RESUMEN
Collagen type XVIII (COL18) is an abundant heparan sulfate proteoglycan in vascular basement membranes. Here, we asked (i) if the loss of COL18 would result in blood-brain barrier (BBB) breakdown, pathological alterations of small arteries and capillaries and neuroinflammation as found in cerebral small vessel disease (CSVD) and (ii) if such changes may be associated with remodeling of synapses and neural extracellular matrix (ECM). We found that 5-month-old Col18a1-/- mice had elevated BBB permeability for mouse IgG in the deep gray matter, and intravascular erythrocyte accumulations were observed brain-wide in capillaries and arterioles. BBB permeability increased with age and affected cortical regions and the hippocampus in 12-month-old Col18a1-/- mice. None of the Col18a1-/- mice displayed hallmarks of advanced CSVD, such as hemorrhages, and did not show perivascular space enlargement. Col18a1 deficiency-induced BBB leakage was accompanied by activation of microglia and astrocytes, a loss of aggrecan in the ECM of perineuronal nets associated with fast-spiking inhibitory interneurons and accumulation of the perisynaptic ECM proteoglycan brevican and the microglial complement protein C1q at excitatory synapses. As the pathway underlying these regulations, we found increased signaling through the TGF-ß1/Smad3/TIMP-3 cascade. We verified the pivotal role of COL18 for small vessel wall structure in CSVD by demonstrating the protein's involvement in vascular remodeling in autopsy brains from patients with cerebral hypertensive arteriopathy. Our study highlights an association between the alterations of perivascular ECM, extracellular proteolysis, and perineuronal/perisynaptic ECM, as a possible substrate of synaptic and cognitive alterations in CSVD.
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Enfermedades de los Pequeños Vasos Cerebrales , Colágeno Tipo XVIII , Enfermedades Neuroinflamatorias , Animales , Humanos , Lactante , Ratones , Enfermedades de los Pequeños Vasos Cerebrales/genética , Enfermedades de los Pequeños Vasos Cerebrales/metabolismo , Colágeno Tipo XVIII/genética , Colágeno Tipo XVIII/metabolismo , Endostatinas , Matriz Extracelular/metabolismo , Proteoglicanos de Heparán Sulfato/metabolismo , Ratones NoqueadosRESUMEN
The tumor extracellular matrix (ECM) critically regulates cancer progression and treatment response. Expression of the basement membrane component collagen XVIII (ColXVIII) is induced in solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII was markedly upregulated in human breast cancer (BC) and was closely associated with a poor prognosis in high-grade BCs. We discovered a role for ColXVIII as a modulator of epidermal growth factor receptor tyrosine kinase (ErbB) signaling and show that it forms a complex with ErbB1 and -2 (also known as EGFR and human epidermal growth factor receptor 2 [HER2]) and α6-integrin to promote cancer cell proliferation in a pathway involving its N-terminal portion and the MAPK/ERK1/2 and PI3K/AKT cascades. Studies using Col18a1 mouse models crossed with the mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT) mammary carcinogenesis model showed that ColXVIII promoted BC growth and metastasis in a tumor cell-autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in the MMTV-PyMT and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII substantially improved the efficacy of ErbB-targeting therapies in both preclinical models. In summary, ColXVIII was found to sustain the stemness properties of BC cells and tumor progression and metastasis through ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have important therapeutic potential.
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Neoplasias de la Mama , Colágeno Tipo XVIII , Ratones , Animales , Humanos , Femenino , Colágeno Tipo XVIII/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Receptor ErbB-2/metabolismo , Transformación Celular Neoplásica , Transducción de SeñalRESUMEN
Knobloch syndrome is an autosomal recessive disorder characterized by high myopia, retinal detachment, and occipital skull defects. Mutations in the COL18A1 gene have been identified to cause KNO1. Here, we successfully generated a human induced pluripotent stem cell (hiPSC) line from the peripheral blood mononuclear cells (PBMCs) of a KNO patient caused by COL18A1 biallelic pathogenic variants, and this iPSC model offers a precious disease model to study the pathological mechanism and possible treatment of KNO in vitro.
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Células Madre Pluripotentes Inducidas , Desprendimiento de Retina , Humanos , Células Madre Pluripotentes Inducidas/patología , Desprendimiento de Retina/genética , Desprendimiento de Retina/patología , Leucocitos Mononucleares/patología , Colágeno Tipo XVIII/genética , Mutación/genéticaRESUMEN
Collagen XVIII (ColXVIII) is a component of the extracellular matrix implicated in embryogenesis and control of tissue homoeostasis. We now provide evidence that ColXVIII has a specific role in renal branching morphogenesis as observed in analyses of total and isoform-specific knockout embryos and mice. The expression of the short and the two longer isoforms differ temporally and spatially during renal development. The lack of ColXVIII or its specific isoforms lead to congenital defects in the 3D patterning of the ureteric tree where the short isoform plays a prominent role. Moreover, the ex vivo data suggests that ColXVIII is involved in the kidney epithelial tree patterning via its N-terminal domains, and especially the Thrombospondin-1-like domain common to all isoforms. This morphogenetic function likely involves integrins expressed in the ureteric epithelium. Altogether, the results point to an important role for ColXVIII in the matrix-integrin-mediated functions regulating renal development.
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Colágeno Tipo XVIII , Riñón , Isoformas de Proteínas , Animales , Ratones , Colágeno Tipo XVIII/genética , Colágeno Tipo XVIII/metabolismo , Integrinas , Riñón/embriología , Riñón/metabolismo , Morfogénesis , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Uréter/embriología , Uréter/metabolismoRESUMEN
Abnormal accumulation of lipids has been highlighted in the progression of clear cell renal cell carcinoma (ccRCC). However, the underlying mechanism remains unclear. Emerging evidence suggests long noncoding RNAs (lncRNAs) participate in the regulation of lipid metabolism. In this study, we found lncRNA COL18A1-AS1 was downregulated in ccRCC and that higher COL18A1-AS1 expression indicated better prognosis. Decreased COL18A1-AS1 expression was caused by DNA methylation at the CpG islands within its promoter. Restoring the epigenetically silenced COL18A1-AS1 repressed tumor progression, promoted lipid browning and consumption in vitro and in vivo. Mechanistically, COL18A1-AS1 could competitively bind miR-1286 to increase the expression of Krüppel-like factor 12 (KLF12). Downregulation of COL18A1-AS1 in ccRCC resulted in the low expression of KLF12. COL18A1-AS1/KLF12 positively regulated uncoupling protein 1 (UCP1)-mediated lipid browning, which promotes tumor cell "slimming" and inhibits tumor progression. When tumor cell "slimming" occurred, lipid droplets turned into tiny pieces, and lipids were consumed without producing ATP energy. Taken together, our findings on COL18A1-AS1-miR-1286/KLF12 axis revealed a potential mechanism of abnormal accumulation of lipids in ccRCC and could be a promising therapeutic target for ccRCC patients.
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Carcinoma de Células Renales , Colágeno Tipo XVIII/genética , Neoplasias Renales , ARN Largo no Codificante , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Lípidos , MicroARNs/genética , ARN Largo no Codificante/genéticaRESUMEN
BACKGROUND: Haemophilic arthropathy (HA) is a major complication in haemophilia. Collagens IV, XV and XVIII are responsible for maintaining the integrity of the vessel wall in the joint. Following joint remodelling and damage, the short isoform of collagen type XVIII (COL-18N) is degraded, releasing measurable fragments. Our goal was to quantify the specific isoform COL-18N in haemophilia A patients and to assess its relation to the clinical and radiological data as well as haemophilia joint health score (HJHS), functional independence score for haemophilia (FISH), and haemophilia quality of life (Haemo-Qol). METHODS: This cross-sectional study included 50 haemophilia A patients recruited from the Paediatric Haematology and Oncology unit, Ain Shams University, Cairo, Egypt. Quantification of COL-18N was done by ELISA. Assessment of joint state clinically using FISH and HJH scores and radiologically by X-rays and ultrasound. RESULTS: Haemophilia A patients had significantly higher median COL-18N levels compared to the control group. Inhibitor positive and negative haemophilia A patients as well as those on non-steroidal anti-inflammatory drug and those not had comparable COL-18N levels. Patients with ≥2 target joints had significantly higher COL-18N level compared to those with one or those without target joints. There were significant positive correlations between COL-18N level and the total HJHS, Haemo-Qol, the HEAD-US score and annual bleeding rate. CONCLUSION: Our results demonstrated a high level of COL-18N in haemophilia A patients and argued its benefit as a potential marker for monitoring the development of haemophilic arthropathy and tailoring the optimal treatment to prevent further joint damage.
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Colágeno Tipo XVIII , Hemartrosis , Hemofilia A , Enfermedades Vasculares , Adolescente , Vasos Sanguíneos/fisiopatología , Niño , Colágeno Tipo XVIII/sangre , Estudios Transversales , Femenino , Hemartrosis/sangre , Hemartrosis/etiología , Hemofilia A/sangre , Hemofilia A/complicaciones , Humanos , Masculino , Isoformas de Proteínas/sangre , Calidad de Vida , Enfermedades Vasculares/sangre , Enfermedades Vasculares/etiologíaRESUMEN
. COL18A1 gene mutations have been associated with Knobloch syndrome, which is characterized by ocular and brain abnormalities. Here we report a 4.5 years-old male child with autism and two novel COL18A1 mutations (NM_030582.4: c.1883_1891dup and c.1787C>T). Hypermetropic astigmatism, but not brain migration disorders, was observed. However, an asymmetric pattern of cerebellar perfusion and a smaller arcuate fascicle were found. Low levels of collagen XVIII were also observed in the patient´s serum. Thus, biallelic loss-of-function mutations in COL18A1 may be a new cause of autism without the brain malformations typically reported in patients with Knobloch syndrome.
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Colágeno Tipo XVIII , Endostatinas , Cerebelo , Preescolar , Colágeno Tipo XVIII/genética , Encefalocele , Endostatinas/genética , Humanos , Masculino , Mutación , Neuroimagen , Degeneración Retiniana , Desprendimiento de Retina/congénitoRESUMEN
BACKGROUND: To establish the molecular diagnosis in two brothers presenting with the ocular features of Knobloch Syndrome using whole genome sequencing (WGS). METHODS: Clinical examination and ophthalmological phenotyping were completed under general anaesthesia. DNA samples were tested on a targeted retinal dystrophy next-generation sequencing panel. Subsequently, WGS was performed to identify additional variants. RESULTS: Clinical examination confirmed the diagnosis of Knobloch Syndrome. Targeted sequencing identified a novel heterozygous frameshift pathogenic variant in COL18A1, c.2864dupC; p.(Gly956ArgfsX20), inherited from their mother. A second paternally inherited heterozygous missense variant was identified in both brothers, c.5014 G > A; p.(Asp1672Asn), which was initially considered to have too high frequency to be pathogenic (MAF 8.8%). This led to an in-depth analysis of the COL18A1 locus using WGS data, which confirmed that Asp1672Asn is a likely pathogenic hypomorphic allele. CONCLUSION: To date, all confirmed genetic diagnoses of Knobloch syndrome are attributable to variants in COL18A1. The family described here has a heterozygous novel loss of function variant. Detailed analysis of WGS data combined with family segregation studies concluded that although Asp1672Asn has a high population frequency, it is the most likely second pathogenic variant in our family. This supports the hypothesis that this is a hypomorphic allele, which, in combination with a loss of function pathogenic variant, leads to Knobloch syndrome.To our knowledge, this is the first time that WGS has been used to confirm a molecular diagnosis of Knobloch syndrome in this way and has provided further insight into the molecular mechanisms in this rare disorder.
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Degeneración Retiniana , Colágeno Tipo XVIII/genética , Encefalocele/diagnóstico , Humanos , Masculino , Mutación , Degeneración Retiniana/diagnóstico , Degeneración Retiniana/genética , Degeneración Retiniana/patología , Desprendimiento de Retina/congénito , Secuenciación Completa del GenomaRESUMEN
Knobloch syndrome is an inherited disorder characterized by high myopia, retinal detachment, and occipital defects. Disease-causing mutations have been identified in the COL18A1 gene. This study aimed to investigate novel variants of COL18A1 in Knobloch syndrome and describe the associated phenotypes in Chinese patients. We reported six patients with Knobloch syndrome from four unrelated families in whom we identified five novel COL18A1 mutations. Clinical examination showed that all probands presented with high myopia, chorioretinal atrophy, and macular defects; one exhibited rhegmatogenous retinal detachment in one eye. Occipital defects were detected in one patient.
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Colágeno Tipo XVIII/genética , Encefalocele/genética , Degeneración Retiniana/genética , Desprendimiento de Retina/congénito , Niño , Preescolar , China , Encefalocele/patología , Femenino , Humanos , Lactante , Masculino , Mutación , Fenotipo , Degeneración Retiniana/patología , Desprendimiento de Retina/genética , Desprendimiento de Retina/patologíaRESUMEN
Low blood fluid shear stress (SS) promotes vascular remodeling and atherosclerosis; however, the effects of high (H)SS on vascular remodeling and atherogenesis is not fully clarified. The major goal of this study was to investigate the role of HSS in atherosclerotic plaque formation. A perivascular SS modifier was implanted in the right carotid artery of apolipoprotein E (ApoE)/ mice to induce HSS, whereas the left carotid artery represented undisturbed (U)SS as a control in vivo. In vitro modeling used human umbilical vein endothelial cells and vascular smooth muscle cells exposed to HSS (2.5 Pa) using a parallelplate flow system. The results demonstrated that there were no plaque formations or endothelial cells in the HSS regions of the carotid artery in ApoE/ mice. The number of umbilical vein endothelial cells was markedly decreased in a timedependent manner in HSS. HSS significantly decreased αsmooth muscle actin and increased osteopontin protein expression levels compared with USS in vascular smooth muscle cells (P<0.05). In addition, HSS significantly increased the protein expression levels of collagen α1(XVIII) chain/endostatin and matrix metalloproteinase8 in vascular smooth muscle cells. These data indicated that HSS may prevent atherosclerotic plaque formation through endothelium denudation and contractiletosynthetic phenotypic conversion of smooth muscle cells.
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Colágeno Tipo XVIII/metabolismo , Endotelio Vascular/metabolismo , Metaloproteinasa 8 de la Matriz/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Placa Aterosclerótica/metabolismo , Estrés Mecánico , Animales , Apolipoproteínas E/genética , Aterosclerosis , Arterias Carótidas/metabolismo , Células Cultivadas , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Fenotipo , Placa Aterosclerótica/prevención & control , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Remodelación VascularRESUMEN
BACKGROUND: Intellectual disability (ID) is a heterogeneous disorder affecting 1-3% of the population. Elucidation of monogenic variants for ID is a current challenge. These variants can be better demonstrated in consanguineous affected families. OBJECTIVE: The study was designed to find the genetic variants of ID in consanguineous families. METHODS: We analyzed five unrelated consanguineous Pakistani families affected with ID using whole exome sequencing (WES). Data was analyzed using different bioinformatics tools and software. RESULTS: We mapped four variants including three novels in four different ID known genes. Each variant is found in a different family, co-segregating with a recessive pattern of inheritance. The novel variants found are; c. 2_4del (p.?) mapped in ROS1 and c. 718G>A (p.Gly240Arg) in GRM1. Another novel causative variant, c.2673del (p.Gly892Aspfs*17) identified in COL18A1 in a recessive form, a gene reported for Knobloch syndrome that manifests ID along with typical retinal abnormalities, and this phenotype was confirmed on reverse phenotyping. A mutation c.2134C>T (p.Arg712*) in TRAPPC9 has been found first time in the homozygous recessive form in our enrolled three affected siblings while it was previously reported in compound heterozygous form in a Caucasian descent. While fifth family remained unsolved. CONCLUSION: These mutations in four different genes with a recessive inheritance would be a contribution to the disease variant database of this devastating disorder.
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Discapacidad Intelectual/genética , Mutación , Adulto , Niño , Colágeno Tipo XVIII/genética , Consanguinidad , Femenino , Humanos , Discapacidad Intelectual/patología , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Linaje , Fenotipo , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Receptores de Glutamato Metabotrópico/genética , Secuenciación del ExomaRESUMEN
For over a decade, diabetic neuropathy has exhibited great emergence in diabetic patients. Though there are numerous impediments in understanding the underlying pathology it is not that enough to conclude. Initially, there was no intricate protocol for diagnosis as its symptoms mimic most of the neurodegenerative disorders and demyelinating diseases. Continuous research on this, reveals many pathological correlates which are also detectable clinically. The most important pathologic manifestation is imbalanced angiogenesis/neo-vascularization. This review is completely focused on established pathogenesis and anti-angiogenic agents which are physiological signal molecules by the origin. Those agents can also be used externally to inhibit those pathogenic pathways. Pathologically DN demonstrates the misbalanced expression of many knotty factors like VEGF, FGF2, TGFb, NF-kb, TNF-a, MMP, TIMP, and many minor factors. Their pathway towards the incidence of DN is quite interrelated. Many anti-angiogenic agents inhibit neovascularization to many extents, but out of them predominantly inhibition of angiogenic activity is shared by endostatin which is now in clinical trial phase II. It inhibits almost all angiogenic factors and it is possible because they share interrelated pathogenesis towards imbalanced angiogenesis. Endostatin is a physiological signal molecule produced by the proteolytic cleavage of collagen XVIII. It has also a broad research profile in the field of medical research and further investigation can show promising therapeutic effects for benefit of mankind.
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Colágeno Tipo XVIII/metabolismo , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/metabolismo , Endostatinas/farmacología , Redes y Vías Metabólicas/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Inhibidores de la Angiogénesis , Colágeno Tipo XVIII/farmacología , Complicaciones de la Diabetes/genética , Complicaciones de la Diabetes/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Neuropatías Diabéticas/complicaciones , Neuropatías Diabéticas/genética , Endostatinas/fisiología , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Redes y Vías Metabólicas/genética , Neovascularización Fisiológica/genéticaRESUMEN
BACKGROUND: The role of collagen type XVIII alpha 1 chain (COL18A1) in anti-tuberculosis drug-induced hepatotoxicity (ATDH) has not been reported. This study aimed to explore the association between of COL18A1 variants and ATDH susceptibility. METHODS: A total of 746 patients were enrolled in our study from December 2016 to April 2018, and all subjects in the study signed an informed consent form. The custom-by-design 2x48-Plex SNPscanTM kit was used to genotype all selected 11 SNPs. Categorical variables were compared by chi-square (χ2 ) or Fisher's exact test, while continuous variables were compared by Mann-Whitney's U test. Plink was utilized to analyze allelic and genotypic frequencies, and genetic models. Multivariate logistic regression analyses were used to adjust potential factors. The odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were also calculated. RESULTS: Among patients with successfully genotyping, there were 114 cases and 612 controls. The mutant A allele of rs12483377 conferred the decreased risk of ATDH (OR = 0.13, 95%CI: 0.02-0.98, P = 0.020), and this significance still existed after adjusting age and gender (P = 0.024). The mutant homozygote AA genotype of rs12483377 was associated with decreased total protein levels (P = 0.018). CONCLUSION: Our study first revealed that the A allele of COL18A1 rs12483377 was associated with the decreased risk of ATDH in the Western Chinese Han population, providing new perspective for the molecular prediction, precise diagnosis, and individual treatment of ATDH.
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Antituberculosos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Colágeno Tipo XVIII/genética , Adulto , Pueblo Asiatico/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Femenino , Frecuencia de los Genes , Haplotipos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Estudios ProspectivosRESUMEN
PURPOSE: Knobloch syndrome is a rare, recessively inherited disorder classically characterized by high myopia, retinal detachment, and occipital encephalocele. Our aim is to report the clinical and genetic findings of four Israeli children affected by Knobloch syndrome. METHODS: Retrospective study of four patients diagnosed with Knobloch syndrome, who underwent full ophthalmic examination, electroretinography, and neuroradiologic imaging. Genetic analysis included whole exome sequencing (WES) and Sanger sequencing. RESULTS: The four patients included in this study had high myopia and nystagmus at presentation. Ocular findings included vitreous syneresis, macular atrophy, macular coloboma, and retinal detachment. One child had iris transillumination defects and an albinotic fundus, initially leading to an erroneous clinical diagnosis of albinism. Electroretinography revealed a marked cone-rod pattern of dysfunction in all four children. Brain imaging demonstrated none to severe occipital pathology. Cutaneous scalp changes were present in three patients. WES analysis, confirmed by Sanger sequencing revealed COL18A1 biallelic null mutations in all affected individuals, consistent with autosomal recessive inheritance. CONCLUSIONS: This report describes variable features in patients with Knobloch syndrome, including marked lack of eye pigment similar to albinism in one child, macular coloboma in two children as well as advanced cone-rod dysfunction in all children. One patient had normal neuroradiologic findings, emphasizing that some affected individuals have isolated ocular disease. Awareness of this syndrome, with its variable phenotype may aid early diagnosis, monitoring for potential complications, and providing appropriate genetic counseling.
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Colágeno Tipo VIII , Encefalocele , Degeneración Retiniana , Desprendimiento de Retina , Niño , Colágeno Tipo VIII/genética , Colágeno Tipo XVIII , Electrorretinografía , Encefalocele/diagnóstico , Encefalocele/genética , Humanos , Mutación , Linaje , Fenotipo , Degeneración Retiniana/diagnóstico , Degeneración Retiniana/genética , Desprendimiento de Retina/congénito , Desprendimiento de Retina/diagnóstico , Estudios Retrospectivos , Trastornos de la VisiónAsunto(s)
Glucosa , Lipodistrofia , Colágeno Tipo XVIII , Matriz Extracelular , Homeostasis , Humanos , LípidosAsunto(s)
Glucosa , Lipodistrofia , Colágeno Tipo XVIII , Homeostasis , Humanos , Metabolismo de los Lípidos , LípidosRESUMEN
Knobloch Syndrome (KS) is a rare autosomal recessive hereditary disease. Despite its clinical heterogeneity, it is characterized by vitreoretinal degeneration and high myopia, with or without occipital skull defects. It is caused by mutations in the COL18A1 gene, which codifies for collagen XVIII, present in retina and vascular endothelium. Since the first description of the disease by doctors Knobloch and Layer in 1972, over 100 cases and 20 pathogenic or likely pathogenic mutations have been reported. We present the case of a child born from a consanguineous couple in Chile with congenital high myopia and dysmorphisms without an occipital skull defect. Whole exome sequencing analysis revealed an inherited homozygous variant in COL18A1, c.4224_4225delinsC, p.Pro1411Leufs*35.
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Colágeno Tipo XVIII/genética , Encefalocele/genética , Predisposición Genética a la Enfermedad , Degeneración Retiniana/genética , Desprendimiento de Retina/congénito , Niño , Encefalocele/complicaciones , Encefalocele/patología , Femenino , Humanos , Mutación , Degeneración Retiniana/complicaciones , Degeneración Retiniana/patología , Desprendimiento de Retina/complicaciones , Desprendimiento de Retina/genética , Desprendimiento de Retina/patología , Secuenciación del ExomaRESUMEN
Cardiorespiratory fitness (CRF) and endurance performance are characterized by a complex genetic trait with high heritability. Although research has identified many physiological and environmental correlates with CRF, the genetic architecture contributing to CRF remains unclear, especially in non-athlete population. A total of 762 Chinese young female participants were recruited and an endurance run test was used to determine CRF. We used a fixed model of genome-wide association studies (GWAS) for CRF. Genotyping was performed using the Affymetrix Axiom and illumina 1 M arrays. After quality control and imputation, a linear regression-based association analysis was conducted using a total of 5,149,327 variants. Four loci associated with CRF were identified to reach genome-wide significance (P < 5.0 × 10-8), which located in 15q21.3 (rs17240160, P = 1.73 × 10-9, GCOM1), 3q25.31 (rs819865, P = 8.56 × 10-9, GMPS), 21q22.3 (rs117828698, P = 9.59 × 10-9, COL18A1), and 17q24.2 (rs79806428, P = 3.85 × 10-8, PRKCA). These loci (GCOM1, GMPS, COL18A1 and PRKCA) associated with cardiorespiratory fitness and endurance performance in Chinese non-athlete young females. Our results suggest that these gene polymorphisms provide further genetic evidence for the polygenetic nature of cardiorespiratory endurance and be used as genetic biomarkers for future research.
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Capacidad Cardiovascular/fisiología , Resistencia Física/genética , Aptitud Física/fisiología , Adolescente , Pueblo Asiatico/genética , Índice de Masa Corporal , Complejo del Señalosoma COP9/genética , Enfermedades Cardiovasculares/epidemiología , China , Colágeno Tipo VIII/genética , Colágeno Tipo XVIII , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Proteína Quinasa C-alfa/genética , Adulto JovenRESUMEN
KEY POINTS: Extracellular matrix is highly remodelled in obesity and associates with the development of metabolic disorders, such as insulin resistance. Previously, we have shown that the lack of specific collagen XVIII isoforms impairs adipocyte differentiation in mice. Here, we show that mice lacking the medium and long isoforms of collagen XVIII develop insulin resistance and glucose intolerance and show elevated serum triglycerides and fat accumulation in the liver. We report that collagen XVIII-deficient mice have increased heat production at low temperatures. These results reveal a new role for collagen XVIII in the regulation of glucose and lipid metabolism, and they expand the understanding of the development of metabolic disorders. ABSTRACT: Liver and adipose tissues play important roles in the regulation of systemic glucose and lipid metabolism. Extracellular matrix synthesis and remodelling are significantly altered in these tissues in obesity and type 2 diabetes. Collagen XVIII is a ubiquitous extracellular matrix component, and it occurs in three isoforms which differ in terms of molecular size, domain structure and tissue distribution. We recently showed that, in mice, the lack of collagen XVIII, and especially its medium and long isoforms, leads to reduced adiposity and dyslipidaemia. To address the metabolic consequences of these intriguing observations, we assessed whole-body glucose homeostasis in mice challenged with a high-fat diet and in normal physiological conditions. We observed that, in the high caloric diet, the overall adiposity was decreased by 30%, serum triglyceride values were threefold higher and the steatotic area in liver was twofold larger in collagen XVIII knockout mice compared with controls. We demonstrated that mice lacking either all three collagen XVIII isoforms, or specifically, the medium and long isoforms develop insulin resistance and glucose intolerance. Furthermore, we found that ablation of collagen XVIII leads to increased heat production in low temperatures and to reduction of the high blood triglyceride levels of the knockout mice to the level of wild-type mice. Our data indicate that collagen XVIII plays a role in the regulation of glucose tolerance, insulin sensitivity and lipid homeostasis, principally through its ability to regulate the expansion of the adipose tissue. These findings advance the understanding of metabolic disorders.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Lipodistrofia , Tejido Adiposo/metabolismo , Animales , Colágeno Tipo XVIII/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa , Glucosa/metabolismo , Homeostasis , Metabolismo de los Lípidos , Lipodistrofia/metabolismo , Hígado/metabolismo , Ratones , Ratones NoqueadosRESUMEN
Diabetic retinopathy is a common complication of diabetes mellitus that causes pathogenic damage to the retina. Particularly, the proliferative diabetic retinopathy (PDR) state can cause abnormal angiogenesis in the retina tissues and trigger the retina destruction in advanced stage. In the clinic, the symptoms during the initiation and progression of PDR are relatively unrecognizable. Therefore, various studies have focused on the pathogenesis of PDR. According to published literature, genetic contributions play an irreplaceable role in the initiation and progression of PDR. Although many computational methods, such as shortest path- and random walk with restart-based methods, have been applied in screening the potential pathogenic factors of PDR, advanced computational methods, which may provide essential supplements for previous ones, are still widely needed. In this study, a novel computational method was presented to infer novel PDR-associated genes. Different from previous methods, the method used in this work employed a different network algorithm, that is, the Laplacian heat diffusion algorithm. This algorithm was applied on the protein-protein interaction network reported in the STRING database. Three screening tests were performed to filter the most likely inferred genes. A total of 26 genes were accessed using the proposed method. Compared with the two previous predictions, most of the identified genes were novel, and only one gene was shared. Several inferred genes, such as CSF3, COL18A1, CXCR2, CCR1, FGF23, CXCL11, and IL13, were related to the pathogenesis of PDR.