RESUMEN
BACKGROUND: Studies have linked matrix metalloproteinases (MMPs) to both thoracic aortic aneurysm and abdominal aortic aneurysm (TAA and AAA). The precise MMPs entailed in this procedure, however, were still unknown. This study used a two-sample Mendelian randomization (MR) analysis to look into the causal relationship between MMPs and the risk of TAA and AAA. METHODS: Eight MMPs, including MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, MMP-12, and MMP-13, were found among people of European ancestry with accessible Genome-Wide Association Studies (GWAS). We employed the findings from Genome-Wide Association Studies (GWAS) for 8 MMPs, and TAA and AAA from the FinnGen consortiums (3,201 cases and 317,899 controls, respectively) were used in a two-sample MR analysis. The primary method of analysis for MR was the inverse variance weighted (IVW) method, along with analyses of heterogeneity and horizontal pleiotropy. 31 single-nucleotide polymorphisms connected to MMP were retrieved. RESULTS: IVW demonstrated a negative causal association between TAA and AAA and serum MMP-12 levels. The incidence of TAA decreased by 1.031% for every 1 ng/mL increase in serum MMP-12 [odds ratio (OR) = 0.897, 95% confidence interval (CI): 0.831-0.968, P = 0.005]. The incidence of AAA fell by 1.653% (OR = 0.835, 95% CI: 0.752-0.926, P = 0.001) for every 1 ng/mL increase in serum MMP-12. There was no horizontal pleiotropy or heterogeneity in the MR data (P > 0.05). CONCLUSIONS: The levels of TAA and AAA and serum MMP-12 are causally related. MMP-12 is a factor that reduces the risk of AAA and TTA. Our study suggested that MMP-12 level is causally associated with a decreased risk of TAA and AAA.
Asunto(s)
Aneurisma de la Aorta Abdominal , Aneurisma de la Aorta Torácica , Metaloproteinasas de la Matriz , Humanos , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/enzimología , Aneurisma de la Aorta Abdominal/diagnóstico por imagen , Aneurisma de la Aorta Abdominal/sangre , Aneurisma de la Aorta Abdominal/epidemiología , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/enzimología , Aneurisma de la Aorta Torácica/sangre , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Aneurisma de la Aorta Torácica/epidemiología , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Incidencia , Metaloproteinasa 12 de la Matriz/genética , Metaloproteinasa 12 de la Matriz/sangre , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/sangre , Análisis de la Aleatorización Mendeliana , Fenotipo , Polimorfismo de Nucleótido Simple , Factores Protectores , Medición de Riesgo , Factores de RiesgoRESUMEN
High temperature requirement serine peptidase A1 (HTRA1) related cerebral small vessel disease (CSVD) includes both symptomatic heterozygous HTRA1 variant carrier and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) patients. Presently, most reported symptomatic heterozygous HTRA1 variant carrier cases are sporadic family reports with a lack of specific characteristics. Additionally, the molecular mechanism of heterozygous HTRA1 gene variants is unclear. We conducted this review to collect symptomatic carriers of heterozygous HTRA1 gene variants reported as of 2022, analyzed all pathogenicity according to American College of Medical Genetics and Genomics (ACMG) variant classification, and summarized the cases with pathogenic and likely pathogenic HTRA1 variants gender characteristics, age of onset, geographical distribution, initial symptoms, clinical manifestations, imaging signs, HTRA1 gene variant information and to speculate its underlying pathogenic mechanisms. In this review, we summarized the following characteristics of pathogenic and likely pathogenic symptomatic HTRA1 variant carriers: to date, the majority of reported symptomatic HTRA1 carriers are in European and Asian countries, particularly in China which was found to have the highest number of reported cases. The age of first onset is mostly concentrated in the fourth and fifth decades. The heterozygous HTRA1 gene variants were mostly missense variants. The two variant sites, 166-182 aa and 274-302 aa, were the most concentrated. Clinicians need to pay attention to de novo data and functional data, which may affect the pathogenicity analysis. The decrease in HtrA1 protease activity is currently the most important explanation for the genetic pathogenesis.
RESUMEN
Alexander disease (AxD) is a rare, autosomal dominant genetic disorder with an incidence of approximately 1 in 27,00.000. It is caused by a missense mutation in the GFAP gene encoding the glial fibrillary acidic protein. Fragile X-associated tremor/ataxia syndrome (FXTAS) is an X-linked dominant genetic disease, usually caused by a pre-mutation: an unmethylated expansion in the range of 50-200 CGG repeats in the fragile X mental retardation 1 (FMR1) gene. The clinical manifestations of these two diseases are complex and have some similarities. Both type II AxD and FXTAS may have ataxia as the first symptom. Here, we describe a case of type II AxD with ataxia as the first symptom accompanying a hemizygous mutation in the FMR1 gene (NM_001185081, exon13, c 0.1256C>T, p.T419M, g 0.147026507C>T). A sporadic genetic mutation led us to misdiagnose the patient with FXTAS initially. Whole-genome sequencing confirmed a heterozygous mutation in the GFAP gene (NM_002055.5, exon4, c 0.1158C>A, p.N386K, g 0.6310C>A). This report indicates that when the patient's clinical manifestation is ataxia, and imaging results suggest that the midbrain, medulla oblongata, and other subcerebellar structures are atrophied, AxD should be considered. Whole-genome sequencing is thus feasible to avoid missed diagnoses and misdiagnoses.
Asunto(s)
Enfermedad de Alexander/diagnóstico , Enfermedad de Alexander/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Mutación/genética , Humanos , Masculino , Persona de Mediana Edad , LinajeRESUMEN
Sertoli cells are essential nurse cells in the testis that regulate the process of spermatogenesis and establish the immune-privileged environment of the blood-testis-barrier (BTB). Here, we report the in vitro reprogramming of fibroblasts to human induced Sertoli-like cells (hiSCs). Initially, five transcriptional factors and a gene reporter carrying the AMH promoter were utilized to obtain the hiSCs. We further reduce the number of reprogramming factors to two, NR5A1 and GATA4, and show that these hiSCs have transcriptome profiles and cellular properties that are similar to those of primary human Sertoli cells. Moreover, hiSCs can sustain the viability of spermatogonia cells harvested from mouse seminiferous tubules. hiSCs suppress the proliferation of human T lymphocytes and protect xenotransplanted human cells in mice with normal immune systems. hiSCs also allow us to determine a gene associated with Sertoli cell only syndrome (SCO), CX43, is indeed important in regulating the maturation of Sertoli cells.
Asunto(s)
Reprogramación Celular , Fibroblastos/metabolismo , Factor de Transcripción GATA4/genética , Síndrome de Sólo Células de Sertoli/genética , Células de Sertoli/metabolismo , Factor Esteroidogénico 1/genética , Animales , Diferenciación Celular/genética , Proliferación Celular , Técnicas de Cocultivo , Fibroblastos/citología , Factor de Transcripción GATA4/metabolismo , Regulación del Desarrollo de la Expresión Génica , Humanos , Masculino , Ratones , Regiones Promotoras Genéticas , Receptores de Péptidos/genética , Receptores de Péptidos/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Túbulos Seminíferos/citología , Túbulos Seminíferos/crecimiento & desarrollo , Túbulos Seminíferos/metabolismo , Síndrome de Sólo Células de Sertoli/metabolismo , Síndrome de Sólo Células de Sertoli/patología , Células de Sertoli/citología , Células de Sertoli/trasplante , Espermatogénesis/genética , Espermatogonias/citología , Espermatogonias/crecimiento & desarrollo , Espermatogonias/metabolismo , Factor Esteroidogénico 1/metabolismo , Linfocitos T/citología , Linfocitos T/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Trasplante Heterólogo/métodos , Proteínas WT1/genética , Proteínas WT1/metabolismoRESUMEN
Mechanotransduction is the conversion of extracellular mechanical stimuli into intracellular biochemical signals, and plays an important role in heart responses to its own mechanical environment. Piezo1 as a distinct stretch-activated channel (SAC) in mammal involves in not only vascular remodeling during embryonic development but also arterial remodeling upon to hypertension at adult stage. In the present study, the expression of Piezo1 was up-regulated in failure heart induced by myocardial infarction (MI) by real-time PCR, Western blot and immunohistochemistry analysis. Expression of Piezo1 mRNA and protein was enhanced by AngiotensinII (AngII) in neonatal rat ventricular myocytes via AT1 receptor depended methods. Furthermore, the Piezo1 expression was attenuated by Erk1/2 chemical inhibitor (U0126) only, but not by p38 MAPK inhibitor (SB203580), or JNK inhibitor (SP600125). Finally, systolic function improvement followed by chronic treatment with angiotensin receptor blocker (ARB) losartan prevented Piezo1 up-regulation in failure heart in vivo. In conclusion, our studies linked mechanotransduction which involved renin-angiotensin system that mediated up-regulation of Piezo1 to a clinically relevant heart failure.