RESUMEN
BACKGROUND: Hereditary actin-related protein 2/3 complex subunit 1B deficiency is characterized clinically by ear, skin, and lung infections, bleeding, eczema, food allergy, asthma, skin vasculitis, colitis, arthritis, short stature, and lymphadenopathy. OBJECTIVE: We aimed to describe the clinical, laboratory, and genetic features of six patients from four Mexican families. METHODS: We performed exome sequencing in patients of four families with suspected actinopathy, collected their data from medical records, and reviewed the literature for reports of other patients with actin-related protein 2/3 complex subunit 1B deficiency. RESULTS: Six patients from four families were included. All had recurrent infections, mainly bacterial pneumonia, and cellulitis. A total of 67% had eczema whereas 50% had food allergies, failure to thrive, hepatomegaly, and bleeding. Eosinophilia was found in all; 84% had thrombocytopenia, 67% had abnormal-size platelets and anemia. Serum levels of IgG, IgA, and IgE were highly increased in most; IgM was normal or low. T cells were decreased in 67% of patients, whereas B and NK cells were increased in half of patients. Two of the four probands had compound heterozygous variants. One patient was successfully transplanted. We identified 28 other patients whose most prevalent features were eczema, recurrent infections, failure to thrive, bleeding, diarrhea, allergies, vasculitis, eosinophilia, platelet abnormalities, high IgE/IgA, low T cells, and high B cells. CONCLUSION: Actin-related protein 2/3 complex subunit 1B deficiency has a variable and heterogeneous clinical spectrum, expanded by these cases to include keloid scars and Epstein-Barr virus chronic hepatitis. A novel deletion in exon 8 was shared by three unrelated families and might be the result of a founder effect.
Asunto(s)
Eccema , Eosinofilia , Infecciones por Virus de Epstein-Barr , Vasculitis , Humanos , Proteína 2 Relacionada con la Actina , Actinas , Insuficiencia de Crecimiento , Herpesvirus Humano 4 , Inmunoglobulina A , Inmunoglobulina E , Reinfección , Proteína 3 Relacionada con la Actina/metabolismoRESUMEN
Integral membrane proteins represent a large and diverse portion of the proteome and are often recalcitrant to purification, impeding studies essential for understanding protein structure and function. By combining co-evolutionary constraints and computational modeling with biochemical validation through site-directed mutagenesis and enzyme activity assays, we demonstrate here a synergistic approach to structurally model purification-resistant topologically complex integral membrane proteins. We report the first structural model of a eukaryotic membrane-bound O-acyltransferase (MBOAT), ghrelin O-acyltransferase (GOAT), which modifies the metabolism-regulating hormone ghrelin. Our structure, generated in the absence of any experimental structural data, revealed an unanticipated strategy for transmembrane protein acylation with catalysis occurring in an internal channel connecting the endoplasmic reticulum lumen and cytoplasm. This finding validated the power of our approach to generate predictive structural models for other experimentally challenging integral membrane proteins. Our results illuminate novel aspects of membrane protein function and represent key steps for advancing structure-guided inhibitor design to target therapeutically important but experimentally intractable membrane proteins.
Asunto(s)
Aciltransferasas/química , Dominio Catalítico , Acetilación , Aciltransferasas/metabolismo , Animales , Ghrelina/química , Ghrelina/metabolismo , Humanos , Células Sf9 , SpodopteraRESUMEN
Among active duty service members, posttraumatic stress disorder (PTSD) diagnoses have increased dramatically since 2000. Because psychiatric comorbidity is more common for PTSD than for other mental health disorders, we examined the prevalence estimates of disorders comorbid or trimorbid with PTSD in this study. The medical records of 523,626 female and male active duty Sailors and Marines who entered the U.S. military between 2006 and 2013 were examined for diagnoses of PTSD and 14 potentially comorbid disorders. Results showed that 1.8% of military members had a PTSD diagnosis; among those with PTSD, 83.3% had a comorbid mental health disorder, and 62.2% had a third (i.e., trimorbid) disorder. Most frequently, PTSD co-occurred with depressive disorder (49.0%), adjustment disorder (37.0%), generalized anxiety disorder (36.1%), and alcohol use disorder (26.9%). All disorders we examined were significantly more likely to be diagnosed in service members with PTSD than in those without PTSD, odds ratios = 1.52-29.63. For service members with PTSD, comorbid mental health disorders are the rule rather than the exception. Consequently, it is important that clinicians also assess for other disorders and select treatment options that address both PTSD and comorbid conditions.