RESUMEN

Continuous cell lines are important and commonly used in vitro models in breast cancer (BC) research. Selection of the appropriate model cell line is crucial and requires consideration of their molecular characteristics. To characterize BC cell line models in depth, we profiled a panel of 29 authenticated and publicly available BC cell lines by mRNA-sequencing, mutation analysis, and immunoblotting. Gene expression profiles separated BC cell lines in two major clusters that represent basal-like (mainly triple-negative BC) and luminal BC subtypes, respectively. HER2-positive cell lines were located within the luminal cluster. Mutation calling highlighted the frequent aberration of TP53 and BRCA2 in BC cell lines, which, therefore, share relevant characteristics with primary BC. Furthermore, we showed that the data can be used to find novel, potential oncogenic fusion transcripts, e.g., FGFR2::CRYBG1 and RTN4IP1::CRYBG1 in cell line MFM-223, and to elucidate the regulatory circuit of IRX genes and KLF15 as novel candidate tumor suppressor genes in BC. Our data indicated that KLF15 was activated by IRX1 and inhibited by IRX3. Moreover, KLF15 inhibited IRX1 in cell line HCC-1599. Each BC cell line carries unique molecular features. Therefore, the molecular characteristics of BC cell lines described here might serve as a valuable resource to improve the selection of appropriate models for BC research.

Asunto(s)

Neoplasias de la Mama , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Femenino , Neoplasias de la Mama/patología , Línea Celular Tumoral , Mama/metabolismo , Proteínas Portadoras , Proteínas Mitocondriales/metabolismo

RESUMEN

BACKGROUND: Biallelic variants in RTN4IP1 are a well-established cause of syndromic and nonsyndromic early-onset autosomal recessive optic neuropathy. They have more recently been reported to cause a concomitant but later-onset rod-cone dystrophy with or without syndromic features. METHODS: A comprehensive evaluation was performed that included assessment of visual and retinal function, clinical examination, and retinal imaging. Childhood ophthalmic records as well as the results of genetic testing were evaluated. RESULTS: A 24-year-old female described longstanding reduced visual acuity with more recent subjective impairment of dark adaptation. Visual acuity was subnormal in both eyes. Goldmann kinetic perimetry demonstrated scotomas in a pattern consistent with the presence of both optic neuropathy and rod-cone dystrophy with fundus exam as well as retinal imaging showing corroborating findings. Full-field electroretinography further confirmed the presence of a rod-cone dystrophy. Genetic testing demonstrated biallelic variants in RTN4IP1, one of which was novel, in association with the ocular findings. CONCLUSIONS: RTN4IP1-associated early-onset bilateral optic neuropathy with rod-cone dystrophy is a recently described clinical entity with limited reports available to-date. The present case provides additional support for this dual phenotype and identifies a novel causative variant.

Asunto(s)

Distrofias de Conos y Bastones , Electrorretinografía , Enfermedades del Nervio Óptico , Femenino , Humanos , Adulto Joven , Proteínas Portadoras/genética , Distrofias de Conos y Bastones/genética , Distrofias de Conos y Bastones/diagnóstico , Proteínas Mitocondriales , Mutación , Enfermedades del Nervio Óptico/genética , Enfermedades del Nervio Óptico/diagnóstico , Fenotipo , Proteínas/genética , Agudeza Visual/fisiología , Pruebas del Campo Visual

RESUMEN

Background: RTN4IP1 interacts with a membranous protein of endoplasmic reticulum (RTN4), this study was to explore the role RTN4IP1 involved in breast cancer (BC). Methods: After RNAseq data of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) project were downloaded, correlations between RTN4IP1 expression and clinicopathologic variables, as well as expression levels between cancerous samples and non-cancerous ones were tested. Differentially expressed genes (DEGs) and functional enrichment, gene set enrichment analysis (GSEA) and immune infiltration analysis were conduct for bioinformatics analysis. After logistic regression, Kaplan-Meier curve of disease-specific survival (DSS), univariate and multivariate COX analysis, a nomogram was established for prognosis. Results: RTN4IP1 expression was up-regulated in BC tissue, significantly associated with estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status (P<0.001). The 771 DEGs linked RTN4IP1 to glutamine metabolism and mitoribosome-associated quality control. Functional enrichment pointed to DNA metabolic process, mitochondrial matrix and inner membrane, ATPase activity, cell cycle and cellular senescence; whereas GSEA indicated regulation of cellular cycle, G1_S DNA damage checkpoints, drug resistance and metastasis. Eosinophil cells, natural killer (NK) cells and Th 2 cells were found to be correlated with RTN4IP1 expression (R=-0.290, -0.277 and 0.266, respectively, P<0.001). RTN4IP1high BC had worse DSS than RTN4IP1low ones [hazard ratio (HR) =2.37, 95% confidential interval (CI): (1.48-3.78), P<0.001], which has independent prognostic value (P<0.05). Conclusions: Overexpressed in BC tissue, RTN4IP1 predicts adverse prognosis for patients with BC, especially in infiltrating ductal carcinoma, infiltrating lobular carcinoma, Stage II, Stages III&IV and luminal A subtype.

RESUMEN

The genetic architecture of mitochondrial disease continues to expand and currently exceeds more than 350 disease-causing genes. Bi-allelic variants in RTN4IP1, also known as Optic Atrophy-10 (OPA10), lead to early-onset recessive optic neuropathy, atrophy, and encephalopathy in the afflicted patients. The gene is known to encode a mitochondrial ubiquinol oxidoreductase that interacts with reticulon 4 and is thought to be a mitochondrial antioxidant NADPH oxidoreductase. Here, we describe two unrelated consanguineous families from the northern region of Saudi Arabia harboring a missense variant (RTN4IP1:NM_032730.5; c.475G

Asunto(s)

Encefalopatías , Atrofia Óptica , Antioxidantes , Proteínas Portadoras/genética , Humanos , Proteínas Mitocondriales/genética , Mutación/genética , NADP/genética , Atrofia Óptica/genética , Oxidorreductasas/genética , Arabia Saudita

RESUMEN

Inherited optic neuropathies (IONs) are neurodegenerative disorders characterized by optic atrophy with or without extraocular manifestations. Optic atrophy-10 (OPA10) is an autosomal recessive ION recently reported to be caused by mutations in RTN4IP1, which encodes reticulon 4 interacting protein 1 (RTN4IP1), a mitochondrial ubiquinol oxydo-reductase. Here we report novel compound heterozygous mutations in RTN4IP1 in a male proband with developmental delay, epilepsy, optic atrophy, ataxia, and choreoathetosis. Workup was notable for transiently elevated lactate and lactate-to-pyruvate ratio, brain magnetic resonance imaging with optic atrophy and T2 signal abnormalities, and a nondiagnostic initial genetic workup, including chromosomal microarray and mitochondrial panel testing. Exome sequencing identified a paternally inherited missense variant (c.263T>G, p.Val88Gly) predicted to be deleterious and a maternally inherited deletion encompassing RTN4IP1. To our knowledge, this is the first report of a non-single nucleotide pathogenic variant associated with OPA10. This case highlights the expanding phenotypic spectrum of OPA10, the association between "syndromic" cases and severe RTN4IP1 mutations, and the importance of nonbiased genetic testing, such as ES, to analyze multiple genes and variants types, in patients suspected of having genetic disease.

Asunto(s)

Proteínas Portadoras/genética , Discapacidades del Desarrollo/genética , Epilepsia/genética , Proteínas Mitocondriales/genética , Atrofia Óptica/genética , Ataxia/diagnóstico por imagen , Ataxia/genética , Ataxia/patología , Proteínas Portadoras/ultraestructura , Preescolar , Discapacidades del Desarrollo/diagnóstico por imagen , Discapacidades del Desarrollo/patología , Epilepsia/diagnóstico por imagen , Epilepsia/patología , Exoma/genética , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Proteínas Mitocondriales/ultraestructura , Mutación/genética , Atrofia Óptica/diagnóstico por imagen , Atrofia Óptica/patología , Linaje , Conformación Proteica , Relación Estructura-Actividad , Secuenciación del Exoma

RESUMEN

Autosomal recessive optic neuropathies (IONs) are extremely rare disorders affecting retinal ganglion cells and the nervous system. RTN4IP1 has recently been identified as the third known gene associated with the autosomal recessive ION optic atrophy 10 (OPA10). Patients with RTN4IP1 mutations show early-onset optic neuropathy that can be followed by additional neurological symptoms such as seizures, ataxia, mental retardation, or even severe encephalopathy. Here, we report two siblings from a Chinese family who presented with early-onset optic neuropathy, epilepsy, and mild intellectual disability. Using whole exome sequencing combined with Sanger sequencing, we identified novel compound heterozygous RTN4IP1 mutations (c.646G > A, p.G216R and c.1162C > T, p.R388X) which both co-segregated with the disease phenotype and were predicted to be disease-causing by prediction software. An in vitro functional study in urine cells obtained from one of the patients revealed low expression of the RTN4IP1 protein. Our results identify novel compound heterozygous mutations in RTN4IP1 which are associated with OPA10, highlighting the frequency of RTN4IP1 mutations in human autosomal recessive IONs. To our knowledge, this is the first report of RTN4IP1 carriers from China.

Asunto(s)

Proteínas Portadoras/genética , Proteínas Mitocondriales/genética , Atrofia Óptica Hereditaria de Leber/genética , Proteínas Portadoras/metabolismo , Niño , Femenino , Heterocigoto , Humanos , Proteínas Mitocondriales/metabolismo , Mutación , Atrofia Óptica Hereditaria de Leber/patología , Secuenciación del Exoma