RESUMEN
The cause for the increased sensitivity of patients with fibromyalgia (FM) to painful stimuli is unclear but sensitization of dorsal horn spinal cord neurons has been suggested. There, critical changes of sensory information occur which depend on the plasticity of second-order neurons and descending pain modulation, including facilitation and inhibition. This study used repetitive stimuli that produce temporal-summation-of-second-pain (TSSP) and central sensitization, relevant mechanisms for patients with chronic pain. We examined spinal cord neural activation during TSSP in patients with FM and healthy controls (HC) and used its functional connectivity with several brainstem nuclei to model the observed blood-oxygen-level-dependent (BOLD) time-course with pain ratings. Sixteen HC and 14 FM participants received repetitive heat stimuli to the hand at 0.4 Hz to achieve TSSP during functional imaging with a 3 T-Philips Achieva MRI scanner. Stimuli were adjusted to each individual's pain sensitivity to achieve maximal pain ratings of 50 ± 10 on a numerical pain scale (0-100). Using a 16-channel neurovascular coil, multiple image series were obtained from the cervical spinal cord to the brainstem using single-shot turbo-spin echo sequences. During repetitive, sensitivity-adjusted heat stimuli, pain ratings of all subjects increased as predicted, consistent with TSSP. HC and FM participants had similar temporal patterns of spinal activation: initial BOLD increase followed by deactivation. Structural equation modeling showed that the observed spinal activity during TSSP was associated with more BOLD activity across/within the brainstem in FM subjects than HC, suggesting differences in pain modulation.NEW & NOTEWORTHY "Windup" and its behavioral correlate "temporal-summation-of-second pain" (TSSP) represent spinal cord mechanisms of pain augmentation associated with central sensitization and chronic pain. Fibromyalgia (FM) is a chronic pain disorder, where abnormal TSSP has been demonstrated. We used fMRI to study spinal cord and brainstem activation during TSSP. We characterized the time course of spinal cord and brainstem BOLD activity during TSSP which showed abnormal brainstem activity in patients with FM, possibly due to deficient pain modulation.
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Fibromialgia/fisiopatología , Umbral del Dolor , Médula Espinal/fisiopatología , Adulto , Tronco Encefálico/diagnóstico por imagen , Tronco Encefálico/fisiopatología , Sensibilización del Sistema Nervioso Central , Conectoma , Femenino , Fibromialgia/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Modelos Neurológicos , Percepción del Dolor , Médula Espinal/diagnóstico por imagenRESUMEN
Heimler syndrome is a rare syndrome associating sensorineural hearing loss with retinal dystrophy and amelogenesis imperfecta due to PEX1 or PEX6 biallelic pathogenic variations. This syndrome is one of the less severe forms of peroxisome biogenesis disorders. In this chapter, we will review clinical, biological, and genetic knowledges about the Heimler syndrome.
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Amelogénesis Imperfecta , Pérdida Auditiva Sensorineural , Uñas Malformadas , Trastorno Peroxisomal , ATPasas Asociadas con Actividades Celulares Diversas/genética , Amelogénesis Imperfecta/genética , Amelogénesis Imperfecta/metabolismo , Amelogénesis Imperfecta/patología , Amelogénesis Imperfecta/fisiopatología , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/metabolismo , Pérdida Auditiva Sensorineural/patología , Pérdida Auditiva Sensorineural/fisiopatología , Humanos , Proteínas de la Membrana/genética , Uñas Malformadas/genética , Uñas Malformadas/metabolismo , Uñas Malformadas/patología , Uñas Malformadas/fisiopatología , Trastorno Peroxisomal/genética , Trastorno Peroxisomal/metabolismo , Trastorno Peroxisomal/patología , Trastorno Peroxisomal/fisiopatologíaRESUMEN
The immune state is an essential component of survival as it directly influences physiological performance and health status. Variation in the leukocyte profile, a significantly increase in body temperature, and a detriment of the eco-physiological performance are among the possible consequences of an unhealthy state. In this study we analyse and discuss how field body temperature, preferred body temperature, the speed for sprint and long runs, locomotor stamina, and body condition can be affected by the immunological state (i.e. leukocyte profile) in a wild population of Liolaemus sarmentoi. Juveniles and adult males with a high percentage of eosinophils, basophils, and a low percentage of monocytes preferred higher body temperatures in a thermal gradient, while pregnant females maintained thermal preferences independently of leukocyte profile. Although juveniles with a high percentage of heterophils showed less locomotor stamina, adult males and pregnant females showed no differences in locomotor performance in relation to leukocyte profile. This study represents a starting point in eco-immunology of a wild lizard population of Liolaemus in cold and temperate environments of Patagonia where the southward shift in the geographic ranges of pathogen populations due to global warming represents a threat to resident host populations.
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Conducta Animal/fisiología , Temperatura Corporal/inmunología , Lagartos/sangre , Lagartos/inmunología , Actividad Motora/inmunología , Aclimatación , Animales , Temperatura Corporal/fisiología , Femenino , Lagartos/fisiología , Masculino , Actividad Motora/fisiología , EmbarazoRESUMEN
Cornelia de Lange syndrome is a multisystemic developmental disorder mainly related to de novo heterozygous NIPBL mutation. Recently, NIPBL somatic mosaicism has been highlighted through buccal cell DNA study in some patients with a negative molecular analysis on leukocyte DNA. Here, we present a series of 38 patients with a Cornelia de Lange syndrome related to a heterozygous NIPBL mutation identified by Sanger sequencing. The diagnosis was based on the following criteria: (i) intrauterine growth retardation and postnatal short stature, (ii) feeding difficulties and/or gastro-oesophageal reflux, (iii) microcephaly, (iv) intellectual disability, and (v) characteristic facial features. We identified 37 novel NIPBL mutations including 34 in leukocytes and 3 in buccal cells only. All mutations shown to have arisen de novo when parent blood samples were available. The present series confirms the difficulty in predicting the phenotype according to the NIPBL mutation. Until now, somatic mosaicism has been observed for 20 cases which do not seem to be consistently associated with a milder phenotype. Besides, several reports support a postzygotic event for those cases. Considering these elements, we recommend a first-line buccal cell DNA analysis in order to improve gene testing sensitivity in Cornelia de Lange syndrome and genetic counselling.
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Síndrome de Cornelia de Lange/genética , Cara/anomalías , Asimetría Facial/genética , Mutación de Línea Germinal , Mutación , Proteínas/genética , Proteínas de Ciclo Celular , Síndrome de Cornelia de Lange/diagnóstico , Asimetría Facial/diagnóstico , Facies , Femenino , Humanos , Leucocitos/metabolismo , Masculino , Mucosa Bucal/metabolismo , Fenotipo , Análisis de Secuencia de ADN/métodosRESUMEN
Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.
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Hibridación Genómica Comparativa/métodos , Asesoramiento Genético/ética , Asesoramiento Genético/métodos , Hallazgos Incidentales , Revelación/ética , Femenino , Francia , Genes Dominantes/genética , Genes Recesivos/genética , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Humanos , Masculino , Análisis por Micromatrices/métodos , Relaciones Médico-Paciente/ética , Estudios Retrospectivos , Encuestas y CuestionariosRESUMEN
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.
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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
Nager syndrome belongs to the group of acrofacial dysostosis, which are characterized by the association of craniofacial and limb malformations. Recently, exome sequencing studies identified the SF3B4 gene as the cause of this condition in most patients. SF3B4 encodes a highly conserved protein implicated in mRNA splicing and bone morphogenic protein (BMP) signaling. We performed SF3B4 sequencing in 14 families (18 patients) whose features were suggestive of Nager syndrome and found nine mutations predicted to result in loss-of-function. SF3B4 is the major gene responsible for autosomal dominant Nager syndrome. All mutations reported predict null alleles, therefore precluding genotype-phenotype correlations. Most mutation-negative patients were phenotypically indistinguishable from patients with mutations, suggesting genetic heterogeneity.
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Predisposición Genética a la Enfermedad/genética , Haploinsuficiencia/genética , Disostosis Mandibulofacial/genética , Fenotipo , Proteínas de Unión al ARN/genética , Secuencia de Bases , Femenino , Genes Dominantes/genética , Humanos , Masculino , Disostosis Mandibulofacial/patología , Datos de Secuencia Molecular , Mutación/genética , Factores de Empalme de ARN , Análisis de Secuencia de ADNRESUMEN
INTRODUCTION: Deletions or variants of the STRC gene coding for stereocilin cause congenital bilateral mild-to-moderate sensorineural hearing loss without vestibular disorder: DFNB16. Stereocilin is a protein present in vestibular kinocilia embedded in the otoconial membrane of the utricular macula. Benign paroxysmal positional vertigo (BPPV) is a rare form of vertigo in children. The present study reports recurrent positional vertigo in two DFNB16 siblings. OBSERVATION: Two patients, 10 and 15 years old, presented with recurrent disabling positional vertigo episodes, triggered by turning over in bed, with a falling sensation. The diagnosis of right posterior canal BPPV was confirmed on Dix-Hallpike maneuvers in one of the patients. Variations in the response of ocular vestibular-evoked myogenic potentials were observed. Probable BPPV was diagnosed in the second patient. Their other two siblings did not have hearing loss or vertigo. CONCLUSION: The absence of stereocilin due to homozygous deletions of the STRC gene in DFNB16 patients can cause vestibular dysfunction, including BPPV.
Asunto(s)
Vértigo Posicional Paroxístico Benigno , Pérdida Auditiva Sensorineural , Niño , Humanos , Adolescente , Vértigo Posicional Paroxístico Benigno/diagnóstico , Vértigo Posicional Paroxístico Benigno/genética , Hermanos , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/genética , Mareo , Péptidos y Proteínas de Señalización IntercelularRESUMEN
OBJECTIVES: Our objective was to reinforce clinical knowledge of hearing impairment in KBG syndrome. KBG syndrome is a rare genetic disorder due to monoallelic pathogenic variations of ANKRD11.The typical phenotype includes facial dysmorphism, costal and spinal malformation and developmental delay. Hearing loss in KBG patients has been reported for many years, but no study has evaluated audiological phenotyping from a clinical and an anatomical point of view. METHODS: This French multicenter study included 32 KBG patients with retrospective collection of data on audiological features, ear imaging and genetic investigations. RESULTS: We identified a typical audiological profil in KBG syndrome: conductive (71%), bilateral (81%), mild to moderate (84%) and stable (69%) hearing loss, with some audiological heterogeneity. Among patients with an abnormality on CT imaging (55%), ossicular chain impairment (67%), fixation of the stapes footplate (33%) and inner-ear malformations (33%) were the most common abnormalities. CONCLUSION: We recommend a complete audiological and radiological evaluation and an ENT-follow up in all patients presenting with KBG Syndrome. Imaging evaluation is necessary to determine the nature of lesions in the middle and inner ear.
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Anomalías Múltiples , Enfermedades del Desarrollo Óseo , Sordera , Discapacidad Intelectual , Anomalías Dentarias , Humanos , Anomalías Múltiples/genética , Discapacidad Intelectual/genética , Enfermedades del Desarrollo Óseo/genética , Anomalías Dentarias/genética , Facies , Estudios Retrospectivos , Proteínas Represoras/genética , FenotipoRESUMEN
Mutations of the COCH gene inherited in an autosomal dominant mode are responsible for late-onset cochleovestibular impairment on both sides. Our objective is to report the youngest patient (3 years) associating a molecular variant of the COCH gene and a cochleovestibular impairment on both sides. The clinical sequence has started with a vestibular dysfunction in a two-year-old child: recurrent rotatory dizziness during 12 months. At the age of 3, a sensorineural hearing loss on both sides has occured associated with spontaneous variation during 6 months. The lack of mutation of the connexin 26, connexin 30 and pendrin genes has reorientated the genetic investigation. A molecular variant of the COCH gene was found in the vWFA2 domain. It was an in-frame deletion predicting the synthesis of an abnormal protein in which 21 aminoacid were missing. Others family members with mutation were asymptomatics. In this isolated case report, the study was in favor of a non pathogenic molecular variant of the COCH gene. For all that, mutations of the COCH gene could be searched in progressive cochleovestibular dysfunctions on both sides in children, even without family affect.
Asunto(s)
Secuencia de Aminoácidos , Proteínas de la Matriz Extracelular/genética , Pérdida Auditiva Sensorineural/genética , Eliminación de Secuencia/genética , Enfermedades Vestibulares/genética , Preescolar , Humanos , MasculinoRESUMEN
NALP proteins, also known as NLRPs, belong to the CATERPILLER protein family involved, like Toll-like receptors, in the recognition of microbial molecules and the subsequent activation of inflammatory and immune responses. Current advances in the function of NALPs support the recently proposed model of a disease continuum bridging autoimmune and autoinflammatory disorders. Among these diseases, hereditary periodic fevers (HPFs) are Mendelian disorders associated with sequence variations in very few genes; these variations are mostly missense mutations whose deleterious effect, which is particularly difficult to assess, is often questionable. The growing number of identified sporadic cases of periodic fever syndrome, together with the lack of discriminatory clinical criteria, has greatly hampered the identification of new disease-causing genes, a step that is, however, essential for appropriate management of these disorders. Using a candidate gene approach, we identified nonambiguous mutations in NALP12 (i.e., nonsense and splice site) in two families with periodic fever syndromes. As shown by means of functional studies, these two NALP12 mutations have a deleterious effect on NF-kappaB signaling. Overall, these data identify a group of HPFs defined by molecular defects in NALP12, opening up new ways to manage these disorders. The identification of these first NALP12 mutations in patients with autoinflammatory disorder also clearly demonstrates the crucial role of NALP12 in inflammatory signaling pathways, thereby assigning a precise function to this particular member of an emerging family of proteins whose putative biological properties are currently inferred essentially through in vitro means.
Asunto(s)
Fiebre Mediterránea Familiar/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Codón sin Sentido/genética , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/fisiología , Masculino , Datos de Secuencia Molecular , Mutación , FN-kappa B/metabolismo , Linaje , Sitios de Empalme de ARN , Empalme del ARN/genética , Análisis de Secuencia de ADNRESUMEN
Lymphocyte function associated antigen 1 (LFA-1) is a leukocyte cell adhesion protein. We have studied a novel human immunodeficiency disease in which LFA-1 and two other proteins which share the same beta subunit are lacking from the surface of leukocytes. The basis of the inherited defect in cell surface expression of both the alpha and beta subunits of LFA-1 was determined by somatic cell fusion of patient or normal human cells with an LFA-1+ mouse T cell line. Human LFA-1 alpha and beta subunits from normal cells could associate with mouse LFA-1 subunits to form interspecies hybrid alpha beta complexes. Surface expression of the alpha but not the beta subunit of patient cells was rescued by the formation of interspecies complexes. The findings show that the LFA-1 alpha subunit in genetically deficient cells is competent for surface expression in the presence of an appropriate beta subunit, and suggest that the genetic lesion affects the beta subunit. The human LFA-1 alpha and beta subunits were mapped to chromosomes 16 and 21, respectively. The genetic defect is inferred to be on chromosome 21.
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Antígenos de Superficie/genética , Mapeo Cromosómico , Síndromes de Inmunodeficiencia/genética , Animales , Antígenos de Superficie/deficiencia , Antígenos de Superficie/inmunología , Cromosomas Humanos 16-18 , Cromosomas Humanos 21-22 e Y , Humanos , Células Híbridas , Antígeno-1 Asociado a Función de Linfocito , Ratones , Hibridación de Ácido NucleicoRESUMEN
Cerebral, ocular, dental, auricular, skeletal syndrome (CODAS, OMIM 600373) is a very rare congenital malformation syndrome. This clinical entity is highly distinctive and associates mental retardation, cataract, enamel abnormalities, malformations of the helix, epiphyseal and vertebral malformations, and characteristic dysmorphic features. Since 1991, only three affected children have been reported. The etiology and pattern of inheritance of CODAS syndrome still remain unknown. We describe a new sporadic case presenting with all the characteristic features of CODAS syndrome associated with previously unreported malformations of the heart, larynx, and liver. All investigations such as karyotype, metabolic screening and array CGH were normal.
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Anomalías Múltiples/diagnóstico , Huesos/anomalías , Catarata/diagnóstico , Corteza Cerebral/anomalías , Atrios Cardíacos/anomalías , Discapacidad Intelectual/diagnóstico , Músculo Esquelético/anomalías , Anomalías Dentarias/diagnóstico , Anomalías Múltiples/genética , Catarata/congénito , Catarata/genética , Preescolar , Humanos , Discapacidad Intelectual/genética , Masculino , Síndrome , Anomalías Dentarias/genéticaRESUMEN
This article focuses on six questions raised by genetic testing in human: (1) the use of genetic tests, (2) information given to relatives of patients affected with genetic disorders, (3) prenatal and preimplantatory diagnosis for late onset genetic diseases and the use of pangenomic tests in prenatal diagnosis, (4) direct-to-consumer genetic testing, (5) population screening in the age of genomic medicine and (6) incidental findings when genetic testing are used.
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Pruebas Genéticas/legislación & jurisprudencia , Confidencialidad/ética , Confidencialidad/legislación & jurisprudencia , Salud de la Familia , Femenino , Francia , Pruebas Genéticas/ética , Humanos , Masculino , Embarazo , Diagnóstico Preimplantación/ética , Diagnóstico Prenatal/ética , AutocuidadoRESUMEN
X-linked deafness is a rare cause of hereditary isolated hearing impairment estimated as at least 1% or 2% of the non-syndromic hearing loss. To date, four loci for DFN have been identified and only one gene, POU3F4 responsible for DFN3, has been cloned. In males, DFN3 is characterized by a progressive deafness associated with perilymphatic gusher at stapes surgery and with a characteristic inner ear malformation. The phenotype of eight independent females carrying POU3F4 anomalies is defined, and a late-onset hearing loss is found in three patients. Only one has an inner ear malformation. No genotype/phenotype correlation is identified.
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Mutación/genética , Factores del Dominio POU/genética , Adulto , Audiometría de Tonos Puros , Femenino , Genotipo , Heterocigoto , Humanos , Persona de Mediana Edad , Fenotipo , Tomografía Computarizada por Rayos XRESUMEN
The adherence of human neutrophils to human umbilical vein endothelial cells (HUVEC) is partially dependent on the CD11/CD18 family of glycoproteins on the neutrophil and ICAM-1 on the HUVEC. The CD18 heterodimer involved in this adherence was evaluated in vitro using subunit-specific monoclonal antibodies (MAbs). The adherence of unstimulated neutrophils to IL-1-stimulated HUVEC was significantly inhibited by anti-CD11a but not CD11b MAbs, while the adherence of fMLP-stimulated neutrophils was significantly inhibited by both anti-CD11a and -CD11b. Anti-CD11a, but not anti-CD11b MAbs, reduced the adherence of unstimulated neutrophils on purified ICAM-1 to the same low level untreated neutrophils exhibited on a control protein, glycophorin. Stimulation with fMLP significantly increased neutrophil attachment to purified ICAM-1, but not to the control protein. Anti-CD11b MAbs reduced this chemotactically augmented adherence to that of unstimulated neutrophils, and in combination with anti-CD11a MAbs reduced adherence to that on the control protein. The results in this report indicate that unstimulated neutrophils exhibit LFA-1-dependent attachment to ICAM-1, and chemotactic stimulation enhances the attachment of human neutrophils to ICAM-1 by a Mac-1-dependent process.
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Antígenos de Diferenciación/inmunología , Antígenos de Superficie/inmunología , Adhesión Celular , Movimiento Celular , Endotelio Vascular/fisiología , Neutrófilos/fisiología , Adulto , Antígenos de Superficie/aislamiento & purificación , Antígenos CD18 , Moléculas de Adhesión Celular , Comunicación Celular , Endotelio Vascular/inmunología , Humanos , Antígeno-1 Asociado a Función de Linfocito , Antígeno de Macrófago-1 , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/fisiología , N-Formilmetionina Leucil-Fenilalanina/farmacología , Neutrófilos/inmunologíaRESUMEN
We have found a human serum, E27, obtained from a multiply transfused patient with systemic lupus erythematosus, which immunoprecipitates the lymphocyte function associated antigen-1 (LFA-1). The immunoprecipitated molecules were identified as the LFA-1 alpha and beta chains by their comigration on SDS-PAGE, two-dimensional SDS-PAGE, and by sequential clearance experiments. Serum E27 did not immunoprecipitate LFA-1 from autologous cells, though LFA-1 molecules were present. In contrast, serum E27 immunoprecipitated LFA-1 from most but not all normal donor lymphocytes. Thus, serum E27 defines two serological phenotypes of LFA-1. 95% of normal individuals tested exhibited the LFA-1 phenotype precipitated by serum E27. Serum E27 appears to be directed at determinants of the LFA-1 alpha-chain and not the beta-chain since it immunoprecipitated LFA-1 molecules but not the Mac-1 molecules. Additional evidence for the alpha chain specificity was provided by immunoprecipitation of mouse-human heterohybridoma cells. LFA-1 was immunoprecipitated by serum E27 from mouse-human heterohybridoma cells expressing the human alpha-chain, not from a hybrid cell line expressing the human beta-chain. Together these findings demonstrate an antigenic polymorphism of the human LFA-1 alpha-chain molecule.
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Antígenos de Superficie/inmunología , Isoanticuerpos/inmunología , Lupus Eritematoso Sistémico/inmunología , Antígenos de Superficie/clasificación , Antígenos de Superficie/genética , Autoanticuerpos/inmunología , Transfusión Sanguínea , Epítopos/genética , Epítopos/inmunología , Humanos , Antígeno-1 Asociado a Función de Linfocito , Polimorfismo GenéticoRESUMEN
BACKGROUND: Usher syndrome, a devastating recessive disorder which combines hearing loss with retinitis pigmentosa, is clinically and genetically heterogeneous. Usher syndrome type 1 (USH1) is the most severe form, characterised by profound congenital hearing loss and vestibular dysfunction. OBJECTIVE: To describe an efficient protocol which has identified the mutated gene in more than 90% of a cohort of patients currently living in France. RESULTS: The five genes currently known to cause USH1 (MYO7A, USH1C, CDH23, PCDH15, and USH1G) were tested for. Disease causing mutations were identified in 31 of the 34 families referred: 17 in MYO7A, 6 in CDH23, 6 in PCDH15, and 2 in USH1C. As mutations in genes other than myosin VIIA form nearly 50% of the total, this shows that a comprehensive approach to sequencing is required. Twenty nine of the 46 identified mutations were novel. In view of the complexity of the genes involved, and to minimise sequencing, a protocol for efficient testing of samples was developed. This includes a preliminary linkage and haplotype analysis to indicate which genes to target. It proved very useful and demonstrated consanguinity in several unsuspected cases. In contrast to CDH23 and PCDH15, where most of the changes are truncating mutations, myosin VIIA has both nonsense and missense mutations. Methods for deciding whether a missense mutation is pathogenic are discussed. CONCLUSIONS: Diagnostic testing for USH1 is feasible with a high rate of detection and can be made more efficient by selecting a candidate gene by preliminary linkage and haplotype analysis.
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Cadherinas/genética , Mutación/genética , Síndromes de Usher/diagnóstico , Síndromes de Usher/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Adolescente , Adulto , Proteínas Relacionadas con las Cadherinas , Proteínas de Ciclo Celular , Niño , Preescolar , Estudios de Cohortes , Proteínas del Citoesqueleto , Análisis Mutacional de ADN , Dineínas/genética , Exones/genética , Haplotipos , Humanos , Intrones/genética , Miosina VIIa , Miosinas/genética , Proteínas del Tejido Nervioso/genéticaRESUMEN
INTRODUCTION: Primary ciliary dyskinesia (PCD) is a rare disease classically transmitted as an autosomal recessive trait and characterised by recurrent airway infections due to abnormal ciliary structure and function. To date, only two autosomal genes, DNAI1 and DNAH5 encoding axonemal dynein chains, have been shown to cause PCD with defective outer dynein arms. Here, we investigated one non-consanguineous family in which a woman with retinitis pigmentosa (RP) gave birth to two boys with a complex phenotype combining PCD, discovered in early childhood and characterised by partial dynein arm defects, and RP that occurred secondarily. The family history prompted us to search for an X linked gene that could account for both conditions. RESULTS: We found perfect segregation of the disease phenotype with RP3 associated markers (Xp21.1). Analysis of the retinitis pigmentosa GTPase regulator gene (RPGR) located at this locus revealed a mutation (631_IVS6+9del) in the two boys and their mother. As shown by study of RPGR transcripts expressed in nasal epithelial cells, this intragenic deletion, which leads to activation of a cryptic donor splice site, predicts a severely truncated protein. CONCLUSION: These data provide the first clear demonstration of X linked transmission of PCD. This unusual mode of inheritance of PCD in patients with particular phenotypic features (that is, partial dynein arm defects and association with RP), which should modify the current management of families affected by PCD or RP, unveils the importance of RPGR in the proper development of both respiratory ciliary structures and connecting cilia of photoreceptors.