders: issues and promise.

Genetic association is a powerful method for identifying genetic variants that contribute to the molecular basis of complex diseases. There is now a wealth of informative, validated and densely-spaced single nucleotide polymorphism (SNP) markers for use in association studies, and the delineation of the genome-wide haplotype architecture will greatly enhance our ability to conduct whole genome association screens, fine mapping of linkage regions, and systematic screening of functional candidate genes. Single nucleotide polymorphism-based genotyping technology has progressed dramatically to the point of high-throughput methods that can assay up to thousands of SNPs on many samples in one experiment. Genotyping cost remains a limiting factor in complex disease studies, where numerous SNPs and large sample sets are needed to maximize statistical power. Strategies designed to reduce cost include DNA pooling and analysis with tagSNPs. As larger clinical samples become available, it will be increasingly important to test for hidden stratification in case-control studies, as well as transmission distortion in family-based studies, either of which can lead to spurious association findings. As yet, there is no widely-accepted genetic association finding in mood disorders, but functional candidate genes, such as the serotonin transporter, and positional candidates, such as G72/G30 on chromosome 13q, are beginning to be identified in several studies. Relating associated variants to the phenotype represents the next critical step toward establishing the pathogenic role of gene variants in mood disorders.

Gene Pool↗