RESUMEN
BACKGROUND: Cerebrotendinous xanthomatosis (CTX, OMIM #213700) is a rare inherited metabolic disease caused by the mutation in the CYP27A1 gene. Spinal CTX is a rare clinical subgroup of CTX which lacks typical symptoms seen in classical CTX. Here we report a spinal CTX case revealed double mutation of CYP27A1 gene. CASE PRESENTATION: A 42-year-old Asian man visited our hospital with spastic gait started at 35. Physical examination showed bilateral masses on his Achilles tendons and were identified as xanthoma on ankle magnetic resonance imaging (MRI). Brain and spinal cord MRI revealed high signal lesions in bilateral cerebellar dentate nuclei and long tract lesions involving lateral corticospinal and gracile tracts. Gene analysis revealed double heterozygous mutation, c.223C > T (p. Gln75Ter) and c.1214G > A (p. Arg405Gln). CONCLUSIONS: We believe that novel mutation detected in our case might have a role in the pathomechanism in CTX. Moreover, spinal CTX should be considered in the patients only presenting with pyramidal symptoms, as CTX shows good prognosis in early treatment with chenodeoxycholic acid.
Asunto(s)
Colestanotriol 26-Monooxigenasa , Imagen por Resonancia Magnética , Mutación , Xantomatosis Cerebrotendinosa , Humanos , Masculino , Xantomatosis Cerebrotendinosa/genética , Xantomatosis Cerebrotendinosa/tratamiento farmacológico , Xantomatosis Cerebrotendinosa/diagnóstico , Xantomatosis Cerebrotendinosa/fisiopatología , Xantomatosis Cerebrotendinosa/complicaciones , Colestanotriol 26-Monooxigenasa/genética , Adulto , Tendón Calcáneo/diagnóstico por imagen , Tendón Calcáneo/patología , Médula Espinal/patología , Médula Espinal/diagnóstico por imagen , Trastornos Neurológicos de la Marcha/etiología , Trastornos Neurológicos de la Marcha/genéticaRESUMEN
Vitamin D-dependent rickets (VDDR) is a group of genetic disorders characterized by early-onset rickets due to deficiency of active vitamin D or a failure to respond to activated vitamin D. VDDR is divided into several subtypes according to the corresponding causative genes. Here we described a new type of autosomal dominant VDDR in a Chinese pedigree. The proband and his mother had severe bone malformations, dentin abnormalities, and lower serum 25 hydroxyvitamin D3 (25[OH]D3) and phosphate levels. The proband slightly responded to a high dose of vitamin D3 instead of a daily low dose of vitamin D3. Whole-exome sequencing, bioinformatic analysis, PCR, and Sanger sequencing identified a nonsense mutation in CYP4A22 (c.900delG). The overexpressed wild-type CYP4A22 mainly localized in endoplasmic reticulum and Golgi apparatus, and synthesized 25(OH)D3 in HepG2 cells. The overexpressed CYP4A22 mutant increased the expression of CYP2R1 and produced little 25(OH)D3 with vitamin D3 supplementation, which was reduced by CYP2R1 siRNA treatment. We concluded that CYP4A22 functions as a new kind of 25-hydroxylases for vitamin D3. Loss-of-function mutations in CYP4A22 lead to a new type of VDDR type 1 (VDDR1C). CYP2R1 and CYP4A22 may have some genetic compensation responding to nonsense-mediated mRNA decay effect of each other.
A nonsense mutation in CYP4A22 was found in a Chinese pedigree with vitamin Ddependent rickets and low serum phosphate. CYP4A22 localizes in endoplasmic reticulum and Golgi apparatus, and processes 25-hydroxylase activity in liver cells. CYP4A22 loss-of-function reduces the synthesis of 25(OH)D3 and causes genetic compensation of CYP2R1.
Asunto(s)
Linaje , Humanos , Masculino , Femenino , Mutación con Pérdida de Función , Células Hep G2 , Colestanotriol 26-Monooxigenasa/genética , Colestanotriol 26-Monooxigenasa/metabolismo , Raquitismo Hipofosfatémico Familiar/genética , Raquitismo Hipofosfatémico Familiar/patología , Familia 2 del Citocromo P450RESUMEN
OBJECTIVE: Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder characterized by progressive neurologic and extraneurologic findings. The aim of this retrospective, descriptive study was to explore the time of presentation and diagnosis, and to expand the phenotype and genotype of CTX, based on a nationwide and comprehensive series of patients in Turkey. METHODS: The demographic, clinical, biochemical and genotypic characteristics of the CTX patients were reviewed. Data on molecular analysis, age of onset and diagnosis, diagnostic delay, neurologic and extraneurologic symptomatology, results of plasma cholestanol levels, brain magnetic resonance imaging and electromyography at the time of diagnosis were reviewed. RESULTS: 100 confirmed CTX patients from 72 families were included. The mean age at diagnosis was 28.16 ± 14.28 years, and diagnostic delay was 18.39 ± 13.71 years. 36 patients were diagnosed in childhood. Frequency of intention tremor (p = 0.069), peripheral neuropathy (p = 0.234) and psychiatric manifestations (p = 0.396) did not differ between two groups, demonstrating the high rate in pediatric patients. Three adult patients showed a milder phenotype without neurologic involvement. Seven patients had normal plasma cholestanol levels despite neurological impairment. Sequencing of the CYP27A1 gene revealed 25 different variants, with a novel c.671_672del variant not previously described in literature. CONCLUSION: Based on the observations of this Turkish CTX cohort, it is emphasized that the true prevalence of CTX is probably underestimated and that it has a wide spectrum of clinical phenotypes even without neurological impairment. In children, abnormal cerebellar findings, peripheral neuropathy and psychiatric findings associated with intellectual disability have been suggested as warning signs to avoid diagnostic delay. In cases of clinical suspicion, molecular analysis is recommended despite normal plasma cholestanol levels, as severe neurologic involvement may occur in CTX patients without elevated cholestanol levels.
Asunto(s)
Colestanotriol 26-Monooxigenasa , Colestanol , Xantomatosis Cerebrotendinosa , Humanos , Xantomatosis Cerebrotendinosa/genética , Xantomatosis Cerebrotendinosa/sangre , Xantomatosis Cerebrotendinosa/diagnóstico , Masculino , Femenino , Adulto , Turquía/epidemiología , Adolescente , Niño , Colestanotriol 26-Monooxigenasa/genética , Adulto Joven , Persona de Mediana Edad , Colestanol/sangre , Estudios Retrospectivos , Preescolar , Imagen por Resonancia Magnética , Fenotipo , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Mutación , Genotipo , Edad de InicioRESUMEN
The presence of vitamin D3 deficiency associated with the presence of metabolic syndrome (MS) has important public health effects. This study aims to investigate the relationship between vitamin D3 deficiency, MS and vitamin D3 receptor (VDR), GC Vitamin D binding protein (GC), and cytochrome P450 family 2 subfamily R member 1 (CYP2R1) gene polymorphisms, and genes whose encoded proteins are responsible for vitamin D3 metabolism and transport. A total of 58 participants were included in this study (age 39 ± 12 years) and were selected over a 12-month period. They were divided into four groups, depending on the presence of polymorphisms in VDR, GC, and CYP2R1 genes and their weight status. At baseline, in months 3, 6, and 12, biochemical parameters including 25(OH)D3, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and homeostatic model assessment (HOMA index), the insulin resistance indicator were measured. Our results show that all subjects in the polymorphism group supplemented with vitamin D3 reached an optimal level of vitamin D3 associated with high concentrations of 25(OH)D3. Weight loss was most significant in patients in the POW group (overweight patients).
Asunto(s)
Colecalciferol , Colestanotriol 26-Monooxigenasa , Síndrome Metabólico , Receptores de Calcitriol , Deficiencia de Vitamina D , Proteína de Unión a Vitamina D , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Colecalciferol/sangre , Colestanotriol 26-Monooxigenasa/genética , Familia 2 del Citocromo P450/genética , Resistencia a la Insulina/genética , Síndrome Metabólico/genética , Polimorfismo Genético , Receptores de Calcitriol/genética , Deficiencia de Vitamina D/genética , Deficiencia de Vitamina D/sangre , Proteína de Unión a Vitamina D/genéticaRESUMEN
Persistent and intense uterine contraction is a risk factor for preterm labor. We previously found that methyl-CpG-binding protein 2 (MeCP2), as a target of infection-related microRNA miR-212-3p, may play an inhibitory role in regulating myometrium contraction. However, the molecular mechanisms by which MeCP2 regulates myometrial contraction are still unknown. In this study, we found that MeCP2 protein expression was lower in myometrial specimens obtained from preterm labor cases, compared to those obtained from term labor cases. Herein, using RNA sequence analysis of global gene expression in human uterine smooth muscle cells (HUSMCs) following siMeCP2, we show that MeCP2 silencing caused dysregulation of the cholesterol metabolism pathway. Notably, MeCP2 silencing resulted in the upregulation of CYP27A1, the key enzyme involved in regulating cholesterol homeostasis, in HUSMCs. Methylation-specific PCR, chromatin immunoprecipitation, and dual luciferase reporter gene technology indicated that MeCP2 could bind to the methylated CYP27A1 promoter region and repress its transcription. Administration of siCYP27A1 in a lipopolysaccharide (LPS)-induced preterm labor mouse model delayed the onset of preterm labor. Human preterm myometrium and the LPS-induced preterm labor mouse model both showed lower expression of MeCP2 and increased expression of CYP27A1. These results demonstrated that aberrant upregulation of CYP27A1 induced by MeCP2 silencing is one of the mechanisms facilitating inappropriate myometrial contraction. CYP27A1 could be exploited as a novel therapeutic target for preterm birth.
Asunto(s)
Proteína 2 de Unión a Metil-CpG , Miometrio , Trabajo de Parto Prematuro , Contracción Uterina , Adulto , Animales , Femenino , Humanos , Ratones , Embarazo , Colestanotriol 26-Monooxigenasa/genética , Colestanotriol 26-Monooxigenasa/metabolismo , Colesterol/metabolismo , Lipopolisacáridos/farmacología , Proteína 2 de Unión a Metil-CpG/metabolismo , Proteína 2 de Unión a Metil-CpG/genética , Miocitos del Músculo Liso/metabolismo , Miometrio/metabolismo , Trabajo de Parto Prematuro/metabolismo , Trabajo de Parto Prematuro/genética , Regiones Promotoras Genéticas , Contracción Uterina/efectos de los fármacosRESUMEN
Vemurafenib has been used as first-line therapy for unresectable or metastatic melanoma with BRAFV600E mutation. However, overall survival is still limited due to treatment resistance after about one year. Therefore, identifying new therapeutic targets for melanoma is crucial for improving clinical outcomes. In the present study, we found that lowering intracellular cholesterol by knocking down DHCR24, the limiting synthetase, impaired tumor cell proliferation and migration and abrogated the ability to xenotransplant tumors. More importantly, administration of DHCR24 or cholesterol mediated resistance to vemurafenib and promoted the growth of melanoma spheroids. Mechanistically, we identified that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol synthesized by the enzyme cytochrome P450 27A1 (CYP27A1), reproduces the phenotypes induced by DHCR24 or cholesterol administration and activates Rap1-PI3K/AKT signaling. Accordingly, CYP27A1 is highly expressed in melanoma patients and upregulated by DHCR24 induction. Dafadine-A, a CYP27A1 inhibitor, attenuates cholesterol-induced growth of melanoma spheroids and abrogates the resistance property of vemurafenib-resistant melanoma cells. Finally, we confirmed that the effects of cholesterol on melanoma resistance require its metabolite 27HC through CYP27A1 catalysis, and that 27HC further upregulates Rap1A/Rap1B expression and increases AKT phosphorylation. Thus, our results suggest that targeting 27HC may be a useful strategy to overcome treatment resistance in metastatic melanoma.
Asunto(s)
Proliferación Celular , Colestanotriol 26-Monooxigenasa , Colesterol , Hidroxicolesteroles , Melanoma , Células Madre Neoplásicas , Vemurafenib , Vemurafenib/farmacología , Vemurafenib/uso terapéutico , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/metabolismo , Melanoma/genética , Hidroxicolesteroles/metabolismo , Hidroxicolesteroles/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Colestanotriol 26-Monooxigenasa/metabolismo , Colestanotriol 26-Monooxigenasa/genética , Colesterol/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Línea Celular Tumoral , Ratones , Resistencia a Antineoplásicos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVES: To observe the effect of electro-scalp acupuncture (ESA) on the expression of cytochrome P450a1/b1 (CYP27a1/b1), cytochrome P45024a (CYP24a), signal transducer and activator of transcription (STAT)4, STAT6, tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß and IL-4 in ischemic cerebral cortex of rats with acute ischemic stroke, so as to explore its mechanism in alleviating inflammatory reaction of ischemic stroke. METHODS: Sixty SD rats were randomly divided into sham-operation, model, vitamin D3 and ESA groups, with 15 rats in each group. The middle cerebral artery occlusion rat model was established with thread ligation according to Zea-Longa's method. Rats in the vitamin D3 group were given 1, 25-VitD3 solution (3 ng·100 g-1·d-1) by gavage, once daily for 7 days. Rats in the ESA group were treated at bilateral anterior parietotemporal slash (MS6) with ESA (2 Hz/100 Hz, 1 mA), 30 min a day for 7 days. Before and after interventions, the neurological deficit score and neurobehavioral score were evaluated. TTC staining was used to detect the volume of cerebral infarction in rats. The positive expressions of CYP24a, CYP27a1 and CYP27b1 in the cerebral cortex of ischemic area were detected by immunofluorescence. The mRNA expressions of STAT4 and STAT6 in the cerebral cortex of ischemic area were detected by quantitative real-time PCR. The protein expression levels of TNF-α, IL-1ß and IL-4 in the cerebral cortex of ischemic area were detected by Western blot. RESULTS: Compared with the sham-operation group, the neurological deficit score, neurobehavioral score, the percentage of cerebral infarction volume, the positive expression level of CYP24a and mRNA expression level of STAT4, protein expression levels of TNF-α and IL-1ß in cerebral cortex were increased (P<0.01), while the positive expression levels of CYP27a1/b1 and STAT6 mRNA, protein expression level of IL-4 were decreased (P<0.01) in the model group. After the treatment and compared with the model group, the neurological deficit score, neurobehavioral score, the percentage of cerebral infarction volume, the positive expression level of CYP24a and mRNA expression level of STAT4, protein expression levels of TNF-α and IL-1ß in cerebral cortex were decreased (P<0.01), while the positive expression levels of CYP27a1/b1 and STAT6 mRNA expression level, protein expression level of IL-4 were increased (P<0.01) in the ESA and vitamin D3 groups. CONCLUSIONS: ESA can alleviate the inflammatory response in ischemic stroke, which maybe related to its function in regulating the balance between CYP27a1/b1 and CYP24a, converting vitamin D into active vitamin D3, inhibiting vitamin D3 degradation, and regulating Th1/Th2 balance.
Asunto(s)
Infarto de la Arteria Cerebral Media , Vitamina D3 24-Hidroxilasa , Animales , Humanos , Masculino , Ratas , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Puntos de Acupuntura , Isquemia Encefálica/terapia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/genética , Corteza Cerebral/metabolismo , Colestanotriol 26-Monooxigenasa/genética , Colestanotriol 26-Monooxigenasa/metabolismo , Citocinas/metabolismo , Citocinas/genética , Electroacupuntura , Infarto de la Arteria Cerebral Media/terapia , Infarto de la Arteria Cerebral Media/genética , Infarto de la Arteria Cerebral Media/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Vitamina D3 24-Hidroxilasa/genética , Vitamina D3 24-Hidroxilasa/metabolismoRESUMEN
BACKGROUND: Vitamin D deficiency is prevalent among the Indonesian population, particularly in individuals diagnosed with leukemia-lymphoma. The regulation of vitamin D metabolism is influenced by the expression of several enzymes, such as CYP2R1, CYP24A1, and the vitamin D receptor (VDR). This study aimed to scrutinize the gene expression profiles in both mRNA and protein levels of VDR, CYP2R1, and CYP24A1 in leukemia and lymphoma patients. METHOD: The research was a cross-sectional study conducted at Cipto Mangunkusumo Hospital (RSCM) in Jakarta, Indonesia. The study included a total of 45 patients aged over 18 years old who have received a diagnosis of lymphoma or leukemia. Vitamin D status was measured by examining serum 25 (OH) D levels. The analysis of VDR, CYP2R1, and CYP24A1 mRNA expression utilized the qRT-PCR method, while protein levels were measured through the ELISA method. CONCLUSION: The study revealed a noteworthy difference in VDR protein levels between men and women. The highest mean CYP24A1 protein levels were observed in the age group > 60 years. This study found a significant, moderately positive correlation between VDR protein levels and CYP24A1 protein levels in the male and vitamin D sufficiency groups. In addition, a significant positive correlation was found between VDR mRNA levels and CYP2R1 mRNA levels, VDR mRNA levels and CYP2R1 mRNA levels, and CYP2R1 mRNA levels and CYP24A1 mRNA levels. However, the expression of these genes does not correlate with the protein levels of its mRNA translation products in blood circulation.
Asunto(s)
Colestanotriol 26-Monooxigenasa , Familia 2 del Citocromo P450 , Leucemia , Linfoma , Receptores de Calcitriol , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Colestanotriol 26-Monooxigenasa/genética , Estudios Transversales , Sistema Enzimático del Citocromo P-450/genética , Familia 2 del Citocromo P450/genética , Perfilación de la Expresión Génica , Leucemia/genética , Leucemia/metabolismo , Linfoma/genética , Linfoma/metabolismo , Receptores de Calcitriol/genética , ARN Mensajero/metabolismo , Vitamina D , Vitamina D3 24-Hidroxilasa/genética , Pueblos del Sudeste Asiático/genéticaRESUMEN
Background: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by bi-allelic pathogenic variants in CYP27A1 gene that results in the deposition of cholestanol in the eyes, tendons, soft tissues and nervous system leading to cataracts, xanthomas, and various neuropsychiatric manifestations. The aim of our study is to describe the clinical, radiological and genetic profile of patients with CTX. Methods: This is a retrospective chart review of patients with CTX diagnosed based on classical clinical and radiological findings. The available clinical details, and investigations, including imaging, electrophysiological, pathological and genetic data, were documented. Results: Five patients (4 males) were recruited in the study. The median age at presentation was 32 years (range: 21-66 years). Walking difficulty was the most common symptom at presentation. All patients had cataracts, tendon xanthomas, eye movement abnormalities, dysarthria, pyramidal signs, ataxia and gait abnormality. Dystonia was noted in three patients. Palatal tremor and parkinsonism were noted in one patient each. In MRI brain, dentate, and corticospinal tract involvement were the most frequent imaging findings. Bilateral hypertrophic olivary degeneration was noted in one patient and hot cross bun sign in two. Three patients underwent genetic testing and all had pathogenic variants confirming the diagnosis. Discussion: CTX is a rare treatable disorder. Apart from the usual neurological presentation with spastic-ataxia, it can present at a later age with parkinsonism. Typical patterns of imaging findings are helpful in early diagnosis which aids in the treatment to prevent the neurological sequelae of the disease.
Asunto(s)
Catarata , Ataxia Cerebelosa , Trastornos Parkinsonianos , Xantomatosis Cerebrotendinosa , Xantomatosis , Masculino , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Xantomatosis Cerebrotendinosa/diagnóstico , Colestanotriol 26-Monooxigenasa/genética , Colestanotriol 26-Monooxigenasa/uso terapéutico , Estudios Retrospectivos , Enfermedades RarasRESUMEN
BACKGROUND: Cerebrotendinous xanthomatosis (CTX, OMIM #213700) is a rare but treatable lipid storage disease resulting from mutations in the CYP27A1 gene. PURPOSE: The study aims to evaluate patients diagnosed with CTX and reveal new information, especially about the signs of CTX and patients' response to the treatment. METHODS: The study was conducted retrospectively in 12 definitively diagnosed CTX patients. The patients' clinical, laboratory, imaging, genetic findings, and chenodeoxycholic acid (CDCA) treatment results were analyzed. RESULTS: The median age at diagnosis for the patients was 16.5 years (minimum-maximum: 7-32). Juvenile cataracts, detected in more than 90% (11/12) of the patients, were the most common clinical finding. Malar rash, not previously reported in the literature for CTX, was present in 75% (9/12) of the patients. Hand tremors, the first neurological symptom, occurred in adolescence and were the initial symptom of the disease in five patients. Hand tremors were present in 83.3% (10/12) of the patients. Hand tremors (in 5 patients) and malar rash (in 2 patients) were clinical findings with full recovery due to the CDCA treatment. CONCLUSION: The study defines the malar rash finding, which has not been reported in the literature before, as a possible new clinical finding in CTX disease, attributed to its partial or full recovery with CDCA treatment. Additionally, as a novelty in the literature, our study highlights the full recovery of neurological findings, such as hand tremors, in CTX. Patients presenting with hand tremors and malar rash, especially in adolescence, should undergo CTX investigation for early diagnosis and treatment.
Asunto(s)
Ácido Quenodesoxicólico , Temblor , Xantomatosis Cerebrotendinosa , Humanos , Xantomatosis Cerebrotendinosa/tratamiento farmacológico , Xantomatosis Cerebrotendinosa/diagnóstico , Xantomatosis Cerebrotendinosa/genética , Xantomatosis Cerebrotendinosa/complicaciones , Ácido Quenodesoxicólico/uso terapéutico , Adolescente , Masculino , Femenino , Temblor/tratamiento farmacológico , Adulto , Niño , Adulto Joven , Estudios Retrospectivos , Exantema , Mano/patología , Colestanotriol 26-Monooxigenasa/genéticaRESUMEN
Bile acids (BAs) are signaling molecules synthesized in the liver initially by CYP7A1 and CYP27A1 in the classical and alternative pathways, respectively. BAs are essential for cholesterol clearance, intestinal absorption of lipids, and endogenous modulators of farnesoid x receptor (FXR). FXR is critical in maintaining BA homeostasis and gut-liver crosstalk. Complex reactions in vivo and the lack of suitable animal models impede our understanding of the functions of individual BAs. In this study, we characterized the in vivo effects of three-day feeding of cholic acid (CA), deoxycholic acid (DCA), or ursodeoxycholic acid (UDCA) at physiological/non-hepatotoxic concentrations in a novel low-BA mouse model (Cyp7a1-/-/Cyp27a1-/-, DKO). Liver injury, BA levels and composition and BA signaling by the FXR-fibroblast growth factor 15 (FGF15) axis were determined. Overall, higher basal inflammation and altered lipid metabolism in DKO mice might be associated with low BAs. CA, DCA, and UDCA feeding activated FXR signals with tissue specificity. Dietary CA and DCA similarly altered tissue BA profiles to be less hydrophobic, while UDCA promoted a more hydrophobic tissue BA pool with the profiles shifted toward non-12α-OH BAs and secondary BAs. However, UDCA did not offer any overt protective effects as expected. These findings allow us to determine the precise effects of individual BAs in vivo on BA-FXR signaling and overall BA homeostasis in liver physiology and pathologies.
Asunto(s)
Ácidos y Sales Biliares , Ácido Cólico , Factores de Crecimiento de Fibroblastos , Hígado , Ratones Noqueados , Receptores Citoplasmáticos y Nucleares , Animales , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Ácidos y Sales Biliares/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/genética , Ácido Cólico/metabolismo , Masculino , Ratones Endogámicos C57BL , Ácido Desoxicólico/toxicidad , Colestanotriol 26-Monooxigenasa/genética , Colestanotriol 26-Monooxigenasa/metabolismo , Ratones , Ácido Ursodesoxicólico/farmacología , Transducción de Señal/efectos de los fármacos , Colesterol 7-alfa-HidroxilasaRESUMEN
Obesity is strongly associated with disturbances of vitamin D (VD) metabolites in the animal models. However, the related epidemiological evidence is still controversial, especially the different degrees of obesity children. Hence, in this present representative case-control study, 106 obesity school-age children aged 7-12 years were included and divided into different subgroups as degree I (the age- and sex-specific BMI≥95th percentile, n=45), II (BMI ≥120% percentile, n=34) and III (BMI ≥140% percentile, n=27) obesity groups across the ranges of body mass index (BMI). While the age- and sex-matched subjects without obesity were as the control group. Notably, it was significantly different of body composition, anthropological and clinical characteristics among the above four subgroups with the dose-response relationships (P<.05). Moreover, comparing with the control group, the serum VD concentrations were higher, VD metabolites like 25(OH)D, 25(OH)D3 and 1,25(OH)2D, and related hydroxylases as CYP27A1, CYP2R1 and CYP27B1 were lower in the degree I, II, and III obesity subgroups (P<.05), which were more disorder with the anthropological and clinical characteristics as the obesity was worsen in a BMI-independent manner (P<.05). However, there was a significant increase of CYP27B1 in the degree III obesity group than those in the degree I and II obesity subgroups. Furthermore, the methylation patterns on the genome-wide (Methylation/Hydroxymethylation) and VD metabolism genes (CYP27A1, CYP2R1 and CYP27B1) were negatively correlated with the worse obesity and their related expressions (P<.05). In summary, these results indicated that obesity could affect the homeostasis of VD metabolism related genes such as CYP27A1, CYP2R1, CYP27B1 and etc through abnormal DNA methylation, resulting in the disorders of VD related metabolites to decrease VD bio-availability with the BMI-independent manner. In turn, the lower levels of VD metabolites would affect the liver function to exacerbate the progression of obesity, as the Degree II and III obesity subgroups.
Asunto(s)
Índice de Masa Corporal , Metilación de ADN , Obesidad Infantil , Vitamina D , Humanos , Niño , Masculino , Femenino , Vitamina D/sangre , Vitamina D/análogos & derivados , Estudios de Casos y Controles , Obesidad Infantil/genética , Obesidad Infantil/metabolismo , Obesidad Infantil/complicaciones , Colestanotriol 26-Monooxigenasa/genética , Colestanotriol 26-Monooxigenasa/metabolismo , Familia 2 del Citocromo P450/genética , Familia 2 del Citocromo P450/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Deficiencia de Vitamina D/genética , Obesidad/genética , Obesidad/metabolismo , Enfermedades Metabólicas/genéticaRESUMEN
BACKGROUND: Cerebrotendinous Xanthomatosis (CTX) is a rare autosomal recessive lipid storage disorder caused by loss of function variants in the CYP27A1 gene which encodes sterol 27-hydroxylase, on chromosome 2q35. Although the symptoms begin commonly in infancy, CTX diagnosis is often delayed. The aim of this study is to review the orthopedic findings of the disease by providing an overview of the clinical features of the disease. It is to raise awareness of this condition for which early diagnosis and treatment are important. METHODS: We retrospectively evaluated the clinical, laboratory, radiological, and genetic findings of eight patients from four families who were admitted to our Orthopedics and Traumatology Department between 2017 and 2022 due to bilateral Achilles tendon xanthomas, were found to have high cholestanol and CYP27A1 gene mutations. RESULTS: The mean age of patients was 37, and five of them were male. The mean age at the onset of symptoms was 9.25 years. The mean age of initial diagnosis was 33.75 years. Between symptom onset and clinical diagnosis, an average delay of 24.5 years was observed. All patients had bilateral Achilles tendon xanthoma. Notably, a novel variant (c.670_671delAA) in CYP27A1 gene was identified in three patients who also presented with peripheral neuropathy and bilateral pes cavus. One patient had osteoporosis and four patients had osteopenia. Five patients had a history of bilateral cataracts. Furthermore, three of the patients had early-onset chronic diarrhea and three of the patients had ataxia. Two of the patients had epilepsy and seven of the patients had behavior-personality disorder. All patients had low intelligence, but none of them had cardiac disease. CONCLUSION: We present the diagnostic process and clinical features which the largest CTX case series ever reported from single orthopedic clinic. We suggest that patients with normal cholesterol levels presenting with xanthoma being genetically analyzed by testing at their serum cholestanol level, and that all siblings of patients diagnosed with CTX be examined.
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Colestanotriol 26-Monooxigenasa , Xantomatosis Cerebrotendinosa , Adulto , Niño , Femenino , Humanos , Masculino , Colestanotriol 26-Monooxigenasa/genética , Colestanol/uso terapéutico , Estudios Retrospectivos , Xantomatosis/genética , Xantomatosis Cerebrotendinosa/diagnóstico , Xantomatosis Cerebrotendinosa/genéticaRESUMEN
PURPOSE: Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive bile acid synthesis disorder. Biallelic pathogenic variants in CYP27A1, encoding for sterol 27-hydroxylase, impair cholic acid (CA) and chenodeoxycholic acid (CDCA) synthesis and lead to accumulation of cholestanol and C27 bile alcohols. Treatment with CDCA decreases the accumulation of these harmful metabolites and slows disease progression. Currently, CDCA is contraindicated for use during pregnancy based on animal studies that showed that high-dose CDCA may cause fetal harm when administered to pregnant animals. Data regarding the safety of CDCA treatment in humans are lacking. METHODS: We present a case series of 19 pregnancies in 9 women with CTX who either received CDCA treatment throughout pregnancy or did not. RESULTS: In 11 pregnancies where mothers continued CDCA treatment, no complications were reported, and newborns were born at or near full term, with normal birth weight and Apgar scores. In 8 pregnancies where mothers did not receive CDCA, 2 newborns experienced elevated bilirubin soon after birth. One woman who stopped treatment during her pregnancy deteriorated neurologically while off treatment. CONCLUSION: The data we present support the benefit of continued CDCA treatment in pregnant women with CTX for both the affected women and their offspring.
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Ácido Quenodesoxicólico , Xantomatosis Cerebrotendinosa , Humanos , Femenino , Ácido Quenodesoxicólico/uso terapéutico , Xantomatosis Cerebrotendinosa/tratamiento farmacológico , Xantomatosis Cerebrotendinosa/genética , Embarazo , Adulto , Colestanotriol 26-Monooxigenasa/genética , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/genética , Recién NacidoRESUMEN
In this article, patients with cerebrotendinous xanthomatosis (CTX) and caregivers detail their experience with lifelong symptoms, diagnosis, treatment and efficacy, and ongoing disease management. One patient and four caregivers describe the challenges associated with pursuing a correct diagnosis for years before testing confirmed a CTX diagnosis. They also detail their ongoing struggles and desire for greater access to physicians with CTX knowledge and to reliable online resources to continue their education about the disease and strategies for symptom management. The expert perspective is a direct response by three CTX researchers, including physicians who are treating patients with CTX in the United States and experts whose laboratories provide genetic and biochemical testing for CTX. They respond to many of the patient and caregiver concerns, including steps that are being taken to identify CTX earlier and provide access to confirmatory diagnostic testing sooner, and suggest the best online resources for CTX-related information and access to webinars and support groups. While the expert perspective is a direct response to the patient and caregiver authors' CTX journeys, it should be beneficial to any patient with CTX or their caregivers.
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Xantomatosis Cerebrotendinosa , Humanos , Xantomatosis Cerebrotendinosa/diagnóstico , Xantomatosis Cerebrotendinosa/complicaciones , Xantomatosis Cerebrotendinosa/genética , Cuidadores , Colestanotriol 26-Monooxigenasa/genéticaRESUMEN
Vitamin D deficiency (VDD) is widespread in the Arab world despite ample sunshine throughout the year. In our previous study, lifestyle and socio-demographic factors could explain only 45% of variability in vitamin D levels in Kuwaiti adolescents, suggesting that genetics might contribute to VDD in this region. Single nucleotide polymorphisms (SNP) in the 25-hydroxylase (CYP2R1) and the GC globulin (GC) genes have been reported to affect vitamin D levels in various ethnic groups in adults. In this study, we investigated the association of two SNPs from GC (rs4588 and rs7041) and three SNPs from CYP2R1 (rs10741657, rs11023374 and rs12794714) with vitamin D levels and VDD in a nationally representative sample of adolescents of Arab ethnicity from Kuwait. Multivariable linear regression, corrected for age, sex, parental education, governorate, body mass index, and exposure to sun, demonstrated that each of the 5 study variants showed significant associations with plasma 25(OH)D levels in one or more of the additive, recessive, and dominant genetic models - the rs10741657 under all the three models, rs12794714 under both the additive and recessive models, rs7041 under the recessive model; and rs4588 and rs11023374 under the dominant model. Minor alleles at rs4588 (T), rs7041 (A), rs11023374 (C), and rs12794714 (A) led to a decrease in plasma 25(OH)D levels - rs4588:[ß (95%CI) = -4.522 (-8.66,-0.38); p=0.033]; rs7041:[ß (95%CI) = -6.139 (-11.12,-1.15); p=0.016]; rs11023374:[ß (95%CI) = -4.296 (-8.18,-0.40); p=0.031]; and rs12794714:[ß (95%CI) = -3.498 (-6.27,-0.72); p=0.014]. Minor allele A at rs10741657 was associated with higher levels of plasma 25(OH)D levels [ß (95%CI) = 4.844 (1.62,8.06); p=0.003)] and lower odds of vitamin D deficiency (OR 0.40; p=0.002). These results suggest that the CYP2R1 and GC SNP variants are partly responsible for the high prevalence of VDD in Kuwait. Genotyping these variants may be considered for the prognosis of VDD in Kuwait.
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Colestanotriol 26-Monooxigenasa , Familia 2 del Citocromo P450 , Deficiencia de Vitamina D , Proteína de Unión a Vitamina D , Vitamina D , Adolescente , Humanos , Árabes/genética , Colestanotriol 26-Monooxigenasa/genética , Etnicidad , Kuwait/epidemiología , Oxigenasas de Función Mixta/genética , Polimorfismo de Nucleótido Simple , Deficiencia de Vitamina D/epidemiología , Deficiencia de Vitamina D/genética , Proteína de Unión a Vitamina D/genética , Vitaminas , Familia 2 del Citocromo P450/genéticaRESUMEN
Oncosterone (6-oxo-cholestane-3ß,5α-diol; OCDO) is an oncometabolite and a tumor promoter on estrogen receptor alpha-positive breast cancer (ER(+) BC) and triple-negative breast cancers (TN BC). OCDO is an oxysterol formed in three steps from cholesterol: 1) oxygen addition at the double bond to give α- or ß- isomers of 5,6-epoxycholestanols (5,6-EC), 2) hydrolyses of the epoxide ring of 5,6-ECs to give cholestane-3ß,5α,6ß-triol (CT), and 3) oxidation of the C6 hydroxyl of CT to give OCDO. On the other hand, cholesterol can be hydroxylated by CYP27A1 at the ultimate methyl carbon of its side chain to give 27-hydroxycholesterol ((25R)-Cholest-5-ene-3beta,26-diol, 27HC), which is a tumor promoter for ER(+) BC. It is currently unknown whether OCDO and its precursors can be hydroxylated at position C27 by CYP27A1, as is the impact of such modification on the proliferation of ER(+) and TN BC cells. We investigated, herein, whether 27H-5,6-ECs ((25R)-5,6-epoxycholestan-3ß,26-diol), 27H-CT ((25R)-cholestane-3ß,5α,6ß,26-tetrol) and 27H-OCDO ((25R)-cholestane-6-oxo-3ß,5α,26-triol) exist as metabolites and can be produced by cells expressing CYP27A1. We report, for the first time, that these compounds exist as metabolites in humans. We give pharmacological and genetic evidence that CYP27A1 is responsible for their production. Importantly, we found that 27-hydroxy-OCDO (27H-OCDO) inhibits BC cell proliferation and blocks OCDO and 27-HC-induced proliferation in BC cells, showing that this metabolic conversion commutes the proliferative properties of OCDO into antiproliferative ones. These data suggest an unprecedented role of CYP27A1 in the control of breast carcinogenesis by inhibiting the tumor promoter activities of oncosterone and 27-HC.
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Neoplasias de la Mama , Oxiesteroles , Humanos , Femenino , Hidroxilación , Colesterol/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Carcinógenos/metabolismo , Colestanotriol 26-MonooxigenasaRESUMEN
BACKGROUND: The association between lipid metabolism disorder and carcinogenesis is well-established, but there is limited research on the connection between lipid metabolism-related genes (LRGs) and lung adenocarcinoma (LUAD). The objective of our research was to identify LRGs as the potential biomarkers for prognosis and assess their impact on immune cell infiltration in LUAD. METHODS: We identified novel prognostic LRGs for LUAD patients via the bioinformatics analysis. CYP27A1 expression level was systematically evaluated via various databases, such as TCGA, UALCAN, and TIMER. Subsequently, LinkedOmics was utilized to perform the CYP27A1 co-expression network and GSEA. ssGSEA was conducted to assess the association between infiltration of immune cells and CYP27A1 expression. CYP27A1's expression level was validated by qRT-PCR analysis. RESULTS: CYP27A1 expression was decreased in LUAD. Reduced CYP27A1 expression was linked to unfavorable prognosis in LUAD. Univariate and multivariate analyses indicated that CYP27A1 was an independent prognostic biomarker for LUAD patients. GSEA results revealed a positive correlation between CYP27A1 expression and immune-related pathways. Furthermore, CYP27A1 expression was positively correlated with the infiltration levels of most immune cells. CONCLUSION: CYP27A1 is a potential biomarker for LUAD patients, and our findings provided a novel perspective to develop the prognostic marker for LUAD patients.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Transcriptoma , Pronóstico , Adenocarcinoma del Pulmón/diagnóstico , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Biomarcadores , Colestanotriol 26-MonooxigenasaRESUMEN
BACKGROUND: The proactive role of vitamin D has been well determined in different cancers. The protein that encodes the components of the vitamin D metabolism could appear to play a pivotal role in vitamin D stability and its maintenance. A polymorphism in vitamin-D-receptor (VDR), carrier globulin/binding protein (GC) and cytochrome P-450 family 2, subfamily R, polypeptide 1 (CYP2R1) genes has been predicted to be associated with the development of cancer. This study was designed to detect the association of VDR, GC Globulin and CYP2R1 gene polymorphism with the risk of esophageal cancer in the North-east Indian population. METHODS: To carry out the study, a total of 100 patients diagnosed with esophageal cancer and 101 healthy controls were enrolled. In a case-control manner, all samples were subjected to do genotype testing for known SNPs on the VDR (rs1544410), GC (rs4588), and CYP2R1 (rs10741657) genes using Restriction-fragment length polymorphism (RFLP) followed by Sanger sequencing. The collected demographic and clinical data were analysed using the statistical software package SPSS v22.0. RESULTS: The VDR haplotype heterozygous TC was found strongly associated with the carcinoma group (OR:1.09, 95%CI:0.67-1.75). The risk factors analysis using the GC globulin rs4588 phenotype, found a positive correlation in terms of mutant AA's harmful influence on the cancer cohort (OR = 1.125, OR=1.125, 95% CI, 0.573-2.206). The influence of the CYP2R1 rs10741657 polymorphism on the malignant cohort revealed that the GG mutant had a significant negative influence on the carcinoma, has an influential role in disease severity ( OR:1.736, at 95% CI; 0.368-8.180). CONCLUSION: In conclusion, this study revealed the potential association of VDR gene polymorphism in the progression and development of esophageal cancer in north east Indian population cohort.
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Carcinoma , Neoplasias Esofágicas , Humanos , Polimorfismo de Nucleótido Simple , Proteína de Unión a Vitamina D/genética , Colestanotriol 26-Monooxigenasa/genética , Receptores de Calcitriol/genética , Vitamina D , Genotipo , Familia 2 del Citocromo P450/genética , Neoplasias Esofágicas/genética , Predisposición Genética a la Enfermedad , Estudios de Casos y ControlesRESUMEN
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by mutations in the sterol 27-hydroxylase gene (CYP27A1). Due to the deficiency of 27-hydroxylase, the synthesis of bile acids from cholesterol is impaired and excessive cholestanol accumulates in various tissues, such as the central nervous system, tendons, and lenses. Patients with CTX typically manifest intellectual decline, pyramidal tract symptoms, cerebellar symptoms, tendon xanthomas, juvenile cataracts, neonatal jaundice, chronic diarrhea, osteoporosis, and premature cardiovascular disease. Here, we report the atypical case of a 35-year-old female with CTX having massive xanthomas but without a considerable increase in serum cholestanol levels (3.9 µg/mL). In the differential diagnosis of xanthoma, CTX should not be ruled out even if the serum levels of cholestanol are not high, and genetic testing is necessary to make the appropriate diagnosis.