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1.
PLoS Genet ; 14(8): e1007602, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30148830

RESUMEN

The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1-deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality defects (situs inversus) and likely male infertility and that MNS1 plays a role in the ODA-DC assembly.


Asunto(s)
Codón sin Sentido , Lateralidad Funcional/genética , Homocigoto , Infertilidad Masculina/genética , Proteínas Nucleares/metabolismo , Adolescente , Adulto , Animales , Dineínas Axonemales/genética , Dineínas Axonemales/metabolismo , Axonema/metabolismo , Proteínas de Ciclo Celular , Niño , Preescolar , Cilios/ultraestructura , Femenino , Regulación de la Expresión Génica , Ligamiento Genético , Humanos , Lactante , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Proteínas Nucleares/deficiencia , Proteínas Nucleares/genética , Linaje , Polimorfismo de Nucleótido Simple , Cola del Espermatozoide , Secuenciación del Exoma , Adulto Joven
2.
Hum Mutat ; 37(4): 396-405, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26777464

RESUMEN

Reduced generation of multiple motile cilia (RGMC) is a novel chronic destructive airway disease within the group of mucociliary clearance disorders with only few cases reported. Mutations in two genes, CCNO and MCIDAS, have been identified as a cause of this disease, both leading to a greatly reduced number of cilia and causing impaired mucociliary clearance. This study was designed to identify the prevalence of CCNO mutations in Israel and further delineate the clinical characteristics of RGMC. We analyzed 170 families with mucociliary clearance disorders originating from Israel for mutations in CCNO and identified two novel mutations (c.165delC, p.Gly56Alafs*38; c.638T>C, p.Leu213Pro) and two known mutations in 15 individuals from 10 families (6% prevalence). Pathogenicity of the missense mutation (c.638T>C, p.Leu213Pro) was demonstrated by functional analyses in Xenopus. Combining these 15 patients with the previously reported CCNO case reports revealed rapid deterioration in lung function, an increased prevalence of hydrocephalus (10%) as well as increased female infertility (22%). Consistent with these findings, we demonstrate that CCNO expression is present in murine ependyma and fallopian tubes. CCNO is mutated more frequently than expected from the rare previous clinical case reports, leads to severe clinical manifestations, and should therefore be considered an important differential diagnosis of mucociliary clearance disorders.


Asunto(s)
Trastornos de la Motilidad Ciliar/diagnóstico , Trastornos de la Motilidad Ciliar/genética , ADN Glicosilasas/genética , Variación Genética , Animales , ADN Glicosilasas/metabolismo , Análisis Mutacional de ADN , Diagnóstico Diferencial , Femenino , Mutación del Sistema de Lectura , Estudios de Asociación Genética , Sitios Genéticos , Pruebas Genéticas , Humanos , Masculino , Ratones , Mutación , Mutación Missense , Fenotipo , Transporte de Proteínas , Radiografía Torácica , Pruebas de Función Respiratoria , Tomografía Computarizada por Rayos X , Xenopus laevis
3.
Respir Med ; 119: 41-47, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27692146

RESUMEN

BACKGROUND: Primary Ciliary Dyskinesia (PCD) is rare and its features in Israel have not been described. AIMS: to assess prevalence utilizing state-of-the-art diagnostic techniques, and describe clinical features, diagnostic and management practices in Israel. METHODS: A national multicenter study from 2012 to 2013 recruited patients diagnosed or suspected of having PCD. Diagnosis was verified using: nasal Nitric Oxide (nNO); High-speed Video Microscope Analysis (HVMA); Transmission Electron Microscopy (TEM) of cilia; Immuno-fluorescence staining (IF) for ciliary proteins, and genetic analysis. RESULTS: Of the 203 patients recruited from 14 pediatric centers, 150 had a PCD diagnosis verified. Median age was 15.05y, with range 0.15-60.5y. PCD prevalence was 1:54,000 for the general population and 1:25,000 in children (5-14 y). For the non-Jewish (mainly Druze and Arab Moslem) compared to Jewish populations, prevalence was 1:16,500 and 1:139,000 respectively (p < 0.0001) and parental consanguinity was 85.4% and 21.9% respectively (p < 0.0001). Clinical features included bronchiectasis (88%), rhinitis (81%), recurrent pneumonia (78%), recurrent otitis (62%), neonatal pneumonia (60%) and situs inversus (42%). Prior diagnostic practices varied widely between centers with TEM assessed in 55% and abnormal in 61% of these. Management included antibiotics and airway clearance. Diagnostic verification revealed for 150 PCD patients: 81% nNO<233 ppb, 62% abnormal HVMA, 51% diagnostic TEM, 58% diagnostic IF and, 57% genetic diagnosis. CONCLUSIONS: PCD in Israel is rare, with comprehensive diagnostic tests showing prevalence in children similar to Europe. Prevalence was higher in non-Jews, associated with parental consanguinity. Diagnostic and management practices vary. Referral centers providing comprehensive diagnostic and care capabilities should be established.


Asunto(s)
Cilios/inmunología , Síndrome de Kartagener/diagnóstico , Síndrome de Kartagener/epidemiología , Prevalencia , Adolescente , Adulto , Niño , Cilios/genética , Cilios/ultraestructura , Femenino , Humanos , Israel/epidemiología , Síndrome de Kartagener/etnología , Síndrome de Kartagener/terapia , Masculino , Microscopía Electrónica de Transmisión/métodos , Óxido Nítrico/metabolismo , Estudios Prospectivos , Adulto Joven
4.
F1000Res ; 5: 2031, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27781089

RESUMEN

Rationale: Primary ciliary dyskinesia (PCD) is under diagnosed and underestimated. Most clinical research has used some form of questionnaires to capture data but none has been critically evaluated particularly with respect to its end-user feasibility and utility. Objective: To critically appraise a clinical data collection questionnaire for PCD used in a large national PCD consortium in order to apply conclusions in future PCD research. Methods: We describe the development, validation and revision process of a clinical questionnaire for PCD and its evaluation during a national clinical PCD study with respect to data collection and analysis, initial completion rates and user feedback. Results: 14 centers participating in the consortium successfully completed the revised version of the questionnaire for 173 patients with various completion rates for various items. While content and internal consistency analysis demonstrated validity, there were methodological deficiencies impacting completion rates and end-user utility. These deficiencies were addressed resulting in a more valid questionnaire. Conclusions: Our experience may be useful for future clinical research in PCD. Based on the feedback collected on the questionnaire through analysis of completion rates, judgmental analysis of the content, and feedback from experts and end users, we suggest a practicable framework for development of similar tools for various future PCD research.

5.
Nat Commun ; 5: 4418, 2014 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-25048963

RESUMEN

Reduced generation of multiple motile cilia (RGMC) is a rare mucociliary clearance disorder. Affected persons suffer from recurrent infections of upper and lower airways because of highly reduced numbers of multiple motile respiratory cilia. Here we report recessive loss-of-function and missense mutations in MCIDAS-encoding Multicilin, which was shown to promote the early steps of multiciliated cell differentiation in Xenopus. MCIDAS mutant respiratory epithelial cells carry only one or two cilia per cell, which lack ciliary motility-related proteins (DNAH5; CCDC39) as seen in primary ciliary dyskinesia. Consistent with this finding, FOXJ1-regulating axonemal motor protein expression is absent in respiratory cells of MCIDAS mutant individuals. CCNO, when mutated known to cause RGMC, is also absent in MCIDAS mutant respiratory cells, consistent with its downstream activity. Thus, our findings identify Multicilin as a key regulator of CCNO/FOXJ1 for human multiciliated cell differentiation, and highlight the 5q11 region containing CCNO and MCIDAS as a locus underlying RGMC.


Asunto(s)
Proteínas de Ciclo Celular/genética , Trastornos de la Motilidad Ciliar/genética , Mutación , Proteínas Nucleares/genética , Adulto , Proteínas Cdc20/genética , Proteínas Cdc20/metabolismo , Proteínas de Ciclo Celular/metabolismo , Diferenciación Celular/genética , Cromosomas Humanos Par 5 , Cilios/patología , Cilios/ultraestructura , Trastornos de la Motilidad Ciliar/etiología , ADN Glicosilasas/genética , ADN Glicosilasas/metabolismo , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica , Humanos , Síndrome de Kartagener/genética , Masculino , Microscopía Electrónica de Transmisión , Depuración Mucociliar/genética , Proteínas Nucleares/metabolismo , Linaje , Factores de Transcripción , Adulto Joven
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