Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, and it is typically caused by PKD1 and PKD2 heterozygous variants. Nonetheless, the extensive phenotypic variability observed among affected individuals, even within the same family, suggests a more complex pattern of inheritance. We describe an ADPKD family in which the proband presented with an earlier and more severe renal phenotype (clinical diagnosis at the age of 14 and end-stage renal disease aged 24), compared to the other affected family members. Next-generation sequencing (NGS)-based analysis of polycystic kidney disease (PKD)-associated genes in the proband revealed the presence of a pathogenic PKD2 variant and a likely pathogenic variant in PKD1, according to the American College of Medical Genetics and Genomics (ACMG) criteria. The PKD2 nonsense p.Arg872Ter variant was segregated from the proband\'s father, with a mild phenotype. A similar mild disease presentation was found in the proband\'s aunts and uncle (the father\'s siblings). The frameshift p.Asp3832ProfsTer128 novel variant within PKD1 carried by the proband in addition to the pathogenic PKD2 variant was not found in either parent. This report highlights that the co-inheritance of two or more PKD genes or alleles may explain the extensive phenotypic variability among affected family members, thus emphasizing the importance of NGS-based techniques in the definition of the prognostic course.

Danon disease is a rare x-linked dominant multisystemic disorder with a clinical triad of severe cardiomyopathy, skeletal myopathy, and intellectual disability. It is caused by defects in the lysosome-associated membrane protein-2 (LAMP2) gene. Numerous different mutations in the LAMP2 protein have been described. Danon disease is typically lethal by the mid-twenties in male patients due to cardiomyopathy and heart failure. Female patients usually present with milder and variable symptoms. This report describes a 42-year-old father and his 3-year-old daughter presenting with mild manifestations of the disease. The father has normal intellectual development and normal physical activity. At the age of 13, he was diagnosed with mild ventricular pre-excitation known as Wolf-Parkinson-White syndrome (WPWs), very mild and mostly asymptomatic cardiomyopathy and left ventricular hypertrophy, and at about the age of 25 presented with visual impairment due to cone-rod dystrophy. His daughter showed normal development and very mild asymptomatic electrocardiographic WPWs abnormalities with left mild ventricular hypertrophy. Genetic testing revealed an Xq24 microdeletion encompassing the entire LAMP2 gene. Relevant literature was reviewed as a reference for the etiology, diagnosis, treatment and case management.

Polycystic ovarian syndrome (PCOS) is a complex endocrine and metabolic condition with several potential causes. Insulin resistance is a hallmark of PCOS that often coexists with hirsutism, hyperandrogenism, being overweight, and hormonal imbalances. The functioning of multiple replication and transcription factors is regulated by tumor suppressor genes (TSGs), which play a crucial role in maintaining genomic integrity and controlling the cell cycle of granulosa cells. In the present study, we examined how three single nucleotide polymorphisms (SNPs) in TP53, a cell cycle regulatory gene, affect the risk of developing PCOS in a sample of an Iranian population. Genomic DNA was extracted from 200 PCOS patients and 200 healthy women to analyze TP53 rs17880604, rs1625895, and rs1042522 SNPs using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Our findings revealed that the majority of PCOS cases were overweight [25 < body mass index (BMI) < 30]. A positive association was observed between the TP53 rs1042522 SNP and the risk of PCOS under codominant heterozygous and overdominant genetic patterns (odds ratio > 1). Meanwhile, a negative association was observed between TP53 SNPs (rs1625895, rs17880604) and susceptibility to PCOS under codominant heterozygous and dominant models of inheritance (odds ratio < 1). Moreover, different genotype and haplotype combinations of rs17880604/rs1625895/rs1042522 conferred a decreased risk of PCOS in our population. We found no statistical difference in the frequency of TP53 genotypes between PCOS cases and/or controls in terms of BMI, waist circumference, prolactin level, and markers of lipid and carbohydrate profile (P > 0.05). Molecular dynamic prediction showed that the missense substitution in the 17p13.1 position (rs1042522) could change the properties and secondary structure of the p53 protein. As inherited risk factors, TP53 variations may play a  pivotal role in the pathogenesis of PCOS among Iranian women. Replicated population-based studies on other ethnicities are required to find the genetic contribution of variants of TP53, or SNPs located in other TSGs, to the etiology of this endocrine disease.

BACKGROUND: HIV elite controllers represent a rare subset of persons living with HIV, able to spontaneously control viral replication without antiviral therapy. HLA-B∗57 and HLA-B∗27 alleles are associated to efficient polyfunctional CD8+ T-cell response and are overrepresented in elite controllers but these alleles alone incompletely explain spontaneous HIV replication control in these subjects. Further mechanisms involved in innate and adaptive immune response and host genetics may contribute to this control. In this context, the homeostatic iron regulator (HFE) gene encodes a major histocompatibility complex-class-I-like molecule involved in both innate immunity, acting also through autophagy regulation, and iron homeostasis, strictly related to immune functions and susceptibility to infections.
METHODS: Homozygousity for the p.His63Asp (H63D) variant in the HFE gene was identified in an 80-year-old HIV-infected woman with spontaneous control of viral replication.
METHODS: HIV-1 RNA was undetectable in patient\'s serum with a routine assay and an ultra-sensitive assay (<1 copy/mL) during the 30 years follow-up. CD4+ and CD8+ T cell counts were stable and normal during all this period.
METHODS: The patient had a history of absence of any physical ailment and no antiviral therapy has been prescribed during the 30 years of follow-up. The subject did not harbor HLA-B∗57 and HLA-B∗27 alleles. HFE gene was sequenced by Sanger, as part of a larger study on a cohort of HIV infected patients, aged >65 years and screened for polymorphisms in genes belonging to several pathways involved in neuroinflammation.
RESULTS: The woman had CD4+ and CD8+ T cell normal values and spontaneously controlled serum HIV-1 RNA levels for 30 years.
CONCLUSIONS: We assume that the interplay between the HFE H63D variant in homozygosity and innate immunity, perhaps through autophagy regulation, could play a role in HIV-1 replication control in our patient. This hypothesis needs to be explored in in vitro and in vivo studies. Understanding mechanisms involved in spontaneous control of HIV-1 replication remains indeed a challenge due to its possible implications for HIV cure research.

The clinical course of a case of infant botulism was characterized by several relapses despite therapy with amoxicillin and metronidazole. Botulism was confirmed by identification of botulinum toxin and Clostridium botulinum in stools. A C. botulinum A2 strain resistant to penicillins and with heterogeneous resistance to metronidazole was isolated from stool samples up to 110 days after onset. Antibiotic susceptibility was tested by disc agar diffusion and MICs were determined by Etest. Whole genome sequencing allowed detection of a gene cluster composed of blaCBP for a novel penicillinase, blaI for a regulator, and blaR1 for a membrane-bound penicillin receptor in the chromosome of the C. botulinum isolate. The purified recombinant penicillinase was assayed. Resistance to β-lactams was in agreement with the kinetic parameters of the enzyme. In addition, the β-lactamase gene cluster was found in three C. botulinum genomes in databanks and in two of 62 genomes of our collection, all the strains belonging to group I C. botulinum. This is the first report of a C. botulinum isolate resistant to penicillins. This stresses the importance of antibiotic susceptibility testing for adequate therapy of botulism.

The contribution of melanocortin-1 receptor (MC1R) gene variants to the development of early-onset melanoma is unknown. Using an Australian population-based, case-control-family study, we sequenced MC1R for 565 cases with invasive cutaneous melanoma diagnosed between ages 18 and 39 years, 409 unrelated controls and 518 sibling controls. Variants were classified a priori into \"R\" variants (D84E, R142H, R151C, I155T, R160W, D294H) and \"r\" variants (all other nonsynonymous variants). We estimated odds ratios (OR) for melanoma using unconditional (unrelated controls) and conditional (sibling controls) logistic regression. The prevalence of having at least one R or r variant was 86% for cases, 73% for unrelated controls and 81% for sibling controls. R151C conferred the highest risk (per allele OR 2.57, 95% confidence interval 1.86-3.56 for the case-unrelated-control analysis and 1.70 (1.12-2.60) for the case-sibling-control analysis). When mutually adjusted, the ORs per R allele were 2.23 (1.77-2.80) and 2.06 (1.47-2.88), respectively, from the two types of analysis, and the ORs per r allele were 1.69 (1.33-2.13) and 1.25 (0.88-1.79), respectively. The associations were stronger for men and those with none or few nevi or with high childhood sun exposure. Adjustment for phenotype, nevi and sun exposure attenuated the overall log OR for R variants by approximately 18% but had lesser influence on r variant risk estimates. MC1R variants explained about 21% of the familial aggregation of melanoma. Some MC1R variants are important determinants of early-onset melanoma. The strength of association with melanoma differs according to the type and number of variants.

Using the lac operon as a paradigmatic example for a gene regulatory system in prokaryotes, we demonstrate how qualitative knowledge can be initially captured using simple discrete (Boolean) models and then stepwise refined to multivalued logical models and finally to continuous (ODE) models. At all stages, signal transduction and transcriptional regulation is integrated in the model description. We first show the potential benefit of a discrete binary approach and discuss then problems and limitations due to indeterminacy arising in cyclic networks. These limitations can be partially circumvented by using multilevel logic as generalization of the Boolean framework enabling one to formulate a more realistic model of the lac operon. Ultimately a dynamic description is needed to fully appreciate the potential dynamic behavior that can be induced by regulatory feedback loops. As a very promising method we show how the use of multivariate polynomial interpolation allows transformation of the logical network into a system of ordinary differential equations (ODEs), which then enables the analysis of key features of the dynamic behavior.

BACKGROUND: Preeclampsia is an important clinical condition with unknown etiology. We used DNA array technique to compare placental gene expression profile in severe early-onset preeclampsia from 25 to 27 gestational weeks with strictly non-affected placental samples from similar gestational weeks.
METHODS: DNA arrays were validated by showing the up-regulation of several genes typical for preeclampsia such as chorionic gonadotrophin beta-chain, tissue factor pathway inhibitor, and intercellular adhesion molecule-1. In DNA array, 5% of genes displayed less than or equal to twofold increase in expression level and only 0.2% of genes showed < or =0.5-fold decrease in expression in preeclampsia versus control. Signs of immunological factors, hypoxia, apoptosis, oxidative stress and altered thrombosis, coagulation as well as endothelial injury were seen in the gene expression profile.
RESULTS: As a new finding, we identified a group of 13 genes with a function in tumor suppression and growth regulation which were significantly up-regulated in preeclampsia. Three out of the five most highly up-regulated genes belonged to this group which included genes, such as protein phosphatase 2, phospholipid scramblase 1, transcription elongation factor, melanoma adhesion molecule, retinoic acid receptor responder 3, and RANTES.
CONCLUSIONS: It is concluded that up-regulation of tumor suppressor and growth regulatory genes may play an important role in the pathogenesis of severe early-onset preeclampsia.

To investigate the evolution pattern and phylogenetic utility of duplicate control regions (CRs) in mitochondrial (mt) genomes, we sequenced the entire mt genomes of three Ixodes species and part of the mt genomes of another 11 species. All the species from the Australasian lineage have duplicate CRs, whereas the other species have one CR. Sequence analyses indicate that the two CRs of the Australasian Ixodes ticks have evolved in concert in each species. In addition to the Australasian Ixodes ticks, species from seven other lineages of metazoa also have mt genomes with duplicate CRs. Accumulated mtDNA sequence data from these metazoans and two recent experiments on replication of mt genomes in human cell lines with duplicate CRs allowed us to re-examine four intriguing questions about the presence of duplicate CRs in the mt genomes of metazoa: (1) Why do some mt genomes, but not others, have duplicate CRs? (2) How did mt genomes with duplicate CRs evolve? (3) How could the nucleotide sequences of duplicate CRs remain identical or very similar over evolutionary time? (4) Are duplicate CRs phylogenetic markers? It appears that mt genomes with duplicate CRs have a selective advantage in replication over mt genomes with one CR. Tandem duplication followed by deletion of genes is the most plausible mechanism for the generation of mt genomes with duplicate CRs. Once duplicate CRs occur in an mt genome, they tend to evolve in concert, probably by gene conversion. However, there are lineages where gene conversion may not always occur, and, thus, the two CRs may evolve independently in these lineages. Duplicate CRs have much potential as phylogenetic markers at low taxonomic levels, such as within genera, within families, or among families, but not at high taxonomic levels, such as among orders.

BACKGROUND: Deposition of beta-amyloid in the brains of patients with Alzheimer\'s disease is thought to precede a chain of events that leads to an inflammatory response by the brain. We postulated that genetic variation in the regulatory region of the gene for the proinflammatory cytokine tumour necrosis factor alpha (TNF-alpha) leads to increased risk of Alzheimer\'s disease and vascular dementia.
METHODS: A polymorphism in the regulatory region of the TNF-alpha gene was analysed in a case-control study. The polymorphism (C-850T) was typed in 242 patients with sporadic Alzheimer\'s disease, 81 patients with vascular dementia, 61 stroke patients without dementia, and 235 normal controls. These groups of individuals were also genotyped for the apolipoprotein E polymorphism, and the vascular dementia and stroke groups were typed at the HLA-DR locus.
RESULTS: The distribution of TNF-alpha genotypes in the vascular dementia group differed significantly from that in the stroke and normal control groups, giving an odds ratio of 2.51 (95% CI 1.49-4.21) for the development of vascular dementia for individuals with a CT or TT genotype. Logistic regression analysis indicated that the possession of the T allele significantly increased the risk of Alzheimer\'s disease associated with carriage of the apolipoprotein E epsilon4 allele (odds ratio 2.73 [1.68-4.44] for those with apolipoprotein E epsilon4 but no TNF-alpha T, vs 4.62 [2.38-8.96] for those with apolipoprotein E epsilon4 and TNF-alpha T; p=0.03).
CONCLUSIONS: Possession of the TNF-alpha T allele significantly increases the risk of vascular dementia, and increases the risk of Alzheimer\'s disease associated with apolipoprotein E. Although further research is needed, these findings suggest a potential role for anti-inflammatory therapy in vascular dementia and Alzheimer\'s disease, and perhaps especially in patients who have had a stroke.