Novel PTCH1 and concurrent TP53 mutations in four patients with numerous non-syndromic basal cell carcinomas: The paradigm of oncogenic synergy.

There has been a significant increase in basal cell carcinoma (BCC) incidence, the most common cancer in humans and the age of presentation with the first diagnosis of BCC has decreased in past decades. In this study, we investigated the possibility of genetic markers that can lead to earlier and closer observation of patients at high risk for development of multiple BCCs. The overall goal is to decrease the morbidity and the economic burden of diagnosis and treatment of recurring and/or advanced BCCs. Four patients with numerous BCCs, some of them exceptionally large, were included in this study. A sample of representative BCCs, normal non-sun-exposed skin and blood samples were obtained from each patient. Whole-exome sequencing of DNA was conducted on all samples, and a series of bioinformatics filtering was performed to identify potentially pathogenic sequence variants. The analysis of the data resulted in detection of oncogenic mutations in PTCH1, two of which being novel, and concurrent mutations in TP53 in BCC tumours of all four patients. Such mutations may explain the numerous and postexcision recurring nature of the BCCs of exceptionally large size observed in all these patients, and they can be suggested to serve as a genetic marker for high-risk patients for early detection, prognostication and close follow-up.

The matriptase-prostasin proteolytic cascade in dermatologic diseases.

The proper development and function of skin and hair are dependent on proteolytic activities. Specifically, the matriptase-prostasin cascade is a series of proteolytic reactions in the epidermis integral to normal regulation of desquamation. An increasing amount of research describing this pathway has recently become available, and the importance of this pathway is exhibited by the association of genetic defects in this pathway with human diseases of the skin and hair. Given the relevance of this pathway to dermatology, we provide a review of the current understanding of its relevance to distinct clinical entities, including ichthyosis-hypotrichosis and Netherton syndromes.

Inherited non-alcoholic fatty liver disease and dyslipidemia due to monoallelic ABHD5 mutations.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition and the most common liver disease worldwide, affecting more than one-third of the population. So far there have been no reports on mendelian inheritance in families with NAFLD. METHODS: We performed whole-exome or targeted next-generation sequencing on patients with autosomal dominant NAFLD. RESULTS: We report a heritable form of NAFLD and/or dyslipidemia due to monoallelic ABHD5 mutations, with complete clinical expression after the fourth decade of life, in 7 unrelated multiplex families encompassing 39 affected individuals. The prevalence of ABHD5-associated NAFLD was estimated to be 1 in 1,137 individuals in a normal population. CONCLUSION: We associate a Mendelian form of NAFLD and/or dyslipidemia with monoallelic ABHD5 mutations. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is a common multifactorial disorder with a strong genetic component. Inherited forms of NAFLD have been suspected but, their molecular pathogenesis has not been disclosed. Here we report a heritable form of NAFLD with clinical expression after 40 years of age, associated with monoallelic ABHD5 mutations.

The genetic basis of hyaline fibromatosis syndrome in patients from a consanguineous background: a case series.

BACKGROUND: Hyaline fibromatosis syndrome (HFS) is a rare heritable multi-systemic disorder with significant dermatologic manifestations. It is caused by mutations in ANTXR2, which encodes a transmembrane receptor involved in collagen VI regulation in the extracellular matrix. Over 40 mutations in the ANTXR2 gene have been associated with cases of HFS. Variable severity of the disorder in different patients has been proposed to be related to the specific mutations in these patients and their location within the gene. CASE PRESENTATION: In this report, we describe four cases of HFS from consanguineous backgrounds. Genetic analysis identified a novel homozygous frameshift deletion c.969del (p.Ile323Metfs*14) in one case, the previously reported mutation c.134 T > C (p.Leu45Pro) in another case, and the recurrent homozygous frameshift mutation c.1073dup (p.Ala359Cysfs*13) in two cases. The epidemiology of this latter mutation is of particular interest, as it is a candidate for inhibition of nonsense-mediated mRNA decay. Haplotype analysis was performed to determine the origin of this mutation in this consanguineous cohort, which suggested that it may develop sporadically in different populations. CONCLUSIONS: This information provides insights on genotype-phenotype correlations, identifies a previously unreported mutation in ANTXR2, and improves the understanding of a recurrent mutation in HFS.

Factors affecting smartphone adoption for accessing information in medical settings.

OBJECTIVES: This study aimed to acquire knowledge about the factors affecting smartphone adoption for accessing information in medical settings in Iranian Hospitals. METHODS: A qualitative and quantitative approach was used to conduct this study. Semi-structured interviews were conducted with 21 medical residents and interns in 2013 to identify determinant factors for smartphone adoption. Afterwards, nine relationships were hypothesised. We developed a questionnaire to test these hypotheses and to evaluate the importance of each factor. Structural equation modelling was used to analyse the causal relations between model parameters and to accurately identify determinant factors. RESULTS: Eight factors were identified in the qualitative phase of the study, including perceived usefulness, perceived ease of use, training, internal environment, personal experience, social impacts, observability and job related characteristics. Among the studied factors, perceived usefulness, personal experience and job related characteristics were significantly associated with attitude to use a smartphone which accounted for 64% of the variance in attitude. Perceived usefulness had the strongest impact on attitude to use a smartphone. CONCLUSION: The factors that emerged from interviews were consistent with the Technology Acceptance Model (TAM) and some previous studies. TAM is a reliable model for understanding the factors of smartphone acceptance in medical settings.

Antipsychotic drugs attenuate aberrant DNA methylation of DTNBP1 (dysbindin) promoter in saliva and post-mortem brain of patients with schizophrenia and Psychotic bipolar disorder.

Due to the lack of genetic association between individual genes and schizophrenia (SCZ) pathogenesis, the current consensus is to consider both genetic and epigenetic alterations. Here, we report the examination of DNA methylation status of DTNBP1 promoter region, one of the most credible candidate genes affected in SCZ, assayed in saliva and post-mortem brain samples. The Illumina DNA methylation profiling and bisulfite sequencing of representative samples were used to identify methylation status of the DTNBP1 promoter region. Quantitative methylation specific PCR (qMSP) was employed to assess methylation of DTNBP1 promoter CpGs flanking a SP1 binding site in the saliva of SCZ patients, their first-degree relatives and control subjects (30, 15, and 30/group, respectively) as well as in post-mortem brains of patients with SCZ and bipolar disorder (BD) versus controls (35/group). qRT-PCR was used to assess DTNBP1 expression. We found DNA hypermethylation of DTNBP1 promoter in the saliva of SCZ patients (∼12.5%, P = 0.036), particularly in drug-naïve patients (∼20%, P = 0.011), and a trend toward hypermethylation in their first-degree relatives (P = 0.085) versus controls. Analysis of post-mortem brain samples revealed an inverse correlation between DTNBP1 methylation and expression, and normalization of this epigenetic change by classic antipsychotic drugs. Additionally, BD patients with psychotic depression exhibited higher degree of methylation versus other BD patients (∼80%, P = 0.025). DTNBP1 promoter DNA methylation may become a key element in a panel of biomarkers for diagnosis, prevention, or therapy in SCZ and at risk individuals pending confirmatory studies with larger sample sizes to attain a higher degree of significance.

The role of miRNA134 in pathogenesis and treatment of intractable epilepsy: a review article.

MicroRNA-134 (miRNA134) has emerged as a critical regulator in the pathogenesis of epilepsy, particularly in intractable cases resistant to conventional therapies. This review explores the multifaceted roles of miRNA134 in epileptogenesis, focusing on its influence on dendritic spine morphology and synaptic plasticity. Through its interactions with proteins such as LIM kinase 1 (LIMK1), Pumilio 2 (PUM2), and Tubby-like protein 1 (TULP1), miRNA134 modulates various molecular pathways implicated in epilepsy development. Preclinical studies have shown pro-mising results in targeting miRNA134 for mitigating seizure activity, highlighting its potential as a therapeutic target. Furthermore, miRNA134 holds promise as a biomarker for epilepsy diagnosis and prognosis, offering opportunities for personalized treatment approaches. However, further research is warranted to elucidate the precise mechanisms underlying miRNA134's effects and to translate these findings into clinical applications.

Principles and Applications of CRISPR Toolkit in Virus Manipulation, Diagnosis, and Virus-Host Interactions.

Viruses are one of the most important concerns for human health, and overcoming viral infections is a worldwide challenge. However, researchers have been trying to manipulate viral genomes to overcome various disorders, including cancer, for vaccine development purposes. CRISPR (clustered regularly interspaced short palindromic repeats) is becoming one of the most functional and widely used tools for RNA and DNA manipulation in multiple organisms. This approach has provided an unprecedented opportunity for creating simple, inexpensive, specific, targeted, accurate, and practical manipulations of viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus-1 (HIV-1), and vaccinia virus. Furthermore, this method can be used to make an effective and precise diagnosis of viral infections. Nevertheless, a valid and scientifically designed CRISPR system is critical to make more effective and accurate changes in viruses. In this review, we have focused on the best and the most effective ways to design sgRNA, gene knock-in(s), and gene knock-out(s) for virus-targeted manipulation. Furthermore, we have emphasized the application of CRISPR technology in virus diagnosis and in finding significant genes involved in virus-host interactions.

Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency.

Epidermolysis bullosa (EB), the paradigm of heritable skin fragility disorders, is associated with mutations in as many as 20 distinct genes. One of the clinical variants, recessive dystrophic EB (RDEB), demonstrates sub-lamina densa blistering accompanied by alterations in anchoring fibrils due to mutations in COL7A1. In this study, we characterized a patient with widespread connective tissue abnormalities, including skin blistering similar to that in RDEB. Whole exome sequencing, combined with genome-wide homozygosity mapping, identified a homozygous missense mutation in PLOD3 encoding lysyl hydroxylase 3 (LH3). No mutations in COL7A1, the gene previously associated with RDEB, were detected. The level of LH3 was dramatically reduced in the skin and fibroblast cultures from the patient. The blistering in the skin occurred below the lamina densa and was associated with variable density and morphology of anchoring fibrils. The level of type VII collagen expression in the skin was markedly reduced. Analysis of hydroxylysine and its glycosylated derivatives (galactosyl-hydroxylysine and glucosyl-galactosyl-hydroxylysine) revealed marked reduction in glycosylated hydroxylysine. Collectively, these findings indicate that PLOD3 mutations can result in a dystrophic EB-like phenotype in the spectrum of connective tissue disorders and add it to the list of candidate genes associated with skin fragility.

Transition to Psychosis: Evaluation of the First-Degree Relatives of Patients with Schizophrenia .

OBJECTIVE: Schizophrenia and other psychoses have devastating personal and social impacts and many efforts have been devoted to study prodromal syndromes for psychosis in order to achieve earlier detection and interventions. However, only few studies have been performed in developing countries on this subject, and there is a dearth of evidence in the Iranian population. In this study, we focused on conversion rate to psychosis and changes in prodromal symptoms in a group of first-degree relatives of patients with schizophrenia and to compare the conversion rate in those with and without prodromal symptoms as assessed by the Structured Interview for Prodromal Syndromes (SIPS) and Scale of Prodromal Symptoms (SOPS). METHOD: Participants were the first-degree relatives of hospitalized patients with schizophrenia at Roozbeh Hospital, Tehran, Iran. At baseline, a trained psychiatrist interviewed the participants using the SIPS and the SOPS and assigned them to high- or low-risk groups either based on the presence of prodromal criteria or seeking mental health services. After 12 months, the same examiner re-evaluated the participants in order to determine the changes in their symptoms and identify the probable transitions to psychosis. RESULTS: One hundred participants, 50 participants within each of high- or low-risk groups, were recruited at baseline. Eight participants dropped out of the study. At the follow-up, the rate of transition to full psychosis among high-risk group was 13% (95% CI [0.029, 0.23]), whereas none of the low-risk participants developed psychosis. None of the high-risk participants demonstrated attenuation in their prodromal states after a one-year follow-up. In contrast, of the 50 low-risk participants, three experienced prodromal symptoms for psychosis during this period. High-risk participant's illustrated higher severity in almost all of the SOPS items compared to the low-risk participants at both baseline and follow-up evaluations. CONCLUSION: Prodromal syndrome for psychosis based on the SIPS and the SOPS was a predictive factor for transition to psychosis after a 12- month period in a group of first-degree relatives of patients with schizophrenia admitted to a psychiatric hospital in Iran. Conducting further studies on this at-risk population is highly recommended in order to provide practical methods for early screening and therapeutic interventions. .