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1.
Medicine (Baltimore) ; 98(30): e16661, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348322

RESUMO

RATIONALE: Small supernumerary marker chromosomes (sSMCs) can be usually discovered in the patients with mental retardation, infertile couples, and prenatal fetus. We aim to characterize the sSMC and explore the correlation between with sSMC and male infertility. PATIENT CONCERNS: A 26-year-old Chinese male was referred for infertility consultation in our center after 1 year of regular unprotected coitus and no pregnancy. DIAGNOSIS: Cytogenetic G-banding analysis initially described a mosaic karyotype 47,X,Yqh-,+mar[28]/46,X,Yqh-[22] for the proband, while his father showed a normal karyotype. The chromosome microarray (CMA) analysis showed there existed a duplication of Yp11.32q11.221, a deletion of Yq11.222q12, a duplication of 20p11.1 for the patient. Azoospermia factor (AZF) microdeletion analysis for the patient showed that he presented a de novo AZFb+c deletion. Fluorescence in situ hybridization further confirmed the sSMC was an sSMC(Y) with SRY signal, Y centromere, and Yq deletion. INTERVENTIONS: The patient would choose artificial reproductive technology to get his offspring according to the genetic counseling. OUTCOMES: The sSMC in our patient was proved to be an sSMC(Y), derived from Yq deletion. The spermatogenesis failure of the proband might be due to the synthetic action of sSMC(Y) mosaicism and AZFb+c microdeletion. LESSONS: It is nearly impossible to detect the chromosomal origin of sSMC through traditional banding techniques. The molecular cytogenetic characterization could be performed for identification of sSMC so that comprehensive genetic counseling would be offered.


Assuntos
Azoospermia/genética , Mosaicismo , Adulto , Análise Citogenética , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Masculino
2.
Pediatr Endocrinol Rev ; 16(4): 431-440, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31245938

RESUMO

Variation in karyotype may be associated with the phenotype of patients with Turner syndrome (TS). Our objective was to identify these associations between karyotype and phenotype in TS patients. This study was part of the European multicentre dsd-LIFE study. We evaluated the associations between different karyotypes of TS patients and age at diagnosis, Turner stigmata, cardiac/renal involvement and gonadal function. Information was available for 328 TS patients. Participants had a monosomy 45,X (46%), mosaicism 45,X/46,XX (10%), karyotype with isochromosome (18%), or other karyotype (26%). The clinical signs of TS were the most severe in patients with monosomy 45,X and the least severe in patients with mosaicism 45,X/46,XX. Patients with isochromosome and y-material showed an intermediate phenotype. Despite the more severe features in patients with monosomy 45,X, the median age at diagnosis was only slightly lower compared to patients with other karyotypes, which suggests opportunities for improvement of knowledge and diagnostics.


Assuntos
Síndrome de Turner , Humanos , Cariótipo , Cariotipagem , Mosaicismo , Fenótipo
3.
Cytogenet Genome Res ; 158(2): 83-87, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31195399

RESUMO

The case presented here describes a female patient with recurrent miscarriages and a normal microarray analysis result. However, the coexistence of a robertsonian (21;21) translocation and complementary mosaic ring chromosome 21 was detected by karyotyping and FISH analysis. Partial trisomy 21 was found with QF-PCR and microarray analysis in one of the fetuses. The aim of this report was to emphasize the diagnostic importance of conventional cytogenetics.


Assuntos
Aborto Espontâneo/epidemiologia , Cromossomos Humanos Par 21/genética , Aborto Espontâneo/genética , Adolescente , Feminino , Humanos , Mosaicismo , Linhagem , Cromossomos em Anel , Translocação Genética
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(6): 571-573, 2019 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-31055807

RESUMO

OBJECTIVE: To carry out prenatal diagnosis for two cases of Pallister-Killian syndrome (PKS) using combined chromosomal microarray analysis (CMA) and fluorescence in situ hybridization (FISH). METHODS: Umbilical cord blood was sampled from the two fetuses and subjected to G-banding chromosomal karyotyping, CMA and FISH assay. RESULTS: Chromosomal karyotyping showed that the two fetuses were mos 47,XX,+i(12)(p10)[3]/46,XX[197] and mos 47,XY,+i(12)(p10)[5]/46,XY[95], respectively. CMA showed that both had carried duplication of 12p. The results of interphase FISH confirmed mosaicism of 12p tetrasomy. Combined with ultrasonographic findings, both fetuses were diagnosed as PKS. CONCLUSION: Prenatal ultrasound examination, karyotype analysis of umbilical cord blood, G-banded chromosomal analysis, CMA and FISH may be used in conjunct for the prenatal diagnosis of PKS.


Assuntos
Transtornos Cromossômicos , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 12 , Feminino , Humanos , Hibridização in Situ Fluorescente , Análise em Microsséries , Mosaicismo , Gravidez , Diagnóstico Pré-Natal
6.
Hautarzt ; 70(7): 506-513, 2019 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-31076812

RESUMO

Solitary congenital or early apparent pigmented macules are usually without relevance; however, when multiple, extensive or in a patterned arrangement, they are not uncommonly the first sign of an underlying genetic syndrome. The present article gives an overview on the clinical significance of multiple café-au-lait macules, multiple lentigines and pigmentary mosaicism and discusses the differential diagnosis of associated syndromes. Early diagnosis with the essential contribution of the dermatologist is not only important for genetic counseling but can also contribute to avoidance of sometimes life-threatening complications.


Assuntos
Manchas Café com Leite , Hiperpigmentação , Lentigo , Anormalidades da Pele/genética , Manchas Café com Leite/diagnóstico , Manchas Café com Leite/genética , Diagnóstico Diferencial , Aconselhamento Genético , Doenças Genéticas Inatas , Humanos , Hiperpigmentação/diagnóstico , Hiperpigmentação/genética , Lentigo/genética , Lentigo/patologia , Mosaicismo , Síndrome
7.
BMC Cancer ; 19(1): 435, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077186

RESUMO

BACKGROUND: Several subunits of the SWI/SNF chromatin remodeling complex are implicated in both cancer and neurodevelopmental disorders (NDD). Though there is no clinical evidence for an increased tumor risk in individuals with NDDs due to germline mutations in most of these genes so far, this has been repeatedly proposed and discussed. A young woman with NDD due to a de novo mutation in ARID1B now presented with a large renal (> 19 cm in diameter) and multiple hepatic angiomyolipomas (AMLs) but no other signs of tuberous sclerosis complex. METHODS: We analyzed tumor and healthy tissue samples with exome and panel sequencing. RESULTS: Additionally to the previously known, germline ARID1B variant we identified a post-zygotic truncating TSC2 variant in both renal and hepatic AMLs but not in any of the healthy tissues. We did not detect any further, obvious tumor driver events. The identification of a passenger variant in SIPA1L3 in both AMLs points to a common clonal origin. Metastasis of the renal AML into the liver is unlikely on the basis of discordant histopathological features. Our findings therefore point to very low-grade mosaicism for the TSC2 variant, possibly in a yet unknown mesenchymal precursor cell that expanded clonally during tumor development. A possible contribution of the germline ARID1B variant to the tumorigenesis remains unclear but cannot be excluded given the absence of any other evident tumor drivers in the AMLs. CONCLUSION: This unique case highlights the blurred line between tumor genetics and post-zygotic events that can complicate exact molecular diagnoses in patients with rare manifestations. It also demonstrates the relevance of multiple disorders in a single individual, the challenges of detecting low-grade mosaicisms, and the importance of proper diagnosis for treatment and surveillance.


Assuntos
Angiomiolipoma/genética , Deficiência Intelectual/complicações , Neoplasias Renais/genética , Neoplasias Hepáticas/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteínas de Ligação a DNA/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Deficiência Intelectual/genética , Mosaicismo , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma , Adulto Jovem
8.
Hautarzt ; 70(8): 638-640, 2019 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-31076816

RESUMO

The case of segmental neurofibromatosis (NF) with a monstrous plexiform neurofibroma in a 53-year-old female patient is described. Segmental NF is a rare form of NF, which is caused by a postzygotic mutation in the NF1 gene. In this mosaic form the typical cutaneous symptoms of NF are limited to certain unilateral dermatomes. Plexiform neurofibromas are clinically and histologically in contrast to locally delimited neurofibromas. They involve the catchment area of a peripheral nerve, affect many fascicles and nerve branches, do not respect growth limits and spread in a reticulated fashion. Plexiform neurofibromas can become malignant. In the presented case large parts of the monstrous plexiform cutaneous neurofibroma were excised and the patient did not wish any further measures to be carried out for the time being.


Assuntos
Neurofibroma Plexiforme/patologia , Neoplasias do Sistema Nervoso Periférico/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Mosaicismo , Neurofibroma Plexiforme/cirurgia , Neurofibromatoses , Neurofibromatose 1 , Neoplasias do Sistema Nervoso Periférico/cirurgia
9.
Nat Commun ; 10(1): 1640, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30967548

RESUMO

Gene-drive systems developed in several organisms result in super-Mendelian inheritance of transgenic insertions. Here, we generalize this "active genetic" approach to preferentially transmit allelic variants (allelic-drive) resulting from only a single or a few nucleotide alterations. We test two configurations for allelic-drive: one, copy-cutting, in which a non-preferred allele is selectively targeted for Cas9/guide RNA (gRNA) cleavage, and a more general approach, copy-grafting, that permits selective inheritance of a desired allele located in close proximity to the gRNA cut site. We also characterize a phenomenon we refer to as lethal-mosaicism that dominantly eliminates NHEJ-induced mutations and favors inheritance of functional cleavage-resistant alleles. These two efficient allelic-drive methods, enhanced by lethal mosaicism and a trans-generational drive process we refer to as "shadow-drive", have broad practical applications in improving health and agriculture and greatly extend the active genetics toolbox.


Assuntos
Alelos , Reparo do DNA por Junção de Extremidades/genética , Drosophila/genética , Tecnologia de Impulso Genético/métodos , Agricultura/métodos , Animais , Animais Geneticamente Modificados/genética , Sistemas CRISPR-Cas/genética , Análise Mutacional de DNA , Feminino , Edição de Genes/métodos , Padrões de Herança/genética , Masculino , Mosaicismo , RNA Guia/genética
10.
PLoS Genet ; 15(4): e1008043, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30973874

RESUMO

Mounting evidence supports that LINE-1 (L1) retrotransposition can occur postzygotically in healthy and diseased human tissues, contributing to genomic mosaicism in the brain and other somatic tissues of an individual. However, the genomic distribution of somatic human-specific LINE-1 (L1Hs) insertions and their potential impact on carrier cells remain unclear. Here, using a PCR-based targeted bulk sequencing approach, we profiled 9,181 somatic insertions from 20 postmortem tissues from five Rett patients and their matched healthy controls. We identified and validated somatic L1Hs insertions in both cortical neurons and non-brain tissues. In Rett patients, somatic insertions were significantly depleted in exons-mainly contributed by long genes-than healthy controls, implying that cells carrying MECP2 mutations might be defenseless against a second exonic L1Hs insertion. We observed a significant increase of somatic L1Hs insertions in the brain compared with non-brain tissues from the same individual. Compared to germline insertions, somatic insertions were less sense-depleted to transcripts, indicating that they underwent weaker selective pressure on the orientation of insertion. Our observations demonstrate that somatic L1Hs insertions contribute to genomic diversity and MeCP2 dysfunction alters their genomic patterns in Rett patients.


Assuntos
Elementos Nucleotídeos Longos e Dispersos , Síndrome de Rett/genética , Adolescente , Adulto , Sequência de Bases , Encéfalo/metabolismo , Estudos de Casos e Controles , Córtex Cerebral/metabolismo , Feminino , Mutação em Linhagem Germinativa , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Mosaicismo , Mutação , Neurônios/metabolismo , Síndrome de Rett/metabolismo , Homologia de Sequência do Ácido Nucleico , Distribuição Tecidual , Transcrição Genética , Adulto Jovem
11.
Cytogenet Genome Res ; 157(3): 153-157, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30933946

RESUMO

Mosaic trisomy 12 is a rare anomaly, and only 9 cases of live births with this condition have been reported in the literature. The clinical phenotype is variable, including neuropsychomotor developmental delay, congenital heart disease, microcephaly, cutaneous spots, facial asymmetry, prominent ears, hypotonia, retinopathy, and sensorineural hearing loss. A 2-year-old female presented with neuropsychomotor developmental delay, prominent forehead, dolichocephaly, patchy skin pigmentation, and unexpected overgrowth at birth. Cytogenetic analysis of her peripheral blood showed normal results, suggesting the presence of a chromosomal alteration in other tissues. Further studies using G-banding and FISH performed on fibroblasts from both hyper- and hypopigmented regions identified a 47,XX,+12/46,XX karyotype. To the best of our knowledge, no patients with mosaic trisomy 12 associated with overgrowth have been reported to date. Congenital overgrowth and neonatal overgrowth have been frequently linked to Pallister-Killian syndrome (PKS; OMIM 601803). This case suggests the possibility of an association of genes present in the 12p region with fetal overgrowth, considering that chromosomal duplications could lead to an increase in the production of aberrant transcripts and disturbing gene dosage effects. This case highlights the importance of cytogenetic analysis in different tissues to provide relevant information to the specific genotype/phenotype correlation.


Assuntos
Cromossomos Humanos Par 12/genética , Fibroblastos/citologia , Trissomia/diagnóstico , Linhagem Celular , Pré-Escolar , Bandeamento Cromossômico , Transtornos Cromossômicos , Feminino , Fibroblastos/química , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Mosaicismo
12.
J Genet ; 982019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30945692

RESUMO

A parental diagnosis was performed for an unborn foetus of a healthy couple, who was due for ultrasound detection of multiple malformations and abnormal amniotic fluid karyotypes. For an accurate diagnosis, routine G-banding analysis and next generation sequencing (NGS) were carried out. Finally, conventional cytogenetic analysis suggested that the foetus had a karyotype of47,XX,+mar[52]/46,XN, meanwhile NGS also revealed a partial tetrasomy of 27.84Mb from 4q26-q31.21 (117,385,735-145,225,759), and G-banding analysis excluded the couple to have carried the 4q26-q31.21 duplication. We have identified a de novo mosaic small supernumerary marker chromosomes (sSMC) derived from 4q26-q31.21 in a foetus with hemivertebra, polydactyly, abnormal ears, and heart and ventricular septal defect.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Cromossomos Humanos Par 4/genética , Feto/patologia , Marcadores Genéticos , Diagnóstico Pré-Natal , Tetrassomia , Adulto , Análise Citogenética , Feminino , Feto/metabolismo , Humanos , Masculino , Mosaicismo , Gravidez
14.
Eur J Endocrinol ; 180(6): 397-406, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30991358

RESUMO

Objective Turner Syndrome is associated with several phenotypic conditions associated with a higher risk of subsequent comorbidity. We aimed to evaluate the prevalence of congenital malformations and the occurrence of age-related comorbid conditions and to determine whether the frequencies of congenital and acquired conditions depend on X chromosome gene dosage, as a function of karyotype subgroup. Design and methods This national retrospective observational cohort study includes 1501 patients. We evaluated the prevalence of congenital malformations and the cumulative incidence of subsequent specific comorbidities at five-year intervals, from the ages of 10 to 30 years, with stratification by karyotype subgroup: 45,X (n = 549), 45,X/46,isoXq (n = 280), 46,X,r(X)/46,XX (n = 106), 45,X/46,XX (n = 221), presence of Y (n = 87). Results Median age was 9.4 (3.7-13.7) years at first evaluation and 16.8 (11.2-21.4) years at last evaluation. Congenital heart (18.9%) malformations were more frequent in 45,X patients, and congenital renal (17.2%) malformations were more frequent in 45,X, 45,X/46,isoXq and 46,X,r(X)/46,XX patients than in those with 45,X/46,XX mosaicism or a Y chromosome (P < 0.0001). The cumulative incidence of subsequent acquired conditions, such as thyroid disease, hearing loss, overweight/obesity, dyslipidemia and, to a lesser extent, celiac disease, glucose intolerance/type 2 diabetes, hypertension and liver dysfunction increased with age, but less markedly for patients with mosaicism than for those with other karyotypes. Patients with a ring chromosome were more prone to metabolic disorders. Conclusion These data suggest that X gene chromosome dosage, particularly for Xp genes, contributes to the risk of developing comorbidities.


Assuntos
Cromossomos Humanos X/genética , Anormalidades Congênitas/genética , Dosagem de Genes , Síndrome de Turner/genética , Adolescente , Adulto , Fatores Etários , Criança , Estudos de Coortes , Comorbidade , Anormalidades Congênitas/epidemiologia , Feminino , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Humanos , Cariótipo , Rim/anormalidades , Nefropatias/congênito , Nefropatias/epidemiologia , Nefropatias/genética , Mosaicismo , Estudos Retrospectivos , Fatores de Risco , Síndrome de Turner/classificação , Síndrome de Turner/complicações , Adulto Jovem
15.
Dermatol Clin ; 37(2): 229-239, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850045

RESUMO

The discoveries of new genes underlying genetic skin diseases have occurred at a rapid pace, supported by advances in DNA sequencing technologies. These discoveries have translated to an improved understanding of disease mechanisms at a molecular level and identified new therapeutic options based on molecular targets. This article highlights just a few of these recent discoveries for a diverse group of skin diseases, including tuberous sclerosis complex, ichthyoses, overgrowth syndromes, interferonopathies, and basal cell nevus syndrome, and how this has translated into novel targeted therapies and improved patient care.


Assuntos
Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/terapia , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/terapia , Síndrome do Nevo Basocelular/diagnóstico , Síndrome do Nevo Basocelular/genética , Síndrome do Nevo Basocelular/terapia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Dermabrasão , Fármacos Dermatológicos/uso terapêutico , Testes Genéticos , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/terapia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Eritrodermia Ictiosiforme Congênita/diagnóstico , Eritrodermia Ictiosiforme Congênita/genética , Eritrodermia Ictiosiforme Congênita/terapia , Inibidores de Janus Quinases/uso terapêutico , Terapia a Laser , Lipoma/diagnóstico , Lipoma/genética , Lipoma/terapia , Técnicas de Diagnóstico Molecular , Mosaicismo , Anormalidades Musculoesqueléticas/diagnóstico , Anormalidades Musculoesqueléticas/genética , Anormalidades Musculoesqueléticas/terapia , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/terapia , Nevo/diagnóstico , Nevo/genética , Nevo/terapia , Pitiríase Rubra Pilar/diagnóstico , Pitiríase Rubra Pilar/genética , Pitiríase Rubra Pilar/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Síndrome de Proteu/diagnóstico , Síndrome de Proteu/genética , Síndrome de Proteu/terapia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Análise de Sequência de DNA , Dermatopatias Genéticas/genética , Protetores Solares/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/genética , Esclerose Tuberosa/terapia , Ustekinumab/uso terapêutico
16.
Mol Genet Genomic Med ; 7(5): e625, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30891959

RESUMO

BACKGROUND: Postzygotic KRAS, HRAS, NRAS, and FGFR1 mutations result in a group of mosaic RASopathies characterized by related developmental anomalies in eye, skin, heart, and brain. These oculocutaneous disorders include oculoectodermal syndrome (OES) encephalo-cranio-cutaneous lipomatosis (ECCL), and Schimmelpenning-Feuerstein-Mims syndrome (SFMS). Here, we report the results of the clinical and molecular characterization of a novel cohort of patients with oculocutaneous mosaic RASopathies. METHODS: Two OES, two ECCL, and two SFMS patients were ascertained in the study. In addition, two subjects with unilateral isolated epibulbar dermoids were also enrolled. Molecular analysis included PCR amplification and Sanger sequencing of KRAS, HRAS, NRAS, and FGFR1 genes in DNA obtained from biopsies (skin/epibulbar dermoids), buccal mucosa, and blood leukocytes. Massive parallel sequencing was employed in two cases with low-level mosaicism. RESULTS: In DNA from biopsies, mosaicism for pathogenic variants, including KRAS p.Ala146Thr in two OES subjects, FGFR1 p.Asn546Lys and KRAS p.Ala146Val in ECCL patients, and KRAS p.Gly12Asp in both SFMS patients, was demonstrated. No mutations were shown in DNA from conjunctival lesions in two subjects with isolated epibubar dermoids. CONCLUSION: Our study allowed the expansion of the clinical spectrum of mosaic RASopathies and supports that mosaicism for recurrent mutations in KRAS and FGFR1 is a commonly involved mechanism in these rare oculocutaneous anomalies.


Assuntos
Cisto Dermoide/genética , Displasia Ectodérmica/genética , Oftalmopatias/genética , Lipomatose/genética , Síndromes Neurocutâneas/genética , Nevo Sebáceo de Jadassohn/genética , Fenótipo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Cisto Dermoide/patologia , Displasia Ectodérmica/patologia , Oftalmopatias/patologia , GTP Fosfo-Hidrolases/genética , Humanos , Lipomatose/patologia , Proteínas de Membrana/genética , Mosaicismo , Síndromes Neurocutâneas/patologia , Nevo Sebáceo de Jadassohn/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética
17.
Proc Natl Acad Sci U S A ; 116(11): 4999-5008, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30814219

RESUMO

In the inner ear sensory epithelia, stereociliary hair bundles atop sensory hair cells are mechanosensory apparatus with planar polarized structure and orientation. This is established during development by the concerted action of tissue-level, intercellular planar cell polarity (PCP) signaling and a hair cell-intrinsic, microtubule-mediated machinery. However, how various polarity signals are integrated during hair bundle morphogenesis is poorly understood. Here, we show that the conserved cell polarity protein Par3 is essential for planar polarization of hair cells. Par3 deletion in the inner ear disrupted cochlear outgrowth, hair bundle orientation, kinocilium positioning, and basal body planar polarity, accompanied by defects in the organization and cortical attachment of hair cell microtubules. Genetic mosaic analysis revealed that Par3 functions both cell-autonomously and cell-nonautonomously to regulate kinocilium positioning and hair bundle orientation. At the tissue level, intercellular PCP signaling regulates the asymmetric localization of Par3, which in turn maintains the asymmetric localization of the core PCP protein Vangl2. Mechanistically, Par3 interacts with and regulates the localization of Tiam1 and Trio, which are guanine nucleotide exchange factors (GEFs) for Rac, thereby stimulating Rac-Pak signaling. Finally, constitutively active Rac1 rescued the PCP defects in Par3-deficient cochleae. Thus, a Par3-GEF-Rac axis mediates both tissue-level and hair cell-intrinsic PCP signaling.


Assuntos
Moléculas de Adesão Celular/metabolismo , Polaridade Celular , Células Ciliadas Auditivas Internas/citologia , Células Ciliadas Auditivas Internas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Feminino , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Masculino , Camundongos , Microtúbulos/metabolismo , Mosaicismo , Órgão Espiral/metabolismo , Fosfoproteínas/metabolismo , Ligação Proteica , Proteína Quinase C/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/metabolismo , Proteínas rac de Ligação ao GTP/metabolismo
18.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(3): 260-262, 2019 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-30835360

RESUMO

OBJECTIVE: To explore the prenatal screening and diagnosis for a pair of monochorionic-diamniotic (MCDA) twins discordant for 45,X/46,XX mosaicism. METHODS: Amniotic fluid samples were taken from both twins for whom non-invasive prenatal testing has signaled a high risk for sex chromosomal abnormality. Uncultured amniotic fluid was analyzed by fluorescence in situ hybridization (FISH) and single nucleotide polymorphism array (SNP-array). Conventional G-banded karyotyping analysis was performed on the cultured amniotic fluid. RESULTS: Metaphase chromosome analysis showed that one of the twins had a mos 45,X[11]/46,XX[26] karyotype, while the other had a normal karyotype. FISH and SNP-array applied on uncultured amniotic fluid revealed about 30% mosaicism in one of the twins. The twins were confirmed to be monozygotic by SNP-array analysis. CONCLUSION: To avoid confusion arising from discordant karyotypes in MCDA twins with abnormal non-invasive prenatal testing (NIPT) results, dual amniocentesis should be carried out to obtain amniotic fluid samples for chromosomal as well as molecular analysis. To determine the ratio of 45,X and 46,XX cells in Turner syndrome can provide valuable information for prenatal genetic counseling.


Assuntos
Mosaicismo , Amniocentese , Cromossomos Humanos X , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Gravidez , Diagnóstico Pré-Natal
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