RESUMEN
BACKGROUND: Individuals with pathogenic variants in SATB2 display intellectual disability, speech and behavioral disorders, dental abnormalities and often features of Pierre Robin sequence. SATB2 encodes a transcription factor thought to play a role in bone remodeling. The primary aim of our study was to systematically review the skeletal manifestations of SATB2-associated syndrome. For this purpose, we performed a non-interventional, multicenter cohort study, from 2017 to 2018. We included 19 patients, 9 females and 10 males ranging in age from 2 to 19 years-old. The following data were collected prospectively for each patient: clinical data, bone markers and calcium and phosphate metabolism parameters, skeletal X-rays and bone mineral density. RESULTS: Digitiform impressions were present in 8/14 patients (57%). Vertebral compression fractures affected 6/17 patients (35%). Skeletal demineralization (16/17, 94%) and cortical thinning of vertebrae (15/17) were the most frequent radiological features at the spine. Long bones were generally demineralized (18/19). The distal phalanges were short, thick and abnormally shaped. C-telopeptide (CTX) and Alkaline phosphatase levels were in the upper normal values and osteocalcin and serum procollagen type 1 amino-terminal propeptide (P1NP) were both increased. Vitamin D insufficiency was frequent (66.7%). CONCLUSION: We conclude that SATB2 pathogenic variants are responsible for skeletal demineralization and osteoporosis. We found increased levels of bone formation markers, supporting the key role of SATB2 in osteoblast differentiation. These results support the need for bone evaluation in children and adult patients with SATB2-associated syndrome (SAS).
Asunto(s)
Fracturas por Compresión , Proteínas de Unión a la Región de Fijación a la Matriz , Fracturas de la Columna Vertebral , Factores de Transcripción , Adolescente , Adulto , Biomarcadores , Densidad Ósea/genética , Huesos , Niño , Preescolar , Estudios de Cohortes , Femenino , Fracturas por Compresión/genética , Fracturas por Compresión/metabolismo , Fracturas por Compresión/patología , Humanos , Masculino , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Estudios Prospectivos , Fracturas de la Columna Vertebral/genética , Fracturas de la Columna Vertebral/metabolismo , Fracturas de la Columna Vertebral/patología , Síndrome , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Adulto JovenRESUMEN
Auriculocondylar syndrome and isolated question mark ear result from dysregulation of the endothelin 1-endothelin receptor type A signaling pathway. Animal models have highlighted the role of the transcription factor MEF2C as an effector of this pathway. We report heterozygous MEF2C loss-of-function as a possible cause of question mark ear associated with intellectual deficiency.
Asunto(s)
Encefalopatías/genética , Enfermedades del Oído/genética , Oído/anomalías , Predisposición Genética a la Enfermedad , Encefalopatías/fisiopatología , Preescolar , Oído/fisiopatología , Enfermedades del Oído/fisiopatología , Estudios de Asociación Genética , Humanos , Lactante , Mutación con Pérdida de Función/genética , Factores de Transcripción MEF2/genética , Masculino , Linaje , FenotipoRESUMEN
Ninety genes have been identified to date that are involved in non-syndromic hearing loss, and more than 300 different forms of syndromic hearing impairment have been described. Mutations in SOX10, one of the genes contributing to syndromic hearing loss, induce a large range of phenotypes, including several subtypes of Waardenburg syndrome and Kallmann syndrome with deafness. In addition, rare mutations have been identified in patients with isolated signs of these diseases. We used the recent characterization of temporal bone imaging aspects in patients with SOX10 mutations to identify possible patients with isolated hearing loss due to SOX10 mutation. We selected 21 patients with isolated deafness and temporal bone morphological defects for mutational screening. We identified two SOX10 mutations and found that both resulted in a non-functional protein in vitro. Re-evaluation of the two affected patients showed that both had previously undiagnosed olfactory defects. Diagnosis of anosmia or hyposmia in young children is challenging, and particularly in the absence of magnetic resonance imaging (MRI), SOX10 mutations can mimic non-syndromic hearing impairment. MRI should complete temporal bones computed tomographic scan in the management of congenital deafness as it can detect brain anomalies, cochlear nerve defects, and olfactory bulb malformation in addition to inner ear malformations.
Asunto(s)
Pérdida Auditiva/genética , Mutación , Factores de Transcripción SOXE/genética , Hueso Temporal/patología , Adolescente , Adulto , Anciano , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Análisis Mutacional de ADN , Diagnóstico Diferencial , Oído Interno/anomalías , Femenino , Estudios de Asociación Genética , Pérdida Auditiva Sensorineural/genética , Humanos , Imagen por Resonancia Magnética , Masculino , Datos de Secuencia Molecular , Fenotipo , Factores de Transcripción SOXE/química , Síndrome de Waardenburg/genéticaRESUMEN
BACKGROUND AND PURPOSE: Waardenburg syndrome, characterized by deafness and pigmentation abnormalities, is clinically and genetically heterogeneous, consisting of 4 distinct subtypes and involving several genes. SOX10 mutations have been found both in types 2 and 4 Waardenburg syndrome and neurologic variants. The purpose of this study was to evaluate both the full spectrum and relative frequencies of inner ear malformations in these patients. MATERIALS AND METHODS: Fifteen patients with Waardenburg syndrome and different SOX10 mutations were studied retrospectively. Imaging was performed between February 2000 and March 2010 for cochlear implant work-up, diagnosis of hearing loss, and/or evaluation of neurologic impairment. Eleven patients had both CT and MR imaging examinations, 3 had MR imaging only, and 1 had CT only. RESULTS: Temporal bone abnormalities were bilateral. The most frequent pattern associated agenesis or hypoplasia of ≥1 semicircular canal, an enlarged vestibule, and a cochlea with a reduced size and occasionally an abnormal shape, but with normal partition in the 13/15 cases that could be analyzed. Three patients lacked a cochlear nerve, bilaterally in 2 patients. In addition, associated abnormalities were found when adequate MR imaging sequences were available: agenesis of the olfactory bulbs (7/8), hypoplastic or absent lacrimal glands (11/14), hypoplastic parotid glands (12/14), and white matter signal anomalies (7/13). CONCLUSIONS: In the appropriate clinical context, bilateral agenesis or hypoplasia of the semicircular canals or both, associated with an enlarged vestibule and a cochlear deformity, strongly suggests a diagnosis of Waardenburg syndrome linked to a SOX10 mutation.
Asunto(s)
Oído Interno/anomalías , Factores de Transcripción SOXE/genética , Hueso Temporal/anomalías , Síndrome de Waardenburg/genética , Síndrome de Waardenburg/patología , Adolescente , Adulto , Niño , Preescolar , Cóclea/anomalías , Cóclea/diagnóstico por imagen , Cóclea/patología , Nervio Coclear/anomalías , Nervio Coclear/diagnóstico por imagen , Nervio Coclear/patología , Diagnóstico Diferencial , Oído Interno/diagnóstico por imagen , Oído Interno/patología , Femenino , Pérdida Auditiva Sensorineural/diagnóstico por imagen , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/patología , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Bulbo Olfatorio/anomalías , Bulbo Olfatorio/diagnóstico por imagen , Bulbo Olfatorio/patología , Glándula Parótida/anomalías , Glándula Parótida/diagnóstico por imagen , Glándula Parótida/patología , Radiografía , Estudios Retrospectivos , Canales Semicirculares/anomalías , Canales Semicirculares/diagnóstico por imagen , Canales Semicirculares/patología , Hueso Temporal/diagnóstico por imagen , Hueso Temporal/patología , Síndrome de Waardenburg/diagnóstico por imagen , Adulto JovenRESUMEN
Waardenburg syndrome (WS) is a genetic disorder characterized primarily by depigmentation of the skin and hair, heterochromia of the irides, sensorineural deafness, and sometimes by dystopia canthorum, and Hirschsprung disease. WS presents a large clinical and genetic heterogeneity. Four different types have been individualized and linked to 5 different genes. We report 2 cases of WS type II and 1 case of WS type IV from Lebanon and Syria. The genetic studies revealed 2 novel mutations in the MITF gene of the WS type II cases and 1 novel homozygous mutation in the EDNRB gene of the WS type IV case. This is the first molecular study of patients from the Arab world. Additional cases will enable a more detailed description of the clinical spectrum of Waardenburg syndrome in this region.
RESUMEN
OBJECTIVE: Although clozapine currently remains the most effective option in treatment-resistant schizophrenia, approximately 40-70% of antipsychotic-resistant patients do not respond, or respond only partially, to clozapine. Because clozapine-resistant patients have limited alternative treatment options, in this study we propose a clozapine augmentation strategy with evidence-based support for some of them. BACKGROUND: Clozapine-resistance is often of metabolic origin. Clozapine is metabolized by N-oxidation and N-demethylation in the liver, predominantly by CYP450 1A2. Due to the influence of inhibitors, inducers, and genetic factors on CYP450 1A2-activity, there is extensive interindividual variability in clozapine plasma concentrations at a fixed dose. Consequently, monitoring of clozapine plasma concentrations is recommended. Several studies have suggested a significantly higher response rate at clozapine plasma concentration of less than 350 microg/l. Unfortunatly, some patients, especially young male smokers, do not achieve this minimum plasma concentration, even at doses higher than 900 mg/day and are nonresponders. CASE-REPORTS: We report the case of a 30 year-old smoker suffering from refractory schizophrenia, and responding poorly to treatments, including clozapine. Monitoring of the clozapine plasma concentration showed a very low level of clozapine, below the minimal effective dose of 350 microg/l. We initially suspected noncompliance with the treatment regime, but genetic analyses revealed another explanation: a gene polymorphism of the CYP450 1A2, principal enzyme that breaks down clozapine. The variability of CYP450 1A2 is explained by a gene polymorphism in intron 1. The A/A genotype confers high CYP450 1A2 inductivity in smokers. Certain smoking patients with A/A polymorphism have ultrarapid CYP450 1A2 activity, which causes the patient to metabolize clozapine too quickly. These patients do not respond to clozapine, even with doses higher than 900 mg/day. However, several factors can counter this elevated CYT activity, in particular fluvoxamine. The interaction between clozapine and fluvoxamine occurs via the inhibition of CYP450 1A2. Several studies have shown that administration of fluvoxamine to patients receiving clozapine therapy may increase the steady-state serum concentrations of clozapine by a factor of 5. Low doses of fluvoxamine inhibit the CYT activity, enough to raise the level of clozapine even when the dose of clozapine was reduced by 50%. The patient unfortunately developed a maniac episode during treatment with fluvoxamine, despite the absence of a previous history of bipolar illness, and we had to initiate treatment with lithium. Together, the three medications stabilized his condition satisfactorily for eight months. We describe three additional cases of treatment-refractory patients with schizophrenia and low-clozapine plasma levels despite high doses. They exhibited similar metabolic abnormality, as confirmed by a caffeine test, because plasma caffeine ratios reflect CYP450 1A2 activity. We then describe its correction, with low doses of fluvoxamine. These patients became responders when the plasma levels increased above the threshold. CONCLUSION: Consequently, we propose a therapeutic drug monitoring strategy. In the case of a clozapine-resistant schizophrenic patient, plasma clozapine levels should be tested. If the rate is normal, the resistance is not metabolic in origin. If the rate is low, a caffeine test should be done. If the results are normal, the patient is noncompliant with the treatment. If the caffeine test is abnormal, metabolic resistance is suspected. In such patients, we propose the addition of low-dose fluvoxamine while closely monitoring clozapine levels. Based on our experience, reducing the clozapine dose by 50% and prescribing 50 mg of fluvoxamine, so as to reach a minimum effective clozapine plasma concentration of more than 350 microg/l should provide an effective therapeutic strategy. This treatment may benefit the significant number of schizophrenic patients whose response to clozapine is hindered by metabolic hyper inductivity. Although this strategy may carry some risks for certain patients, the protocol we propose reduces the latter and the potential benefits should outweigh them.
Asunto(s)
Antipsicóticos/farmacocinética , Antipsicóticos/uso terapéutico , Clozapina/farmacocinética , Clozapina/uso terapéutico , Sistema Enzimático del Citocromo P-450/metabolismo , Fluvoxamina/farmacocinética , Fluvoxamina/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Adulto , Encéfalo/metabolismo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Mutations in SOX10, a transcription modulator crucial in the development of the enteric nervous system (ENS), melanocytes and glial cells, are found in Shah-Waardenburg syndrome (WS4), a neurocristopathy that associates intestinal aganglionosis, pigmentation defects and sensorineural deafness. Expression of MITF and RET, two genes that play important roles during melanocyte and ENS development, respectively, are controlled by SOX10. The observation that some WS4 patients present with myelination defects of the central and peripheral nervous systems correlates with the recent finding that P(0), a major component of the peripheral myelin, is another transcriptional target of SOX10. These phenotypic features suggest that SOX10 could regulate expression of other genes involved in the myelination process as well. Thus, we tested the ability of SOX10 to regulate expression of MBP, PMP22 and Connexin 32, three major proteins of the peripheral myelin. Our study shows that this factor, in synergy with EGR2, strongly activates Cx32 expression in vitro by directly binding to its promoter. In agreement with this finding, SOX10 and EGR2 mutants identified in patients with peripheral myelin defects fail to transactivate the Cx32 promoter. Moreover, we show that a mutation of the Cx32 promoter previously described in a patient with the X-linked form of Charcot-Marie-Tooth (CMTX) disease impairs SOX10 function. In addition to providing new insights into the molecular mechanisms underlying some of the peripheral myelin defects observed in CMTX disease, these results further extend the spectrum of genes that are regulated by SOX10.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Conexinas/genética , Proteínas de Unión al ADN/fisiología , Regulación de la Expresión Génica , Proteínas del Grupo de Alta Movilidad/fisiología , Factores de Transcripción/fisiología , Sitios de Unión , Conexinas/fisiología , Células HeLa , Humanos , Proteína Básica de Mielina/genética , Proteínas de la Mielina/genética , Mutación Puntual , Regiones Promotoras Genéticas , Unión Proteica , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción SOXE , Cromosoma X , Proteína beta1 de Unión ComunicanteRESUMEN
The SOX10 transcription factor is involved in development of neural crest derivatives and fate determination in glial cells. SOX10 mutations have been found in patients with intestinal aganglionosis and depigmentation with deafness (Waardenburg-Hirschsprung). Associated neurological signs have been reported in some cases, including a patient exhibiting a central and peripheral myelin deficiency. Therefore, we screened for SOX10 mutations in a large cohort of patients with peripheral and central myelin disorders. 56 were affected by classical demyelinating Charcot-Marie-Tooth disease without identified mutations in the genes encoding PNS myelin proteins (PMP22, P0), connexin 32 and the zinc-finger transcription factor, EGR2. 88 patients with undetermined leukodystrophy were selected from a large European prospective study. Associated clinical, magnetic resonance imaging and electrophysiological signs were consistent with a defect in CNS myelination in 83 and with an active degeneration of the CNS myelin in 5. No abnormalities in the proteolipid protein gene (PLP) were found. The absence of SOX100 mutation in this large cohort of patients suggests that this gene is not frequently involved in peripheral or central inherited myelin disorders.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Proteínas de Unión al ADN/genética , Proteínas del Grupo de Alta Movilidad/genética , Esfingolipidosis/genética , Enfermedad de Charcot-Marie-Tooth/patología , Estudios de Cohortes , Análisis Mutacional de ADN , Cartilla de ADN , Humanos , Linaje , Factores de Transcripción SOXE , Esfingolipidosis/patología , Factores de TranscripciónAsunto(s)
Endotelina-3/genética , Enfermedad de Hirschsprung/genética , Síndrome de Waardenburg/genética , Secuencia de Aminoácidos , ADN/química , ADN/genética , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Salud de la Familia , Resultado Fatal , Femenino , Heterocigoto , Proteínas del Grupo de Alta Movilidad/genética , Enfermedad de Hirschsprung/patología , Homocigoto , Humanos , Lactante , Recién Nacido , Masculino , Datos de Secuencia Molecular , Mutación , Cresta Neural/metabolismo , Cresta Neural/patología , Linaje , Fenotipo , Receptor de Endotelina B , Receptores de Endotelina/genética , Factores de Transcripción SOXE , Factores de Transcripción , Síndrome de Waardenburg/patologíaRESUMEN
We describe the case of a girl with an unusual congenital phenotype, combining peculiar peripheral nerve lesions with hypomyelination, chronic intestinal pseudoobstruction, and deafness. She was found to have a de novo heterozygous frameshift mutation in the gene encoding the SOX10 transcription factor. The likely role of SOX10 in determining the fate of Schwann cells during early embryogenesis may explain the peripheral nervous system developmental disorder observed in this patient.
Asunto(s)
Proteínas de Unión al ADN/genética , Sordera/genética , Proteínas del Grupo de Alta Movilidad/genética , Seudoobstrucción Intestinal/genética , Vaina de Mielina/ultraestructura , Cresta Neural/fisiopatología , Enfermedades del Sistema Nervioso Periférico/genética , Secuencia de Aminoácidos/genética , Sordera/fisiopatología , Femenino , Humanos , Lactante , Seudoobstrucción Intestinal/fisiopatología , Cariotipificación , Datos de Secuencia Molecular , Mutación/genética , Conducción Nerviosa/genética , Conducción Nerviosa/fisiología , Enfermedades del Sistema Nervioso Periférico/patología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Fenotipo , Factores de Transcripción SOXE , Síndrome , Factores de TranscripciónRESUMEN
Waardenburg syndrome (WS) is an autosomal dominant disorder with an incidence of 1 in 40 000 that manifests with sensorineural deafness and pigmentation defects. It is classified into four types depending on the presence or absence of additional symptoms. WS1 and WS3 are due to mutations in the PAX3 gene whereas some WS2 cases are associated with mutations in the microphthalmia-associated transcription factor (MITF) gene. The WS4 phenotype can result from mutations in the endothelin-B receptor gene (EDNRB), in the gene for its ligand, endothelin-3 (EDN3), or in the SOX10 gene. PAX3 has been shown to regulate MITF gene expression. The recent implication of SOX10 in WS4 prompted us to test whether this transcription factor, known to cooperate in vitro with PAX3, is also able to regulate expression from the MITF promoter. Here we show that SOX10, in synergy with PAX3, strongly activates MITF expression in transfection assays. Analyses revealed that PAX3 and SOX10 interact directly by binding to a proximal region of the MITF promoter containing binding sites for both factors. Moreover, SOX10 or PAX3 mutant proteins fail to transactivate this promoter, providing further evidence that the two genes act in concert to directly regulate expression of MITF. In situ hybridization experiments carried out in the dominant megacolon (DOM:) mouse, confirmed that SOX10 dysfunction impairs MITF: expression as well as melanocytic development and survival. These experiments, which demonstrate an interaction between three of the genes that are altered in WS, could explain the auditory-pigmentary symptoms of this disease.
Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas del Grupo de Alta Movilidad/genética , Factores de Transcripción/genética , Síndrome de Waardenburg/genética , Animales , Células COS , Proteínas de Unión al ADN/metabolismo , Genes Reporteros , Células HeLa , Proteínas del Grupo de Alta Movilidad/metabolismo , Humanos , Hibridación in Situ , Luciferasas/genética , Luciferasas/metabolismo , Ratones , Ratones Endogámicos , Factor de Transcripción Asociado a Microftalmía , Mutación , Factor de Transcripción PAX3 , Factores de Transcripción Paired Box , Regiones Promotoras Genéticas , Unión Proteica , Factores de Transcripción SOXE , Factores de Transcripción/metabolismo , Activación Transcripcional , Transfección , Síndrome de Waardenburg/metabolismoRESUMEN
Waardenburg syndrome type 4 (WS4), also called Shah-Waardenburg syndrome, is a rare neurocristopathy that results from the absence of melanocytes and intrinsic ganglion cells of the terminal hindgut. WS4 is inherited as an autosomal recessive trait attributable to EDN3 or EDNRB mutations. It is inherited as an autosomal dominant condition when SOX10 mutations are involved. We report on three unrelated WS4 patients with growth retardation and an as-yet-unreported neurological phenotype with impairment of both the central and autonomous nervous systems and occasionally neonatal hypotonia and arthrogryposis. Each of the three patients was heterozygous for a SOX10 truncating mutation (Y313X in two patients and S251X [corrected] in one patient). The extended spectrum of the WS4 phenotype is relevant to the brain expression of SOX10 during human embryonic and fetal development. Indeed, the expression of SOX10 in human embryo was not restricted to neural-crest-derived cells but also involved fetal brain cells, most likely of glial origin. These data emphasize the important role of SOX10 in early development of both neural-crest-derived tissues, namely melanocytes, autonomic and enteric nervous systems, and glial cells of the central nervous system.
Asunto(s)
Encéfalo/embriología , Encéfalo/metabolismo , Proteínas de Unión al ADN/genética , Proteínas del Grupo de Alta Movilidad/genética , Eliminación de Secuencia/genética , Síndrome de Waardenburg/genética , Sistema Nervioso Autónomo/citología , Sistema Nervioso Autónomo/embriología , Sistema Nervioso Autónomo/metabolismo , Encéfalo/citología , Niño , Análisis Mutacional de ADN , Proteínas de Unión al ADN/química , Embrión de Mamíferos/citología , Embrión de Mamíferos/metabolismo , Femenino , Genes Dominantes/genética , Heterocigoto , Proteínas del Grupo de Alta Movilidad/química , Humanos , Hibridación in Situ , Recién Nacido , Masculino , Cresta Neural/citología , Cresta Neural/metabolismo , Linaje , Fenotipo , Polimorfismo Conformacional Retorcido-Simple , ARN Mensajero/análisis , ARN Mensajero/genética , Factores de Transcripción SOXE , Factores de Transcripción , Síndrome de Waardenburg/fisiopatologíaRESUMEN
The Yemenite deaf-blind hypopigmentation syndrome was first observed in a Yemenite sister and brother showing cutaneous hypopigmented and hyperpigmented spots and patches, microcornea, coloboma and severe hearing loss. A second case, observed in a girl with similar skin symptoms and hearing loss but without microcornea or coloboma, was reported as a mild form of this syndrome. Here we show that a SOX10 missense mutation is responsible for the mild form, resulting in a loss of DNA binding of this transcription factor. In contrast, no SOX10 alteration could be found in the other, severe case of the Yemenite deaf-blind hypopigmentation syndrome. Based on genetic, clinical, molecular and functional data, we suggest that these two cases represent two different syndromes. Moreover, as mutations of the SOX10 transcription factor were previously described in Waardenburg-Hirschsprung disease, these results show that SOX10 mutations cause various types of neurocristopathy.
Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas del Grupo de Alta Movilidad/genética , Hipopigmentación/genética , Secuencia de Aminoácidos , Células Cultivadas , Anomalías Craneofaciales/genética , Análisis Mutacional de ADN , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , Proteínas del Grupo de Alta Movilidad/química , Factor C1 de la Célula Huésped , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Proteínas Nucleares/análisis , Factor 1 de Transcripción de Unión a Octámeros , Polimorfismo Conformacional Retorcido-Simple , Unión Proteica/genética , Estructura Terciaria de Proteína , Factores de Transcripción SOXE , Síndrome , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , YemenRESUMEN
The Sry-related protein Sox10 is selectively expressed in neural crest cells during early stages of development and in glial cells of the peripheral and central nervous systems during late development and in the adult. Mutation of the Sox10 gene leads to neural crest defects in the Dominant megacolon mouse mutant and to combined Waardenburg-Hirschsprung syndrome in humans. Here, we have studied the four Sox10 mutations found to date in Waardenburg-Hirschsprung patients both in the context of the rat and the human cDNA. Unlike the rat Sox10 protein, which failed to show transcriptional activity on its own, human Sox10 displayed a weak, but reproducible, activity as a transcriptional activator. All mutant Sox10 proteins, including the one that only lacked the 106 last amino acids were deficient in this capacity, indicating that the carboxyl terminus of human Sox10 carries a transactivation domain. Whereas all four mutants failed to transactivate, only two failed to synergistically enhance the activity of other transcription factors. Synergy required both the ability to bind to DNA and a region in the amino-terminal part of Sox10. Those mutants that failed to synergize were unable to bind to DNA. Analysis of the naturally occurring Sox10 mutations not only helps to dissect Sox10 structure, but also allows limited predictions on the severity of the disease.
Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas del Grupo de Alta Movilidad/genética , Enfermedad de Hirschsprung/genética , Mutación , Transactivadores/genética , Síndrome de Waardenburg/genética , Animales , Proteínas de Unión al ADN/metabolismo , Proteínas del Grupo de Alta Movilidad/metabolismo , Humanos , Sistema Nervioso/embriología , Unión Proteica , Ratas , Ratas Mutantes , Factores de Transcripción SOXE , Transactivadores/metabolismo , Factores de Transcripción , Activación TranscripcionalRESUMEN
SOX10, a new member of the SOX gene family, is a transcription factor defective in the Dom (Dominant megacolon) mouse and in the human Shah-Waardenburg syndrome. To help unravel its physiological role during human development, we studied SOX10 gene expression in embryonic, fetal, and adult human tissues by Northern blot and in situ hybridization. As in mice, the human SOX10 gene was essentially expressed in the neural crest derivatives that contribute to the formation of the peripheral nervous system, and in the adult central nervous system. Nevertheless, it was more widely expressed in humans than in rodents. The spatial and temporal pattern of SOX10 expression supports an important function in neural crest development.
Asunto(s)
Proteínas de Unión al ADN/genética , Embrión de Mamíferos/química , Desarrollo Embrionario y Fetal/genética , Proteínas del Grupo de Alta Movilidad/genética , Northern Blotting , Sistema Nervioso Central/química , Sistema Nervioso Central/embriología , Expresión Génica/genética , Humanos , Hibridación in Situ , Cresta Neural/química , Cresta Neural/citología , Cresta Neural/embriología , ARN Mensajero/análisis , ARN Mensajero/genética , Factores de Transcripción SOXE , Distribución Tisular , Factores de Transcripción/genéticaRESUMEN
The spontaneous mouse mutant Dominant megacolon (Dom) is a valuable model for the study of human congenital megacolon (Hirschsprung disease). Here we report that the defect in the Dom mouse is caused by mutation of the gene encoding the Sry-related transcription factor Sox10. This assignment is based on (i) colocalization of the Sox10 gene with the Dom mutation on chromosome 15; (ii) altered Sox10 expression in the gut and in neural-crest derived structures of cranial ganglia of Dom mice; (iii) presence of a frameshift in the Sox10 coding region, and (iv) functional inactivation of the resulting truncated protein. These results identify the transcriptional regulator Sox10 as an essential factor in mouse neural crest development and as a further candidate gene for human Hirschsprung disease, especially in cases where it is associated with features of Waardenburg syndrome.
Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas del Grupo de Alta Movilidad/genética , Enfermedad de Hirschsprung/genética , Intestinos/inervación , Cresta Neural/fisiología , Secuencia de Aminoácidos , Animales , Encéfalo/metabolismo , Mapeo Cromosómico , Regulación del Desarrollo de la Expresión Génica , Humanos , Hibridación in Situ , Intestinos/embriología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Datos de Secuencia Molecular , ARN Mensajero/genética , Factores de Transcripción SOXE , Alineación de Secuencia , Factores de TranscripciónRESUMEN
Waardenburg syndrome (WS; deafness with pigmentary abnormalities) and Hirschsprung's disease (HSCR; aganglionic megacolon) are congenital disorders caused by defective function of the embryonic neural crest. WS and HSCR are associated in patients with Waardenburg-Shah syndrome (WS4), whose symptoms are reminiscent of the white coat-spotting and aganglionic megacolon displayed by the mouse mutants Dom (Dominant megacolon), piebald-lethal (sl) and lethal spotting (ls). The sl and ls phenotypes are caused by mutations in the genes encoding the Endothelin-B receptor (Ednrb) and Endothelin 3 (Edn3), respectively. The identification of Sox10 as the gene mutated in Dom mice (B.H. et al., manuscript submitted) prompted us to analyse the role of its human homologue SOX10 in neural crest defects. Here we show that patients from four families with WS4 have mutations in SOX10, whereas no mutation could be detected in patients with HSCR alone. These mutations are likely to result in haploinsufficiency of the SOX10 product. Our findings further define the locus heterogeneity of Waardenburg-Hirschsprung syndromes, and point to an essential role of SOX10 in the development of two neural crest-derived human cell lineages.
Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas del Grupo de Alta Movilidad/genética , Enfermedad de Hirschsprung/genética , Síndrome de Waardenburg/genética , Secuencia de Aminoácidos , Animales , Línea Celular , Elementos Transponibles de ADN , Proteínas de Unión al ADN/química , Exones , Femenino , Mutación del Sistema de Lectura , Proteínas del Grupo de Alta Movilidad/química , Humanos , Masculino , Ratones , Datos de Secuencia Molecular , Linaje , Mutación Puntual , Ratas , Factores de Transcripción SOXE , Alineación de Secuencia , Eliminación de Secuencia , Homología de Secuencia de Aminoácido , Factores de Transcripción/química , Factores de Transcripción/genéticaRESUMEN
Hirschsprung disease (HSCR) is a congenital disorder of the enteric nervous system characterized by the absence of enteric ganglia. Three genes for HSCR have been identified: the RET proto-oncogene, the gene coding for the endothelin B receptor (EDNRB), and the endothelin 3 gene (EDN3). In mice, natural and in vitro-induced mutations affecting the Ret, Ednrb, and Edn3 genes generate a phenotype similar to human HSCR. Another model of HSCR disease is the Dominant megacolon (Dom), a spontaneous mouse mutation for which the target gene has not yet been identified. The Dom mutation has been mapped to the middle-terminal region of mouse chromosome 15, between D15Mit68 and D15Mit2. Using new or known polymorphisms for conserved human/mouse genes, we established the homology between the Dom locus and human chromosome 22q12-q13. Two genes, Smstr3 and Adsl, not previously mapped in the mouse genome, were located on mouse Chromosome 15. Three genes (Smstr3, Lgals1, and Pdgfb) are possible Dom candidates, as they do not recombine with the Dom mutation in a 252 Dom/+ animal backcross.
Asunto(s)
Enfermedad de Hirschsprung/genética , Animales , Mapeo Cromosómico , Cromosomas Humanos Par 22 , Modelos Animales de Enfermedad , Genes Dominantes , Haplotipos , Humanos , Megacolon/genética , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Proto-Oncogenes MasRESUMEN
Considering that platelet response to thrombin receptor activation might be critical for the development of arterial thrombosis, we measured the dense granule release under stimulation by the thrombin receptor activating peptide (TRAP) in a series of 102 healthy volunteers. The threshold TRAP concentration which initiated a secretion ranged from 3 to 20 microM. A good concordance (79%, k=0.677) between two tests performed at a 1 month interval indicated that platelet response to thrombin receptor activation was characteristic of each individual donor. Since the threshold concentration required to initiate secretion corresponded to the threshold concentration which induced a biphasic aggregation, all volunteers were genotyped for the PlA2 polymorphism, the Pro33 variant of GPIIIa. Platelets from subjects with the PlA2 polymorphism required higher TRAP concentrations to aggregate than those from subjects with no PlA2 allele (P=0.0012). However, they also required a higher ADP concentration to aggregate. In order to exclude any influence of GPIIIa polymorphism on TRAP-induced secretion, we studied the variability of platelet response to TRAP among the 77 individuals with no PlA2 allele, and found the same interdonor variability with the same distribution of threshold TRAP concentrations as for the 102 individuals. The results suggest that (i) platelet secretion in response to thrombin receptor activation could be a genetically controlled phenotype independent of the GPIIIa polymorphism; (ii) the PlA2 polymorphism is associated with platelet hypoaggregability.