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1.
Hum Mol Genet ; 21(17): 3883-95, 2012 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-22678061

RESUMEN

Huntington's disease (HD) is characterized by a late clinical onset despite ubiquitous expression of the mutant gene at all developmental stages. How mutant huntingtin impacts on signalling pathways in the pre-symptomatic period has remained essentially unexplored in humans due to a lack of appropriate models. Using multiple human embryonic stem cell lines derived from blastocysts diagnosed as carrying the mutant huntingtin gene by pre-implantation genetic diagnosis, we explored early developmental changes in gene expression using differential transcriptomics, combined with gain and loss of function strategies. We demonstrated a down-regulation of the HTT gene itself in HD neural cells and identified three genes, the expression of which differs significantly in HD cells when compared with wild-type controls, namely CHCHD2, TRIM4 and PKIB. Similar dysregulation had been observed previously for CHCDH2 and TRIM4 in blood cells from patients. CHCHD2 is involved in mitochondrial function and PKIB in protein kinase A-dependent pathway regulation, which suggests that these functions may be precociously impacted in HD.


Asunto(s)
Células Madre Embrionarias/metabolismo , Enfermedad de Huntington/genética , Mutación/genética , Neuronas/metabolismo , Transcripción Genética , Transcriptoma/genética , Línea Celular , Células Madre Embrionarias/patología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Proteína Huntingtina , Modelos Biológicos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Neuronas/patología , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
2.
Stem Cell Res ; 76: 103350, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38387169

RESUMEN

Human induced Pluripotent Stem Cells (hiPSCs) represent an invaluable source of primary cells to investigate development, establish cell and disease models, provide material for regenerative medicine and allow more physiological high-content screenings. Here, we generated three healthy hiPSC control lines - IPi001-A/B/C - from primary amniotic fluid cells (AFCs), an infrequently used source of cells, which can be readily obtained from amniocentesis for the prenatal diagnosis of numerous genetic disorders. These AFCs were reprogrammed by non-integrative viral transduction. The resulting hiPSCs displayed normal karyotype and expressed classic pluripotency hallmarks.


Asunto(s)
Células Madre Pluripotentes Inducidas , Embarazo , Femenino , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Reprogramación Celular , Diferenciación Celular/fisiología , Líquido Amniótico/metabolismo , Medicina Regenerativa
3.
Stem Cell Res ; 69: 103104, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37148821

RESUMEN

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare and severe genetic disease responsible for blistering of the skin and mucosa caused by a wide variety of mutations in COL7A1 encoding type VII collagen. We have generated Induced Pluripotent Stem Cells (iPSCs) from two RDEB patients' fibroblasts harboring homozygous recurrent mutations in COL7A1. Their pluripotent state was confirmed by gene and protein expression of stem cell markers OCT4, SOX2, TRA1/60 and SSEA4. Embryoid body formation followed by immunostaining and TaqMan scorecard analysis confirmed the capacity of RDEB iPSCs to differentiate into cell types from the three germ layers in vitro.


Asunto(s)
Epidermólisis Ampollosa Distrófica , Células Madre Pluripotentes Inducidas , Humanos , Epidermólisis Ampollosa Distrófica/genética , Epidermólisis Ampollosa Distrófica/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Genes Recesivos , Piel/metabolismo , Colágeno Tipo VII/genética , Colágeno Tipo VII/metabolismo , Mutación/genética
4.
Stem Cell Res ; 68: 103057, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36868038

RESUMEN

Mutations in UNC45A, a co-chaperone for myosins, were recently found causative of a syndrome combining cholestasis, diarrhea, loss of hearing and bone fragility. We generated induced pluripotent stem cells (iPSCs) from a patient with a homozygous missense mutation in UNC45A. Cells from this patient, which were reprogrammed using integration-free Sendaï virus, have normal karyotype, express pluripotency markers and are able to differentiate into the three germ cell layers.


Asunto(s)
Células Madre Pluripotentes Inducidas , Síndromes de Malabsorción , Mucolipidosis , Humanos , Mutación Missense , Mutación , Péptidos y Proteínas de Señalización Intracelular/genética
5.
Biomaterials ; 295: 122033, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36764194

RESUMEN

Human pluripotent stem cells (hPSCs) have emerged as the most promising cellular source for cell therapies. To overcome the scale-up limitations of classical 2D culture systems, suspension cultures have been developed to meet the need for large-scale culture in regenerative medicine. Despite constant improvements, current protocols that use microcarriers or generate cell aggregates only achieve moderate amplification performance. Here, guided by reports showing that hPSCs can self-organize in vitro into cysts reminiscent of the epiblast stage in embryo development, we developed a physio-mimetic approach for hPSC culture. We engineered stem cell niche microenvironments inside microfluidics-assisted core-shell microcapsules. We demonstrate that lumenized three-dimensional colonies significantly improve viability and expansion rates while maintaining pluripotency compared to standard hPSC culture platforms such as 2D cultures, microcarriers, and aggregates. By further tuning capsule size and culture conditions, we scale up this method to industrial-scale stirred tank bioreactors and achieve an unprecedented hPSC amplification rate of 277-fold in 6.5 days. In brief, our findings indicate that our 3D culture system offers a suitable strategy both for basic stem cell biology experiments and for clinical applications.


Asunto(s)
Técnicas de Cultivo de Célula , Células Madre Pluripotentes , Humanos , Técnicas de Cultivo de Célula/métodos , Diferenciación Celular , Células Cultivadas , Reactores Biológicos
6.
Stem Cell Res ; 61: 102755, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35334405

RESUMEN

Human pluripotent stem cells are a powerful tool to study development, to model diseases or as cellular substrates for drug screening. We generated a human induced pluripotent stem cell (hiPSC) line from a healthy control donor. Peripheral blood mononuclear cells (PBMCs) from this donor were reprogrammed using integration-free Sendai virus. This cell line had normal karyotype, expressed pluripotency hallmarks and differentiated into the three primary germ layers.


Asunto(s)
Células Madre Pluripotentes Inducidas , Diferenciación Celular , Línea Celular , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Leucocitos Mononucleares , Virus Sendai/genética
7.
J Vis Exp ; (181)2022 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-35389978

RESUMEN

Primary cilia (PC) are non-motile dynamic microtubule-based organelles that protrude from the surface of most mammalian cells. They emerge from the older centriole during the G1/G0 phase of the cell cycle, while they disassemble as the cells re-enter the cell cycle at the G2/M phase boundary. They function as signal hubs, by detecting and transducing extracellular signals crucial for many cell processes. Similar to most cell types, all neocortical neural stem and progenitor cells (NSPCs) have been shown harboring a PC allowing them to sense and transduce specific signals required for the normal cerebral cortical development. Here, we provide detailed protocols to generate and characterize two-dimensional (2D) and three-dimensional (3D) cell-based models from human induced pluripotent stem cells (hIPSCs) to further dissect the involvement of PC during neocortical development. In particular, we present protocols to study the PC biogenesis and function in 2D neural rosette-derived NSPCs including the transduction of the Sonic Hedgehog (SHH) pathway. To take advantage of the three-dimensional (3D) organization of cerebral organoids, we describe a simple method for 3D imaging of in toto immunostained cerebral organoids. After optical clearing, rapid acquisition of entire organoids allows detection of both centrosomes and PC on neocortical progenitors and neurons of the whole organoid. Finally, we detail the procedure for immunostaining and clearing of thick free-floating organoid sections preserving a significant degree of 3D spatial information and allowing for the high-resolution acquisition required for the detailed qualitative and quantitative analysis of PC biogenesis and function.


Asunto(s)
Células Madre Pluripotentes Inducidas , Neocórtex , Animales , Diferenciación Celular/fisiología , Cilios/metabolismo , Proteínas Hedgehog/metabolismo , Humanos , Mamíferos/metabolismo , Organoides/metabolismo
8.
J Clin Invest ; 132(10)2022 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-35575086

RESUMEN

Variants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism underlying intestinal failure in UNC45A deficiency remains unclear. Here, biallelic variants in UNC45A were identified by next-generation sequencing in 6 patients with congenital diarrhea. Corroborating in silico prediction, variants either abolished UNC45A expression or altered protein conformation. Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in UNC45AKO Caco-2 cells. In keeping with impaired myosin VB function, UNC45AKO Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and UNC45AKO 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli. All those features resembled the subcellular abnormalities observed in duodenal biopsies from patients with microvillus inclusion disease. Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish. Taken together, our results provide evidence that UNC45A plays an essential role in epithelial morphogenesis through its cochaperone function of myosin VB and that UNC45A loss causes a variant of microvillus inclusion disease.


Asunto(s)
Diarrea Infantil , Síndromes de Malabsorción , Mucolipidosis , Miosina Tipo V , Animales , Células CACO-2 , Diarrea Infantil/metabolismo , Diarrea Infantil/patología , Facies , Retardo del Crecimiento Fetal , Enfermedades del Cabello , Humanos , Lactante , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Síndromes de Malabsorción/metabolismo , Microvellosidades/genética , Microvellosidades/patología , Mucolipidosis/genética , Mucolipidosis/metabolismo , Mucolipidosis/patología , Miosina Tipo V/genética , Miosina Tipo V/metabolismo , Fenotipo , Pez Cebra/genética , Pez Cebra/metabolismo
9.
Proc Natl Acad Sci U S A ; 105(43): 16707-12, 2008 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-18922775

RESUMEN

Substitutive cell therapy using fetal striatal grafts has demonstrated preliminary clinical success in patients with Huntington's disease, but the logistics required for accessing fetal cells preclude its extension to the relevant population of patients. Human embryonic stem (hES) cells theoretically meet this challenge, because they can be expanded indefinitely and differentiated into any cell type. We have designed an in vitro protocol combining substrates, media, and cytokines to push hES cells along the neural lineage, up to postmitotic neurons expressing striatal markers. The therapeutic potential of such hES-derived cells was further substantiated by their in vivo differentiation into striatal neurons following xenotransplantation into adult rats. Our results open the way toward hES cell therapy for Huntington's disease. Long-term proliferation of human neural progenitors leads, however, to xenograft overgrowth in the rat brain, suggesting that the path to the clinic requires a way to switch them off after grafting.


Asunto(s)
Cuerpo Estriado/citología , Fosfoproteína 32 Regulada por Dopamina y AMPc , Células Madre Embrionarias/citología , Neuronas/citología , Trasplante de Células Madre , Animales , Técnicas de Cultivo de Célula , Diferenciación Celular , Proliferación Celular , Medios de Cultivo , Citocinas/farmacología , Células Madre Embrionarias/trasplante , Humanos , Enfermedad de Huntington/terapia , Ácido Quinolínico , Ratas , Trasplante Heterólogo
10.
Stem Cell Res ; 46: 101878, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32585588

RESUMEN

Mutations in the NPHS2 gene, encoding podocin, are responsible for the majority of familial cases of steroid-resistant nephrotic syndrome (SRNS), a rare glomerulopathy that rapidly progresses to end-stage renal disease. We obtained peripheral blood mononuclear cells (PBMCs) from a patient carrying the homozygous c.413G>A substitution (p.R138Q) in NPHS2 gene, which is the most prevalent mutation in the European population. The PBMCs were reprogrammed by non-integrative viral transduction of the Yamanaka's factors. The resulting iPSCs display normal karyotype, express pluripotency hallmarks and are capable of multilineage differentiation, offering a useful tool to study pathological mechanisms of SRNS and perform drug testing.


Asunto(s)
Células Madre Pluripotentes Inducidas , Síndrome Nefrótico , Humanos , Péptidos y Proteínas de Señalización Intracelular , Leucocitos Mononucleares , Proteínas de la Membrana , Mutación , Síndrome Nefrótico/genética , Esteroides/uso terapéutico
11.
Stem Cell Res ; 48: 101959, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32866896

RESUMEN

Human pluripotent stem cells offer a limitless source of cells for regenerative medicine. They are also highly valuable as tools to study development and pathologies or as cellular substrates to screen and test new drugs. We generated human induced pluripotent stem cell (hiPSC) lines from two unrelated healthy control donors. Peripheral blood mononuclear cells (PBMCs) from these donors were reprogrammed by non-integrative viral transduction, had normal karyotypes and expressed pluripotency hallmarks.


Asunto(s)
Células Madre Pluripotentes Inducidas , Línea Celular , Humanos , Leucocitos Mononucleares , Medicina Regenerativa
12.
Stem Cell Res ; 50: 102107, 2020 Dec 02.
Artículo en Inglés | MEDLINE | ID: mdl-33340797

RESUMEN

Mutation in STING1gene, which encodes stimulator of type I IFN gene (STING) leads to its constitutive activation and thereby to a severe vasculopathy and sometimes a lupus-like disease. We generated induced pluripotent stem cells (iPSCs) from a patient carrying a rare heterozygous variant c.463G > A (resulting in a p.V155M substitution) in STING1. Cells from this patient, which were reprogrammed by non-integrative viral transduction, had normal karyotype, expressed pluripotency markers and were able to differentiate into the three germ cell layers.

13.
Stem Cell Res ; 48: 101936, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32795927

RESUMEN

Mutations of SOX10 result in a broad range of phenotypes including Waardenburg syndrome (WS types 2 and 4) that can be found in association with peripheral demyelinating neuropathy and/or central dysmyelinating leukodystrophy. Here, we generated induced pluripotent stem cells (iPSCs) from a patient carrying a de novo heterozygous missense mutation in the SOX10 gene (MIM* 602229, NM006941.3c.523C > G; p.Pro175Ala) presenting with deafness, depigmentation and progressive neurological impairment. Cells were reprogrammed by non-integrative viral transduction from blood sample, have normal karyotype, express pluripotency markers and are able to differentiate into the three germ cell layers.


Asunto(s)
Sordera , Células Madre Pluripotentes Inducidas , Síndrome de Waardenburg , Sordera/genética , Humanos , Mutación , Mutación Missense , Factores de Transcripción SOXE/genética , Síndrome de Waardenburg/genética
14.
Nat Commun ; 11(1): 6087, 2020 11 30.
Artículo en Inglés | MEDLINE | ID: mdl-33257696

RESUMEN

Inositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the multiple inositol-polyphosphate phosphatase 1 gene (MINPP1). Patients are found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We find that patient-derived and genome edited MINPP1-/- induced stem cells exhibit an inefficient neuronal differentiation combined with an increased cell death. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis.


Asunto(s)
Enfermedades Cerebelosas/metabolismo , Quelantes/metabolismo , Citoplasma/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Ácido Fítico/metabolismo , Animales , Muerte Celular , Diferenciación Celular , Enfermedades Cerebelosas/diagnóstico por imagen , Enfermedades Cerebelosas/patología , Niño , Preescolar , Femenino , Técnicas de Inactivación de Genes , Células HEK293 , Homeostasis , Humanos , Lactante , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Trastornos del Neurodesarrollo/metabolismo , Monoéster Fosfórico Hidrolasas/genética , Monoéster Fosfórico Hidrolasas/farmacología , Fosforilación , Células Madre/efectos de los fármacos , Transcriptoma
15.
Mol Biol Cell ; 17(4): 1652-63, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16452635

RESUMEN

Alterations of mitochondrial function may play a central role in neuronal death in Huntington's disease (HD). However, the molecular mechanisms underlying such functional deficits of mitochondria are not elucidated yet. We herein showed that the expression of two important constituents of mitochondrial complex II, the 30-kDa iron-sulfur (Ip) subunit and the 70-kDa FAD (Fp) subunit, was preferentially decreased in the striatum of HD patients compared with controls. We also examined several mitochondrial proteins in striatal neurons that were infected with lentiviral vectors coding for the N-terminus part of huntingtin (Htt) with either a pathological (Htt171-82Q) or physiological (Htt171-19Q) polyglutamine tract. Compared with Htt171-19Q, expression of Htt171-82Q preferentially decreased the levels of Ip and Fp subunits and affected the dehydrogenase activity of the complex. The Htt171-82Q-induced preferential loss of complex II was not associated with a decrease in mRNA levels, suggesting the involvement of a posttranscriptional mechanism. Importantly, the overexpression of either Ip or Fp subunit restored complex II levels and blocked mitochondrial dysfunction and striatal cell death induced by Htt171-82Q in striatal neurons. The present results strongly suggest that complex II defects in HD may be instrumental in striatal cell death.


Asunto(s)
Apoptosis , Cuerpo Estriado/enzimología , Complejo II de Transporte de Electrones/metabolismo , Enfermedad de Huntington/enzimología , Enfermedad de Huntington/genética , Proteínas Hierro-Azufre/metabolismo , Mitocondrias/enzimología , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Subunidades de Proteína/metabolismo , Succinato Deshidrogenasa/metabolismo , Cuerpo Estriado/citología , Regulación hacia Abajo , Complejo II de Transporte de Electrones/genética , Vectores Genéticos/genética , Humanos , Proteína Huntingtina , Lentivirus/genética , Mitocondrias/genética , Proteínas Mitocondriales/metabolismo , Mutagénesis , Mutación , Neuronas/enzimología , Péptidos/genética , Subunidades de Proteína/genética , Transfección
16.
Elife ; 72018 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-30311906

RESUMEN

Proper brain development relies highly on protein N-glycosylation to sustain neuronal migration, axon guidance and synaptic physiology. Impairing the N-glycosylation pathway at early steps produces broad neurological symptoms identified in congenital disorders of glycosylation. However, little is known about the molecular mechanisms underlying these defects. We generated a cerebellum specific knockout mouse for Srd5a3, a gene involved in the initiation of N-glycosylation. In addition to motor coordination defects and abnormal granule cell development, Srd5a3 deletion causes mild N-glycosylation impairment without significantly altering ER homeostasis. Using proteomic approaches, we identified that Srd5a3 loss affects a subset of glycoproteins with high N-glycans multiplicity per protein and decreased protein abundance or N-glycosylation level. As IgSF-CAM adhesion proteins are critical for neuron adhesion and highly N-glycosylated, we observed impaired IgSF-CAM-mediated neurite outgrowth and axon guidance in Srd5a3 mutant cerebellum. Our results link high N-glycan multiplicity to fine-tuned neural cell adhesion during mammalian brain development.


Asunto(s)
Cerebelo/metabolismo , Neuronas/citología , Neuronas/metabolismo , Polisacáridos/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/deficiencia , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismo , Animales , Orientación del Axón , Adhesión Celular , Moléculas de Adhesión Celular/metabolismo , Diferenciación Celular , Membrana Celular/metabolismo , Cerebelo/embriología , Gránulos Citoplasmáticos/metabolismo , Eliminación de Gen , Glicosilación , Inmunoglobulinas/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/metabolismo , Ratones Noqueados , Actividad Motora , Mutación/genética , Vías Nerviosas/metabolismo , Proteómica , Células de Purkinje/metabolismo , Reproducibilidad de los Resultados , Respuesta de Proteína Desplegada
18.
Exp Hematol ; 34(12): 1720-9, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17157169

RESUMEN

OBJECTIVE: The Notch pathway plays a key role in cell fate choices and in T-cell development. The goal of our study was to evaluate whether a short in vitro stimulation of the Notch pathway may alter human progenitor cell behavior. METHODS: CD34+ cord blood progenitors were exposed for 4 days to either immobilized Notch ligand Delta-4 or in control conditions. Phenotypic and molecular changes induced by the short stimulation were assessed at day 4. Next, long-term alteration of the fate of these progenitors was assessed in culture conditions suitable for B (coculture with MS5 stromal cells) and T (FTOC and OP9 stromal cells expressing Delta-4 systems) cell differentiation. RESULTS: Notch activation was sufficient to trigger immunophenotypic and molecular changes consistent with early T-cell lineage differentiation. Delta-4 induced, in 4 days, CD7+cytCD3epsilon+ cells. This paralleled at the gene-transcription level with de novo expression of several T cell-related transcription factors and TCRgamma rearrangement, while B cell transcripts were simultaneous silenced. As compared to non-Delta-4 primed cells, these early changes translated to long-term alteration of the potential of cells. Delta-4 priming led to an acceleration of T-cell development, including a completion of the TCR rearrangement, when cells were cultured in systems suitable for T-cell development while B-cell development was inhibited. CONCLUSION: A transient Notch activation is sufficient to promote T-cell differentiation from cord blood CD34+ cells. This system may be a useful tool for the amplification and the quantification of the T potential of CD34+ cells in various disease conditions.


Asunto(s)
Antígenos CD34/biosíntesis , Diferenciación Celular/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/farmacología , Linfocitos T/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Proteínas de Unión al Calcio , Diferenciación Celular/inmunología , Células Cultivadas , Células Madre Hematopoyéticas/inmunología , Humanos , Transducción de Señal/efectos de los fármacos , Linfocitos T/inmunología
19.
Mol Vis ; 11: 1012-7, 2005 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-16319821

RESUMEN

PURPOSE: To investigate a role of common polymorphisms of the CYP1B1 gene in French patients with primary open-angle glaucoma (POAG). METHODS: Six common CYP1B1 variants, 5 coding and one in promoter, were compared in 224 unrelated French Caucasian POAG patients, excluding those with a CYP1B1 mutation, and in 47 population-matched controls with a normal ophthalmic examination. Allelic associations were assessed with the D' and r2 parameters. An effect of the representative variants on subphenotypes, including the age and the intraocular pressure at diagnosis, the cup to disk ratio, and the visual field alteration, was tested by multivariate analyses. RESULTS: Allele and haplotype frequencies were similar in patients and in controls. Five variants formed two groups with tightly correlated alleles while the sixth one, N453S, was independent. The age and the intraocular pressure at diagnosis were not influenced by any of the variants. In contrast, the 453*Serine allele was associated with decreased cupping of the optic disk (Odds ratio=0.32, 95% CI: 0.15-0.70; p=0.0036) and with a milder alteration of the visual field (p=0.025). CONCLUSIONS: The common N453S coding variant of CYP1B1 is potentially a factor of severity in POAG patients.


Asunto(s)
Sistema Enzimático del Citocromo P-450/genética , Glaucoma de Ángulo Abierto/genética , Disco Óptico/patología , Enfermedades del Nervio Óptico/genética , Polimorfismo de Nucleótido Simple , Trastornos de la Visión/genética , Campos Visuales , Alelos , Hidrocarburo de Aril Hidroxilasas , Citocromo P-450 CYP1B1 , Francia/epidemiología , Genotipo , Glaucoma de Ángulo Abierto/etnología , Humanos , Presión Intraocular , Reacción en Cadena de la Polimerasa , Pruebas del Campo Visual
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