RESUMEN
Cholesterol is essential in the brain from the earliest stages of embryonic development. Disruption of cholesterol synthesis pathways that leads to cholesterol deficiency underlies a few syndromes, including desmosterolosis and Smith-Lemli-Opitz syndrome. In both syndromes, brain anomalies can occur. The LSS gene encodes lanosterol synthase (LSS), an important enzyme in the cholesterol biosynthesis pathway. Biallelic pathogenic variants in this gene cause alopecia-intellectual disability type 4 syndrome (APMR4, MIM 618840), a rare autosomal recessive disorder. Here, we describe two new LSS variants (c.1016C > T; p. Ser339Leu and c.1522G > C; p. Gly508Arg) found in a compound heterozygous fetus diagnosed prenatally with brain abnormalities by ultrasound scanning. Two of his siblings from the same parents also harbored these variants. Both siblings had alopecia, mild intellectual disability, autism spectrum disorder, and cataracts. To the best of our knowledge, this case represents the first prenatal diagnosis of APMR4 first suspected by ultrasound. In addition, the phenotypic features of the siblings are extensive compared with those described in previous reports and include abnormal corpus callosum, cataracts, alopecia, and developmental delay.
Asunto(s)
Trastorno del Espectro Autista , Catarata , Discapacidad Intelectual , Embarazo , Femenino , Humanos , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/genética , Diagnóstico Prenatal , Alopecia/genética , Colesterol/genética , Colesterol/metabolismoRESUMEN
Approximately 10% of cancers have a hereditary predisposition. However, no genetic diagnosis is available in 60%-80% of familial cancers. In some of these families, immune dysregulation-mediated disease is frequent. The immune system plays a critical role in identifying and eliminating tumors; thus, dysregulation of the immune system can increase the risk of developing cancer. This review focuses on some of the genes involved in immune dysregulation the promote the risk for cancer. Genetic counseling for patients with cancer currently focuses on known genes that raise the risk of cancer. In missing hereditary familial cases, the history family of immune dysregulation should be recorded, and genes related to the immune system should be analyzed in relevant families. On the other hand, patients with immune disorders diagnosed with a pathogenic mutation in an immune regulatory gene may have an increased risk of cancer. Therefore, those patients need to be under surveillance for cancer. Gene panel and exome sequencing are currently standard methods for genetic diagnosis, providing an excellent opportunity to jointly test cancer and immune genes.
Asunto(s)
Predisposición Genética a la Enfermedad , Neoplasias , Humanos , Secuenciación del Exoma , Neoplasias/genética , Mutación/genéticaRESUMEN
Background: Autosomal dominant hyper-IgE syndrome (AD-HIES) caused by dominant negative (DN) variants in the signal transducer and activator of transcription 3 gene (STAT3) is characterized by recurrent Staphylococcal abscesses, severe eczema, chronic mucocutaneous candidiasis (CMC), and non-immunological facial and skeletal features. Objectives: To describe our experience with the diagnosis and treatment of adult patients with AD-HIES induced by DN-STAT3 variants. Methods: The medical records of adult patients (>18 years) treated at the Allergy and Clinical Immunology Clinic of Hadassah Medical Center, Jerusalem, Israel, were retrospectively analyzed. Immune and genetic workups were used to confirm diagnosis. Results: Three adult patients (2 males; age 29-41 years) were diagnosed with DN-STAT3 variants. All patients had non-immunological features, including coarse faces and osteopenia. Serious bacterial infections were noted in all patients, including recurrent abscesses, recurrent pneumonia, and bronchiectasis. CMC and diffuse dermatophytosis were noted in two patients. Two patients had severe atopic dermatitis refractory to topical steroids and phototherapy. Immune workup revealed elevated IgE in three patients and eosinophilia in two patients. Whole exome sequencing revealed DN-STAT3 variants (c.1166C>T; p.Thr389Ile in two patients and c.1268G>A; p. Arg423Gln in one patient). Variants were located in DNA-binding domain (DBD) and did not hamper STAT3 phosphorylation Treatment included antimicrobial prophylaxis with trimethoprim/sulfamethoxazole (n=2) and amoxycillin-clavulanic acid (n=1), and anti-fungal treatment with fluconazole (n=2) and voriconazole (n=1). Two patients who had severe atopic dermatitis, were treated with dupilumab with complete resolution of their rash. No adverse responses were noted in the dupilumab-treated patients. Discussion: Dupilumab can be used safely as a biotherapy for atopic dermatitis in these patients as it can effectively alleviate eczema-related symptoms. Immunologists and dermatologists treating AD-HIES adult patients should be aware of demodicosis as a possible manifestation. DN-STAT3 variants in DBD do not hamper STAT3 phosphorylation.
Asunto(s)
Dermatitis Atópica , Eccema , Síndrome de Job , Factor de Transcripción STAT3 , Adulto , Humanos , Masculino , Absceso , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/genética , Síndrome de Job/diagnóstico , Síndrome de Job/genética , Síndrome de Job/terapia , Estudios Retrospectivos , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , FemeninoRESUMEN
Signal transducer and activator of transcription (STAT)1 heterozygous gain-of-function (GOF) mutations are known to induce immune dysregulation and chronic mucocutaneous candidiasis (CMCC). Previous reports suggest an association between demodicosis and STAT1 GOF. However, immune characterization of these patients is lacking. Here, we present a retrospective analysis of patients with immune dysregulation and STAT1 GOF who presented with facial and ocular demodicosis. In-depth immune phenotyping and functional studies were used to characterize the patients. We identified five patients (three males) from two non-consanguineous Jewish families. The mean age at presentation was 11.11 (range = 0.58-24) years. Clinical presentation included CMCC, chronic demodicosis and immune dysregulation in all patients. Whole-exome and Sanger sequencing revealed a novel heterozygous c.1386C>A; p.S462R STAT1 GOF mutation in four of the five patients. Immunophenotyping demonstrated increased phosphorylated signal transducer and activator of transcription in response to interferon-α stimuli in all patients. The patients also exhibited decreased T cell proliferation capacity and low counts of interleukin-17-producing T cells, as well as low forkhead box protein 3+ regulatory T cells. Specific antibody deficiency was noted in one patient. Treatment for demodicosis included topical ivermectin and metronidazole. Demodicosis may indicate an underlying primary immune deficiency and can be found in patients with STAT1 GOF. Thus, the management of patients with chronic demodicosis should include an immunogenetic evaluation.
Asunto(s)
Mutación con Ganancia de Función , Enfermedades Genéticas Congénitas , Enfermedades del Sistema Inmune , Infestaciones por Ácaros , Ácaros/inmunología , Factor de Transcripción STAT1 , Enfermedades Cutáneas Parasitarias , Adolescente , Adulto , Animales , Niño , Enfermedad Crónica , Femenino , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/inmunología , Enfermedades Genéticas Congénitas/parasitología , Humanos , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/parasitología , Lactante , Masculino , Persona de Mediana Edad , Infestaciones por Ácaros/genética , Infestaciones por Ácaros/inmunología , Estudios Retrospectivos , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/inmunología , Enfermedades Cutáneas Parasitarias/genética , Enfermedades Cutáneas Parasitarias/inmunologíaRESUMEN
Medical, industrial, and basic research relies heavily on the use of viruses and vectors. Therefore, it is important that bioscience undergraduates learn the practicalities of handling viruses. Teaching practical virology in a student laboratory setup presents safety challenges, however. The aim of this article is to describe the design and implementation of a virology laboratory, with emphasis on student safety, for biotechnology undergraduates. Cell culture techniques, animal virus infection, quantification, and identification are taught at a biosafety level 2 for a diverse group of undergraduates ranging from 20 to 50 students per group. © 2017 by The International Union of Biochemistry and Molecular Biology, 45(6):537-543, 2017.
Asunto(s)
Biotecnología/educación , Contención de Riesgos Biológicos , Laboratorios , Estudiantes , Universidades , Virología/educación , Humanos , EnseñanzaRESUMEN
Viruses cause a variety of illnesses in humans, yet only a few antiviral drugs have been developed; thus, new antiviral drugs are urgently needed. Plants could be a good source of antiviral drugs, they do not have mobility and can only defend themselves by producing compounds against pathogens such as viruses in their own fix environment. These compounds may have the potential to inhibit animal and human viruses as well. In this study, a fast and reliable method for screening plant extracts for specific antiviral activity against Herpes simplex virus type-1 (HSV-1) was developed. This method distinguishes between host cell death due to infectivity and multiplicity of the virus versus toxicity of the plant extract. Extracts from 80 plant and plant organs were screened using this approach. Six plant extracts showed potential to exert specific HSV-1 growth inhibition activity. In two cases, different organs from the same plant showed similar active results. With this method it is possible to screen a large number of extracts in a rapid and accurate way to detect antiviral substances against HSV-I and other viruses.
Asunto(s)
Antivirales/aislamiento & purificación , Evaluación Preclínica de Medicamentos/métodos , Herpesvirus Humano 1/efectos de los fármacos , Extractos Vegetales/aislamiento & purificación , Animales , Antivirales/farmacología , Antivirales/toxicidad , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Herpesvirus Humano 1/fisiología , Ensayos Analíticos de Alto Rendimiento/métodos , Extractos Vegetales/farmacología , Extractos Vegetales/toxicidad , Células Vero , Replicación Viral/efectos de los fármacosRESUMEN
Expression of free short peptides could potentially be used to modulate biochemical cascades and consequently to change cellular phenotypes. Here we demonstrate that expression of a short peptide of 15 amino acids, including the pseudo-substrate site of the baculovirus-apoptosis inhibitor P35, Asp-Gln-Met-Asp (DQMD), leads to abrogation of the apoptotic cascade. Treatment of cells, expressing the DQMD peptide with two apoptosis inducers, etoposide and sodium nitroprusside, (SNP) results in blocking of the apoptotic cascade, indicated by DNA fragmentation and caspase activation. Consequently, stable expression of the DQMD peptide led to protection of cells, following induction of apoptosis and to the outgrowth and enrichment of resistant cell colonies. The results presented in this work demonstrate for the first time the feasibility of expressing in cells functional short peptides that block apoptotic cascade, and to rescue the phenotypically altered cells in a stable fashion. This approach is general and could be applied to the study of other peptides and the respective biochemical cascades.