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2.
Invest Ophthalmol Vis Sci ; 60(12): 4021-4032, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31560767

RESUMO

Purpose: Connexins and aquaporins play essential roles in maintaining lens homeostasis and transparency and there is a close physical and functional relationship between these two proteins. Aquaporin 0 (AQP0), in addition to its role in water transport in the lens, acts as a cell-cell adhesion molecule. Recently, we showed a new role of connexin (Cx) 50 in mediating cell-cell adhesion. However, the cooperative roles of these two proteins in the lens in vivo have not been reported. Methods: We generated an AQP0/Cx50 double knockout (dKO) mouse model. Light, fluorescence, transmission thin section, and freeze-fracture electron microscopy, as well as wheat germ agglutinin and phalloidin labeling were used to evaluate lens structure. Mechanical properties of lenses were determined by mechanical compression testing. Results: DKO mice exhibited small eyes and lenses with severe cataracts, along with lens posterior defects, including posterior capsule rupture. The dKO mouse lenses had severe structural disruption associated with increased spaces between lens fiber cells when compared with wild-type lenses or lenses deficient in either Cx50 or AQP0. DKO mice also exhibited greater reduction in lens size compared with Cx50 KO mice. Gap-junction plaque size was greatly decreased in cortical fiber cells in dKO mice. Moreover, lens stiffness and elasticity were completely diminished, exhibiting a gelatinous texture in adult dKO mice. Conclusions: This novel mouse model reveals that Cx50 and AQP0 play an important role in mediating cell-cell adhesion function in the lens fiber cells and their deficiency impairs lens fiber organization, integrity, mechanical properties, and lens development.


Assuntos
Aquaporinas/fisiologia , Catarata/metabolismo , Conexinas/fisiologia , Anormalidades do Olho/metabolismo , Proteínas do Olho/fisiologia , Cristalino/metabolismo , Animais , Catarata/patologia , Adesão Celular/fisiologia , Anormalidades do Olho/patologia , Feminino , Técnica de Fratura por Congelamento , Cristalino/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Pupila/fisiologia
5.
J Pediatr Endocrinol Metab ; 32(8): 797-802, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31323007

RESUMO

PHACE syndrome is an uncommon disorder of posterior fossa anomalies, cervicofacial infantile hemangiomas, arterial anomalies, cardiac defects, eye anomalies, and midline/ventral defects. Endocrine abnormalities including hypopituitarism and ectopic thyroid were rarely described. In this article we review occurrence, onset, presenting symptoms, hormonal treatments and outcomes of all endocrine abnormalities in PHACE syndrome. Eleven of 20 (55%) had hypothalamic-pituitary dysfunction and 10 of 20 (50%) had thyroid dysgenesis. A thorough understanding of the endocrine manifestations is important for clinicians to early identify endocrine involvement in PHACE and develop plans for monitoring and treatment of its complications.


Assuntos
Anormalidades Múltiplas/etiologia , Coartação Aórtica/etiologia , Doenças do Sistema Endócrino/complicações , Anormalidades do Olho/etiologia , Síndromes Neurocutâneas/etiologia , Anormalidades Múltiplas/patologia , Coartação Aórtica/patologia , Fossa Craniana Posterior/patologia , Anormalidades do Olho/patologia , Neoplasias Faciais/etiologia , Neoplasias Faciais/patologia , Cardiopatias Congênitas/etiologia , Cardiopatias Congênitas/patologia , Hemangioma/etiologia , Hemangioma/patologia , Humanos , Síndromes Neurocutâneas/patologia , Síndrome
6.
Gene ; 713: 143973, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31301482

RESUMO

Eye development in vertebrates is a highly coordinated multistep process while defects in key factors might lead to severe congenital ocular disorders. SMO encodes a G protein-coupled receptor that functions in Hedgehog signal transduction, an essential step during eye development. Here we reported the first identification of compound heterozygous mutations (c.G338A; p.R113Q and c.C1619T; p.A540V) in the SMO gene in a patient with both anterior segment dysgenesis (congenital corneal opacity, cataract) and morning glory syndrome, using trio-based whole exome sequencing. The clinical manifestations of this patient were quite consistent with the phenotypes observed in murine SMO null mutants. In silico bioinformatics analyses showed that the newly identified mutations revealed extremely low allele frequencies in the general populations, and were predicted to affect SMO protein stability and residues physiochemical properties. Further investigations revealed a significant decrease of SMO expression in the patient compared with healthy controls (0.71 ±â€¯0.04 vs. 1.49 ±â€¯0.29, P = 0.0265). Therefore, this study pinpoints, for the first time, the potential key sites in SMO that contribute to the maintenance of healthy ocular development, highlighting potential targets for upcoming gene therapy.


Assuntos
Segmento Anterior do Olho/anormalidades , Segmento Anterior do Olho/patologia , Anormalidades do Olho/genética , Mutação , Receptor Smoothened/genética , Anormalidades do Olho/patologia , Feminino , Humanos , Masculino , Linhagem , Fenótipo
7.
Semin Ophthalmol ; 34(5): 375-379, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31244378

RESUMO

Purpose: To investigate the coexistence of cilioretinal arteries (CRAs) with optic disc pit (ODP), and to delineate the characteristics of CRAs related to their number, location of their emergence and their association with the size of ODP. Methods: 47 patients (49 eyes) with ODP were diagnosed and followed-up between 1997 and 2017, using slit-lamp biomicroscopy, color fundus photographs, fluorescein angiography and indocyanine green angiography. The presence of CRAs was recorded in association with the size of the ODP, along with their number and location of emergence. The fellow normal eyes of patients were also analyzed. Results: 42 out of 49 eyes with ODP (85.7%) presented CRAs. In 35 out of 42 eyes (83.3%) CRAs emerged from the pit, either from bottom or from its margin. In 7.1% of cases, CRAs were emerged outside the ODP, while in 9.6% of cases, the type of CRA emergence could be characterized as mixed. The number of CRAs, that ranged from 1 to 4, was positively associated with ODP size. In the fellow normal eyes, CRAs was found in 22.2% of cases, difference which was significant compared to patients with ODP. Conclusion: Based on the high percentage of CRAs coexistence with ODP and the excessive frequency of their emergence from ODP (83.3%), it is supported that ODP as a developmental disorder could go along with further anatomic peculiarities, that also include the presence of multiple CRAs.


Assuntos
Artérias Ciliares/patologia , Anormalidades do Olho/patologia , Disco Óptico/anormalidades , Doenças do Nervo Óptico/patologia , Vasos Retinianos/patologia , Adolescente , Adulto , Feminino , Angiofluoresceinografia , Humanos , Masculino , Estudos Retrospectivos , Tomografia de Coerência Óptica , Adulto Jovem
8.
PLoS One ; 14(6): e0218282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31188886

RESUMO

BACKGROUND: Ischemic retinopathies (IRs) are leading causes of visual impairment. They are characterized by an initial phase of microvascular degeneration and a second phase of aberrant pre-retinal neovascularization (NV). microRNAs (miRNAs) regulate gene expression, and a number play a role in normal and pathological NV. But, post-transcriptional modulation of miRNAs in the eye during the development of IRs has not been systematically evaluated. AIMS & METHODS: Using Next Generation Sequencing (NGS) we profiled miRNA expression in the retina and choroid during vasodegenerative and NV phases of oxygen-induced retinopathy (OIR). RESULTS: Approximately 20% of total miRNAs exhibited altered expression (up- or down-regulation); 6% of miRNA were found highly expressed in retina and choroid of rats subjected to OIR. During OIR-induced vessel degeneration phase, miR-199a-3p, -199a-5p, -1b, -126a-3p displayed a robust decreased expression (> 85%) in the retina. While in the choroid, miR-152-3p, -142-3p, -148a-3p, -532-3p were upregulated (>200%) and miR-96-5p, -124-3p, -9a-3p, -190b-5p, -181a-1-3p, -9a-5p, -183-5p were downregulated (>70%) compared to controls. During peak pathological NV, miR-30a-5p, -30e-5p and 190b-5p were markedly reduced (>70%), and miR-30e-3p, miR-335, -30b-5p strongly augmented (by up to 300%) in the retina. Whereas in choroid, miR-let-7f-5p, miR-126a-5p and miR-101a-3p were downregulated by (>81%), and miR-125a-5p, let-7e-5p and let-7g-5p were upregulated by (>570%) during NV. Changes in miRNA observed using NGS were validated using qRT-PCR for the 24 most modulated miRNAs. In silico approach to predict miRNA target genes (using algorithms of miRSystem database) identified potential new target genes with pro-inflammatory, apoptotic and angiogenic properties. CONCLUSION: The present study is the first comprehensive description of retinal/choroidal miRNAs profiling in OIR (using NGS technology). Our results provide a valuable framework for the characterization and possible therapeutic potential of specific miRNAs involved in ocular IR-triggered inflammation, angiogenesis and degeneration.


Assuntos
Anormalidades do Olho/genética , Proteínas do Olho/genética , Isquemia/genética , MicroRNAs/genética , Oxigênio/toxicidade , Neovascularização Retiniana/genética , Vasos Retinianos/anormalidades , Retinite/genética , Malformações Vasculares/genética , Animais , Animais Recém-Nascidos , Corioide/efeitos dos fármacos , Corioide/metabolismo , Corioide/patologia , Modelos Animais de Doenças , Anormalidades do Olho/induzido quimicamente , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Proteínas do Olho/metabolismo , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Isquemia/metabolismo , Isquemia/patologia , MicroRNAs/classificação , MicroRNAs/metabolismo , Ratos , Ratos Sprague-Dawley , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Neovascularização Retiniana/induzido quimicamente , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Retinite/induzido quimicamente , Retinite/metabolismo , Retinite/patologia , Transdução de Sinais , Malformações Vasculares/induzido quimicamente , Malformações Vasculares/metabolismo , Malformações Vasculares/patologia
9.
Medicine (Baltimore) ; 98(23): e15908, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31169704

RESUMO

RATIONALE: Cerebral, ocular, dental, auricular, skeletal anomalies (CODAS) syndrome is a very rare multisystem disorder, which shows malformations of the central nervous system, ears, eyes, teeth, and skeleton that was first reported in 1991. Only a few cases that sporadically occurred have been reported worldwide. The research investigating the pathogenesis and patterns of CODAS inheritance is still ongoing. There is no satisfactory treatment for this rare genetic disease yet. Due to the lack of curative medical treatment, rehabilitation could play a major role in treatment for genetic disease. PATIENT CONCERNS: To our best knowledge, the 2 children described in this study are the only CODAS syndromes siblings reported in the world so far. These Korean siblings show highly distinctive features consisting of developmental delay, cataracts, vulnerability to tooth decay, epiphyseal dysplasia, and anomalous ears. DIAGNOSES: CODAS syndrome. INTERVENTIONS: Comprehensive long-term rehabilitation treatment during 5 years. OUTCOMES: We report on the progress of the comprehensive long-term rehabilitation treatment at 5-year follow-up. Their fine motor and language skills development improved similarly to that of same-aged children. We observed the positive effect of rehabilitation on the quality of life. LESSONS: The therapy of genetic disorders is challenging for pediatric neurologists and pediatric physiatrists. We suggest that rehabilitation is the best treatment currently available for this genetic disease that yields satisfactory therapeutic effect.


Assuntos
Anormalidades Craniofaciais/patologia , Anormalidades Craniofaciais/reabilitação , Anormalidades do Olho/patologia , Anormalidades do Olho/reabilitação , Transtornos do Crescimento/patologia , Transtornos do Crescimento/reabilitação , Luxação Congênita de Quadril/patologia , Luxação Congênita de Quadril/reabilitação , Osteocondrodisplasias/patologia , Osteocondrodisplasias/reabilitação , Irmãos , Anormalidades Dentárias/patologia , Anormalidades Dentárias/reabilitação , Criança , Feminino , Humanos , Masculino , Qualidade de Vida , República da Coreia
10.
BMJ Case Rep ; 12(4)2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036736

RESUMO

PHACES syndrome is an uncommon neurocutaneous disorder first identified in 1996. Patients with PHACES syndrome often require surgical treatment for their anomalies, including intracranial vasculopathy, coarctation/interruption of the aorta, intracardiac defects, glaucoma/cataract and sternal defects. Risk factors associated with the symptoms of intraoperative/perioperative management include ischaemic stroke due to the cerebral vasculopathy, airway obstruction due to the subglottic/tracheal haemangiomas and massive bleeding due to the large haemangiomas. Recently, propranolol is considered as first-line therapy for patients with infantile haemangiomas (IHs). However, until now, there have been no reported cases of PHACES syndrome treated by propranolol to reduce the surgical risks associated with IH. In this report, we describe a case of a 14-month-old Japanese girl with PHACES syndrome treated by propranolol for IH before surgical closure of the ventricular septum defect. Oral administration of propranolol was effective in decreasing the size of IH, leading to the uneventful perioperative course.


Assuntos
Anormalidades Múltiplas/cirurgia , Coartação Aórtica/cirurgia , Anormalidades do Olho/cirurgia , Hemangioma/tratamento farmacológico , Síndromes Neurocutâneas/cirurgia , Propranolol/administração & dosagem , Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/patologia , Administração Oral , Antagonistas Adrenérgicos beta , Obstrução das Vias Respiratórias/complicações , Obstrução das Vias Respiratórias/prevenção & controle , Coartação Aórtica/tratamento farmacológico , Coartação Aórtica/patologia , Ecocardiografia/métodos , Anormalidades do Olho/tratamento farmacológico , Anormalidades do Olho/patologia , Feminino , Comunicação Interventricular/diagnóstico por imagem , Comunicação Interventricular/cirurgia , Hemangioma/diagnóstico por imagem , Humanos , Lactente , Imagem por Ressonância Magnética , Síndromes Neurocutâneas/tratamento farmacológico , Síndromes Neurocutâneas/patologia , Cuidados Pré-Operatórios/normas , Propranolol/efeitos adversos , Doenças Raras , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/prevenção & controle , Resultado do Tratamento
11.
Mol Med Rep ; 19(6): 4711-4718, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059048

RESUMO

Autosomal recessive cornea plana is a very rare hereditary ocular disease, characterized by a flattened corneal curvature, marked hyperopia due to low refractive power and frequently consequent accommodative esotropia. Other features include various cornea anterior segment abnormalities, without systemic problems. The purpose of the present study was to investigate the clinical and molecular alterations in a Chinese family with cornea plana. Full ophthalmic examinations of the patients were performed, including slit­lamp examination, fundus examination and ocular ultrasound. Whole­exome sequencing data were screened for pathological variants in the proband, which were confirmed by Sanger sequencing. One novel missense mutation, c.242A>G (p.N81S) and another novel 7 base­pair deletion mutation, c.772­779del (p.G258Cfs*30), were detected in the keratocan (KERA) gene; two affected siblings inherited these variations in a compound heterozygous state, which were derived from the clinically unaffected heterozygous father (c.772_779del) and mother (c.242A>G), respectively. Neither mutation was observed in unrelated healthy controls (n=200). Multiple computer software predictions supported the pathogenicity of the two variants. Furthermore, protein modeling prediction was performed to better understand the molecular basis of cornea plana, particularly the importance of the leucine­rich repeat domain. This study presents the 14th pathogenic KERA mutations identified worldwide and the first in East Asia so far, to the best of our knowledge. These findings guided prenatal diagnosis for the family in question and expand on the variant spectrum of KERA, therefore facilitating genetic counseling.


Assuntos
Doenças da Córnea/genética , Genes Recessivos/genética , Proteoglicanas/genética , Grupo com Ancestrais do Continente Asiático , Sequência de Bases , China , Córnea/anormalidades , Córnea/patologia , Doenças da Córnea/diagnóstico , Doenças da Córnea/patologia , Distrofias Hereditárias da Córnea/diagnóstico , Distrofias Hereditárias da Córnea/genética , Análise Mutacional de DNA , Éxons/genética , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Feminino , Humanos , Mutação de Sentido Incorreto , Linhagem , Análise de Sequência , Deleção de Sequência , Sequenciamento Completo do Exoma
14.
J Fr Ophtalmol ; 42(5): 451-456, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30962069

RESUMO

PURPOSE: The management of A or V pattern deviation associated with esotropia can be challenging since the horizontal deviation changes with position of gaze. This study aimed to assess the effect of unilateral horizontal rectus surgery for the correction of horizontal deviation associated with A or V pattern in children with non-comitant infantile esotropia. METHODS: Twenty-seven children with infantile esotropia and A-V pattern, more than 10 and 15 prism diopters respectively, were included in this retrospective observational single-center study. Horizontal rectus surgery was performed on the most deviated eye under general anesthesia. The patients were divided into two groups: A pattern and V pattern. The outcome measures were change in the amount of pattern and rate of regression after surgery. The amount of pattern was characterized by the difference in esodeviation between upgaze and downgaze. RESULTS: Horizontal deviation at distance and near fixation decreased significantly (P<0.0001). Vertical gaze esotropia disparity decreased significantly (P=0.01 and P=0.0002 for A and V patterns respectively). A pattern esotropia was reported in only 2 (7%) cases after surgery compared to 9 (33%) before surgery. The number of subjects with V pattern esotropia decreased from 18 (67%) to 3 (11%) after surgery. CONCLUSIONS: The mechanisms involved in the pathophysiology of A and V patterns may not always be related to oblique muscle dysfunction. These findings suggest that unilateral horizontal rectus surgery may be an effective procedure to correct both horizontal deviation and A-V pattern in non-comitant infantile esotropia.


Assuntos
Esotropia/congênito , Esotropia/cirurgia , Anormalidades do Olho/cirurgia , Músculos Oculomotores/cirurgia , Procedimentos Cirúrgicos Oftalmológicos/métodos , Adolescente , Criança , Pré-Escolar , Esotropia/epidemiologia , Esotropia/patologia , Anormalidades do Olho/epidemiologia , Anormalidades do Olho/patologia , Feminino , Humanos , Masculino , Músculos Oculomotores/patologia , Estudos Retrospectivos , Estrabismo/congênito , Estrabismo/epidemiologia , Estrabismo/patologia , Estrabismo/cirurgia , Resultado do Tratamento , Visão Binocular
15.
Mol Vis ; 25: 129-142, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30820148

RESUMO

Purpose: To identify the effects of a single copy deletion of Yap1 (Yap1 +/-) in the mouse eye, the ocular phenotypic consequences of Yap1 +/- were determined in detail. Methods: Complete ophthalmic examinations, as well as corneal esthesiometry, the phenol red thread test, intraocular pressure, and Fourier-domain optical coherence tomography were performed on Yap1 +/- and age-matched wild-type (WT) mice between eyelid opening (2 weeks after birth) and adulthood (2 months and 1 year after birth). Following euthanasia, enucleated eyes were characterized histologically. Results: Microphthalmia with small palpebral fissures, corneal fibrosis, and reduced corneal sensation were common findings in the Yap1 +/- mice. Generalized corneal fibrosis precluded clinical examination of the posterior structures. Histologically, thinning and keratinization of the corneal epithelium were observed in the Yap1 +/- mice in comparison with the WT mice. Distorted collagen fiber arrangement and hypercellularity of keratocytes were observed in the stroma. Descemet's membrane was extremely thin and lacked an endothelial layer in the Yap1 +/- mice. The iris was adherent to the posterior cornea along most of its surface creating a distorted contour. Most of the Yap1 +/- eyes were microphakic with swollen fibers and bladder cells. The retinas of the Yap1 +/- mice were normal at 2 weeks and 2 months of age, but the presence of retinal abnormalities, including retinoschisis and detachment, was markedly increased in the Yap1 +/- mice at 1 year of age. Conclusions: The results show that the heterozygous deletion of the Yap1 gene in mice leads to complex ocular abnormalities, including microphthalmia, corneal fibrosis, anterior segment dysgenesis, and cataract.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Catarata/genética , Anormalidades do Olho/genética , Microftalmia/genética , Fenótipo , Fosfoproteínas/genética , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Animais , Catarata/diagnóstico por imagem , Catarata/metabolismo , Catarata/patologia , Proteínas de Ciclo Celular , Substância Própria/diagnóstico por imagem , Substância Própria/metabolismo , Substância Própria/patologia , Lâmina Limitante Posterior/diagnóstico por imagem , Lâmina Limitante Posterior/metabolismo , Lâmina Limitante Posterior/patologia , Epitélio Anterior/diagnóstico por imagem , Epitélio Anterior/metabolismo , Epitélio Anterior/patologia , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Feminino , Fibrose , Expressão Gênica , Heterozigoto , Pressão Intraocular/fisiologia , Iris/diagnóstico por imagem , Iris/metabolismo , Iris/patologia , Masculino , Camundongos , Camundongos Knockout , Microftalmia/diagnóstico por imagem , Microftalmia/metabolismo , Microftalmia/patologia , Fosfoproteínas/deficiência , Retina/diagnóstico por imagem , Retina/metabolismo , Retina/patologia , Tomografia de Coerência Óptica , Tonometria Ocular
18.
J Dermatol ; 46(5): 422-425, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30809829

RESUMO

A Chinese female infant presented with ectodermal dysplasia, cleft palate and severe skin erosions at birth. Although all the typical clinical features of ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome were present, the ankyloblepharon was not very marked. We misdiagnosed epidermolysis bullosa and congenital ichthyosiform erythroderma at first and confirmed the diagnosis of AEC syndrome only when she presented with the typical clinical manifestation of recurrent infected scalp erosions at 1 year of age. Mutation analysis of exon 13 of the p63 gene revealed a missense mutation Ile482Thr (c.1445T>C) in the sterile alpha motive domain. In this work we review the clinical features, differential diagnosis and prognosis in AEC syndrome.


Assuntos
Fenda Labial/diagnóstico , Fissura Palatina/diagnóstico , Erros de Diagnóstico , Displasia Ectodérmica/diagnóstico , Epidermólise Bolhosa/diagnóstico , Anormalidades do Olho/diagnóstico , Pálpebras/anormalidades , Eritrodermia Ictiosiforme Congênita/diagnóstico , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Biópsia , Fenda Labial/genética , Fenda Labial/patologia , Fenda Labial/terapia , Fissura Palatina/genética , Fissura Palatina/patologia , Fissura Palatina/terapia , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Displasia Ectodérmica/terapia , Epidermólise Bolhosa/patologia , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Anormalidades do Olho/terapia , Pálpebras/patologia , Feminino , Testes Genéticos , Heterozigoto , Humanos , Eritrodermia Ictiosiforme Congênita/patologia , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro , Mutação de Sentido Incorreto , Pele/patologia
19.
Dev Biol ; 448(1): 36-47, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30695685

RESUMO

Joubert syndrome (JBTS) is a predominantly autosomal recessive neurodevelopmental disorder that presents with characteristic malformations of the cerebellar vermis, superior cerebellar peduncles and midbrain in humans. Accompanying these malformations are a heterogeneous set of clinical symptoms, which frequently include deficits in motor and muscle function, such as hypotonia (low muscle tone) and ataxia (clumsiness). These symptoms are attributed to improper development of the hindbrain, but no direct evidence has been reported linking these in JBTS. Here, we describe muscle developmental defects in a mouse with a targeted deletion of the Abelson helper integration site 1 gene, Ahi1, one of the genes known to cause JBTS in humans. While FVB/NJ Ahi1-/- mice display no gross malformations of the cerebellum, deficits are observed in several measures of motor function, strength, and body development. Specifically, Ahi1-/- mice show delayed physical development, delays in surface reflex righting as neonates, and reductions in grip strength and spontaneous locomotor activity as adults. Additionally, Ahi1-/- mice showed evidence of muscle-specific contributions to this phenotype, such as reductions in 1) myoblast differentiation potential in vitro, 2) muscle desmin expression, and 3) overall muscle mass, myonuclear domain, and muscle fiber cross-sectional area. Together, these data suggest that loss of Ahi1 may cause abnormalities in the differentiation of myoblasts to mature muscle cells. Moreover, Ahi1 loss impacts muscle development directly, outside of any indirect impact of cerebellar malformations, revealing a novel myogenic cause for hypotonia in JBTS.


Assuntos
Anormalidades Múltiplas/embriologia , Diferenciação Celular , Cerebelo/anormalidades , Anormalidades do Olho/embriologia , Doenças Renais Císticas/embriologia , Desenvolvimento Muscular , Transtornos do Neurodesenvolvimento/metabolismo , Proteínas Proto-Oncogênicas/deficiência , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Proteínas Adaptadoras de Transporte Vesicular , Animais , Cerebelo/embriologia , Cerebelo/patologia , Desmina/genética , Desmina/metabolismo , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Locomoção/genética , Camundongos , Camundongos Knockout , Força Muscular/genética , Mioblastos/metabolismo , Mioblastos/patologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Proteínas Proto-Oncogênicas/metabolismo , Reflexo de Endireitamento/genética , Retina/embriologia , Retina/patologia
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