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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 686-689, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302911

RESUMO

OBJECTIVE: To explore the pathogenesis of two fetuses from one family affected with Joubert syndrome (JS). METHODS: Whole exome sequencing was employed to screen potential mutations in both fetuses. Suspected mutations were verified by Sanger sequencing. Impact of intronic mutations on DNA transcription was validated by cDNA analysis. RESULTS: Two novel TCTN1 mutations, c.342-8A>G and c.1494+1G>A, were identified in exons 2 and 12, respectively.cDNA analysis confirmed the pathogenic nature of both mutations with interference of normal splicing resulting in production of truncated proteins. CONCLUSION: The genetic etiology of the family affected with JS has been identified.Above findings have enriched the mutation spectrum of TCTN1gene and facilitated understanding of the genotype-phenotype correlation of JS.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades do Olho/diagnóstico , Humanos , Doenças Renais Císticas/diagnóstico , Mutação , Linhagem , Sequenciamento Completo do Exoma
2.
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
3.
BMC Med Genet ; 20(1): 105, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31185933

RESUMO

BACKGROUND: Axenfeld-Rieger syndrome (ARS) is an autosomal dominant genetic disorder that is characterized by specific abnormalities of the anterior segment of the eye. Heterozygous mutations in two developmental transcription factor genes PITX2 and FOXC1 have been identified within ARS patients, accounting for 40 to 70% of cases. Our purpose is to describe clinical and genetic findings in a Chinese family with ARS. METHODS: An ARS family with three affected members was recruited. The patients underwent a series of complete ophthalmologic examinations, general physical examination and dental radiography. DNA samples of proband II-1 were used for targeted exome sequencing of the FOXC1 and PITX2 genes. Sanger sequencing was used to validate the variation in PITX2. Quantitative real-time PCR was carried out to detect the expression of PITX2 in patients and normal controls. RESULTS: All affected members showed iris atrophy, corectopia, shallow anterior chamber, complete or partial angle closure, and advanced glaucoma. In addition, they revealed systemic anomalies, including microdontia, hypodontia, and redundant periumbilical skin. A novel heterozygous frameshift variation, c.515delA, in PITX2 was found in the proband, which might lead to a truncated PITX2 protein (p.Gln172ArgfsX36). Sanger sequencing validated that the variation completely cosegregated with the ARS phenotype among this family, but was absent in 100 unrelated controls. Quantitative real-time PCR analysis revealed that the mRNA expression of PITX2 was significantly decreased in patients compared with that in unrelated normal controls. CONCLUSIONS: PITX2 c.515delA (p.Gln172ArgfsX36) was the genetic etiology of our pedigree. The mutation led to decreased PITX2 gene expression and a truncated mRNA transcript.


Assuntos
Segmento Anterior do Olho/anormalidades , Anormalidades do Olho/genética , Oftalmopatias Hereditárias/genética , Mutação da Fase de Leitura , Predisposição Genética para Doença/genética , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma/métodos , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático , China , Anormalidades do Olho/etnologia , Oftalmopatias Hereditárias/etnologia , Saúde da Família , Feminino , Predisposição Genética para Doença/etnologia , Humanos , Masculino , Linhagem , Adulto Jovem
4.
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
5.
BMC Med Genet ; 20(1): 63, 2019 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-31029096

RESUMO

BACKGROUND: We performed clinical and genetic characterization of a family with cavitary optic disc anomaly (CODA), an autosomal dominant condition that causes vision loss due to adult-onset maculopathy in the majority of cases. CODA is characterized by a variably excavated optic nerve appearance such as morning glory, optic pit, atypical coloboma, and severe optic nerve cupping. METHODS: Four affected and fourteen unaffected family members of a multi-generation pedigree were phenotyped by visual acuity, intraocular pressure, dilated fundus examination, fundus photography, and optical coherence tomography. Genetic analysis was performed by breakpoint polymerase chain reaction (PCR), long range PCR, and direct Sanger sequencing. The functional relevance of the copy number alteration region was assessed by in silico analysis. RESULTS: We found progressive optic nerve cupping in three affected members of a family with CODA. In one individual, an optic pit developed over time from a normal optic nerve. By two independent methods, we detected a previously described intergenic triplication that segregated with disease in all adults of the family. The copy number alteration was also detected in five children with normal optic nerves. eQTL analysis demonstrated that this CNA region regulates expression of up to 4 genes in cis. CONCLUSIONS: Morning glory, optic pit and atypical coloboma are currently considered congenital anomalies of the optic nerve, but our data indicate that in CODA, the excavated optic nerve appearance may develop after birth and into adulthood. In silico analysis of the CNA, may explain why vairable expressivity is observed in CODA.


Assuntos
Variações do Número de Cópias de DNA , Anormalidades do Olho/genética , Disco Óptico/patologia , Nervo Óptico/patologia , Locos de Características Quantitativas , Adolescente , Criança , Pré-Escolar , Progressão da Doença , Anormalidades do Olho/etiologia , Feminino , Humanos , Masculino , Linhagem
6.
PLoS Genet ; 15(3): e1008050, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30856164

RESUMO

CENP-F is a large, microtubule-binding protein that regulates multiple cellular processes including chromosome segregation and mitochondrial trafficking at cytokinesis. This multiplicity of functions is mediated through the binding of various partners, like Bub1 at the kinetochore and Miro at mitochondria. Due to the multifunctionality of CENP-F, the cellular phenotypes observed upon its depletion are difficult to interpret and there is a need to genetically separate its different functions by preventing binding to selected partners. Here we engineer a CENP-F point-mutant that is deficient in Miro binding and thus is unable to localize to mitochondria, but retains other localizations. We introduce this mutation in cultured human cells using CRISPR/Cas9 system and show it causes a defect in mitochondrial spreading similar to that observed upon Miro depletion. We further create a mouse model carrying this CENP-F variant, as well as truncated CENP-F mutants lacking the farnesylated C-terminus of the protein. Importantly, one of these truncations leads to ~80% downregulation of CENP-F expression. We observe that, despite the phenotypes apparent in cultured cells, mutant mice develop normally. Taken together, these mice will serve as important models to study CENP-F biology at organismal level. In addition, because truncations of CENP-F in humans cause a lethal disease termed Strømme syndrome, they might also be relevant disease models.


Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Sistemas CRISPR-Cas , Linhagem Celular , Proteínas Cromossômicas não Histona/química , Proteínas Cromossômicas não Histona/genética , Anormalidades do Olho/genética , Humanos , Atresia Intestinal/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Microcefalia/genética , Proteínas dos Microfilamentos/química , Proteínas dos Microfilamentos/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/química , Proteínas Mitocondriais/genética , Mutação Puntual , Prenilação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteínas rho de Ligação ao GTP/química , Proteínas rho de Ligação ao GTP/genética
7.
Cornea ; 38(6): 718-722, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30865045

RESUMO

PURPOSE: Brittle cornea syndrome (BCS) is a rare recessive disorder affecting connective tissues, most prominently in the eye. Pathogenic mutations causing BCS have been identified in PRDM5 and ZNF469 genes. This study investigates the genetic cause of BCS in a large, consanguineous Pakistani family with 4 affected and 3 unaffected individuals. METHODS: The coding region and exon-intron splice junctions of PRDM5 and ZNF469 genes were amplified by polymerase chain reaction, and bidirectional Sanger sequencing was performed to find the pathogenic change responsible for causing the disease in the family. RESULTS: A novel homozygous duplication c.9831dupC (p.Arg3278GlnfsX197) in the ZNF469 gene was identified, which was found to be co-segregating with the disease in the family. CONCLUSIONS: This is the first report of a ZNF469 homozygous mutation causing a BCS phenotype in a consanguineous Pakistani family. Our data extend the mutation spectrum of ZNF469 variants implicated in BCS.


Assuntos
Anormalidades do Olho/genética , Instabilidade Articular/congênito , Mutação , Anormalidades da Pele/genética , Fatores de Transcrição/genética , Criança , Pré-Escolar , Feminino , Humanos , Instabilidade Articular/genética , Masculino , Paquistão
8.
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 , 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
9.
Proc Natl Acad Sci U S A ; 116(9): 3662-3667, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808755

RESUMO

Kaufman oculocerebrofacial syndrome (KOS) is a recessive neurodevelopmental disorder characterized by intellectual disability and lack of speech. KOS is caused by inactivating mutations in UBE3B, but the underlying biological mechanisms are completely unknown. We found that loss of Ube3b in mice resulted in growth retardation, decreased grip strength, and loss of vocalization. The brains of Ube3b -/- mice had hypoplasia of the corpus callosum, enlarged ventricles, and decreased thickness of the somatosensory cortex. Ube3b -/- cortical neurons had abnormal dendritic morphology and synapses. We identified 22 UBE3B interactors and found that branched-chain α-ketoacid dehydrogenase kinase (BCKDK) is an in vivo UBE3B substrate. Since BCKDK targets several metabolic pathways, we profiled plasma and cortical metabolomes from Ube3b -/- mice. Nucleotide metabolism and the tricarboxylic acid cycle were among the pathways perturbed. Substrate-induced mitochondrial respiration was reduced in skeletal muscle but not in liver of Ube3b -/- mice. To assess the relevance of these findings to humans, we identified three KOS patients who had compound heterozygous UBE3B mutations. We discovered changes in metabolites from similar pathways in plasma from these patients. Collectively, our results implicate a disease mechanism in KOS, suggest that it is a metabolic encephalomyopathy, and provide an entry to targeted therapies.


Assuntos
Anormalidades do Olho/genética , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Deformidades Congênitas dos Membros/genética , Microcefalia/genética , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Animais , Encéfalo/fisiopatologia , Criança , Anormalidades do Olho/fisiopatologia , Facies , Humanos , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Knockout , Microcefalia/fisiopatologia , Mutação , Fenótipo , Ubiquitina/genética
10.
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
11.
Klin Monbl Augenheilkd ; 236(3): 269-285, 2019 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-30736081

RESUMO

To control the development of the ocular phenotype, several coordinated steps of temporally- and spatially-organized networked triggers (inductions) are necessary. This is regulated at the level of transcription. Crucial here are the so-called master genes or DNA-binding transcription factors PAX6, FOXC1, SOX2, FOXE3, OTX2, PITX2 and PAX2. Depending on the disease phenotype, it is possible to conclude on the gestational period in which ocular development was profoundly disrupted. The so-called neural crest cells contribute significantly to the development of eye structures, especially of the anterior segment. The review first presents a brief overview of the embryologic development of ocular structures and then describes major profound developmental disorders of the eyes: phenotypic and genetic features in the MAC spectrum (microphthalmia, anophthalmia, coloboma) as well as anterior segment dysgenesis (Axenfeld-Rieger spectrum, aniridia, Peters anomaly). It also outlines the systemic involvement of these diseases. In clinical and genetic diagnostic pathways, the determining factor is the exact phenotypic characterization that must be preceded by any genetic diagnosis and the further choice of diagnostic options. "Shotgun diagnostics" on all of the described genes involved in ocular developmental disorders is costly and less effective than a phenotypically-oriented selection of the genes common to the phenotypical syndrome described, and only then should it be followed by the analysis of rarer genes in a second or third molecular genetic step.


Assuntos
Aniridia , Anormalidades do Olho , Aniridia/diagnóstico , Aniridia/genética , Segmento Anterior do Olho , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Proteínas de Homeodomínio/genética , Humanos , Mutação
12.
Hum Genet ; 138(8-9): 799-830, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30762128

RESUMO

Eye formation is the result of coordinated induction and differentiation processes during embryogenesis. Disruption of any one of these events has the potential to cause ocular growth and structural defects, such as anophthalmia and microphthalmia (A/M). A/M can be isolated or occur with systemic anomalies, when they may form part of a recognizable syndrome. Their etiology includes genetic and environmental factors; several hundred genes involved in ocular development have been identified in humans or animal models. In humans, around 30 genes have been repeatedly implicated in A/M families, although many other genes have been described in single cases or families, and some genetic syndromes include eye anomalies occasionally as part of a wider phenotype. As a result of this broad genetic heterogeneity, with one or two notable exceptions, each gene explains only a small percentage of cases. Given the overlapping phenotypes, these genes can be most efficiently tested on panels or by whole exome/genome sequencing for the purposes of molecular diagnosis. However, despite whole exome/genome testing more than half of patients currently remain without a molecular diagnosis. The proportion of undiagnosed cases is even higher in those individuals with unilateral or milder phenotypes. Furthermore, even when a strong gene candidate is available for a patient, issues of incomplete penetrance and germinal mosaicism make diagnosis and genetic counseling challenging. In this review, we present the main genes implicated in non-syndromic human A/M phenotypes and, for practical purposes, classify them according to the most frequent or predominant phenotype each is associated with. Our intention is that this will allow clinicians to rank and prioritize their molecular analyses and interpretations according to the phenotypes of their patients.


Assuntos
Anoftalmia/genética , Anormalidades do Olho/genética , Microftalmia/genética , Animais , Exoma/genética , Olho/patologia , Humanos , Fenótipo , Síndrome
13.
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 , 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
15.
Am J Med Genet A ; 176(12): 2740-2750, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30548201

RESUMO

The oculoauriculofrontonasal syndrome (OAFNS) is a rare disorder characterized by the association of frontonasal dysplasia (widely spaced eyes, facial cleft, and nose abnormalities) and oculo-auriculo-vertebral spectrum (OAVS)-associated features, such as preauricular ear tags, ear dysplasia, mandibular asymmetry, epibulbar dermoids, eyelid coloboma, and costovertebral anomalies. The etiology is unknown so far. This work aimed to identify molecular bases for the OAFNS. Among a cohort of 130 patients with frontonasal dysplasia, accurate phenotyping identified 18 individuals with OAFNS. We describe their clinical spectrum, including the report of new features (micro/anophtalmia, cataract, thyroid agenesis, polymicrogyria, olfactory bulb hypoplasia, and mandibular cleft), and emphasize the high frequency of nasal polyps in OAFNS (56%). We report the negative results of ALX1, ALX3, and ALX4 genes sequencing and next-generation sequencing strategy performed on blood-derived DNA from respectively, four and four individuals. Exome sequencing was performed in four individuals, genome sequencing in one patient with negative exome sequencing result. Based on the data from this series and the literature, diverse hypotheses can be raised regarding the etiology of OAFNS: mosaic mutation, epigenetic anomaly, oligogenism, or nongenetic cause. In conclusion, this series represents further clinical delineation work of the rare OAFNS, and paves the way toward the identification of the causing mechanism.


Assuntos
Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Orelha Externa/anormalidades , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Padrões de Herança , Fenótipo , Anormalidades do Sistema Respiratório/diagnóstico , Anormalidades do Sistema Respiratório/genética , Coluna Vertebral/anormalidades , Adolescente , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Facies , Feminino , Proteínas de Homeodomínio/genética , Humanos , Lactente , Recém-Nascido , Masculino , Locos de Características Quantitativas , Crânio/anormalidades , Crânio/diagnóstico por imagem , Tomografia Computadorizada Espiral , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma
16.
Eur J Pediatr ; 177(11): 1727-1731, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30088137

RESUMO

Sweating deficiency has been reported to represent a cardinal symptom of ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome and ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome, two rare p63-associated disorders. According to online resources, hypohidrosis may lead to most life-threatening complications in affected patients. Thus, counseling on the prevention of hyperthermia would be indispensable in case of such syndromes, although detailed information on this issue is missing in the literature. We investigated 14 individuals with ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome (age range 2-48 years) and 9 individuals with ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome (0.5-60 years of age) by confocal laser scanning microscopy to determine their palmar sweat duct density and by quantification of pilocarpine-induced sweating. Genotype-phenotype correlations were assessed. In 12 of 23 patients (52%), a normal amount of sweat ducts was detected. These individuals (9 with ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome, 3 with ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome) produced sufficient sweat volumes (≥ 20 µl) in response to pilocarpine. All other patients had clearly reduced sweating ability and fewer sweat glands, but no anhidrosis. Alteration of a specific proline residue (Pro590) of p63 was consistently linked to impaired perspiration.Conclusion: Hypohidrosis in p63-associated syndromes is less common and potentially less severe than previously thought and may be attributable to certain genotypes. What is Known: • Hypohidrosis which has been listed as a cardinal symptom of AEC and EEC syndromes may lead to life-threatening hyperthermia. What is New: • Patients with EEC and AEC syndromes often can sweat normally. • Hypohidrosis seems to be attributed to certain TP63 genotypes.


Assuntos
Fenda Labial/complicações , Fissura Palatina/complicações , Displasia Ectodérmica/complicações , Anormalidades do Olho/complicações , Pálpebras/anormalidades , Hipo-Hidrose/etiologia , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Criança , Pré-Escolar , Fenda Labial/genética , Fissura Palatina/genética , Displasia Ectodérmica/genética , Anormalidades do Olho/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Pilocarpina/administração & dosagem , Glândulas Sudoríparas/anormalidades , Sudorese/fisiologia , Adulto Jovem
18.
Dev Biol ; 441(2): 221-234, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30031755

RESUMO

Astyanax mexicanus consists of two different populations: a sighted surface-dwelling form (surface fish) and a blind cave-dwelling form (cavefish). In the cavefish, embryonic expression of sonic hedgehog a (shha) in the prechordal plate is expanded towards the anterior midline, which has been shown to contribute to cavefish specific traits such as eye degeneration, enhanced feeding apparatus, and specialized brain anatomy. However, it is not clear how this expanded expression is achieved and which signaling pathways are involved. Nodal signaling has a crucial role for expression of shh and formation of the prechordal plate. In this study, we report increased expression of prechordal plate marker genes, nodal-related 2 (ndr2) and goosecoid (gsc) in cavefish embryos at the tailbud stage. To investigate whether Nodal signaling is responsible for the anterior expansion of the prechordal plate, we used an inhibitor of Nodal signaling and showed a decreased anterior expansion of the prechordal plate and increased pax6 expression in the anterior midline in treated cavefish embryos. Later in development, the lens and optic cup of treated embryos were significantly larger than untreated embryos. Conversely, increasing Nodal signaling in the surface fish embryo resulted in the expansion of anterior prechordal plate and reduction of pax6 expression in the anterior neural plate together with the formation of small lenses and optic cups later in development. These results confirmed that Nodal signaling has a crucial role for the anterior expansion of the prechordal plate and plays a significant role in cavefish eye development. We showed that the anterior expansion of the prechordal plate was not due to increased total cell number, suggesting the expansion is achieved by changes in cellular distribution in the prechordal plate. In addition, the distribution of presumptive prechordal plate cells in Spemann's organiser was also altered in the cavefish. These results suggested that changes in the cellular arrangement of Spemann's organiser in early gastrulae could have an essential role in the anterior expansion of the prechordal plate contributing to eye degeneration in the cavefish.


Assuntos
Caraciformes , Anormalidades do Olho , Olho/embriologia , Proteínas de Peixes , Transdução de Sinais/genética , Animais , Caraciformes/embriologia , Caraciformes/genética , Anormalidades do Olho/embriologia , Anormalidades do Olho/genética , Proteínas de Peixes/biossíntese , Proteínas de Peixes/genética , Gástrula/embriologia
19.
Dev Biol ; 441(2): 235-241, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30017604

RESUMO

The phenotype of lens-ablated Mexican tetra (Astyanax mexicanus) compared to wild-type surface fish has been described and includes, among other effects, eye degeneration, changes in tooth number and cranial bone changes. Here, we investigate the spatiotemporal expression patterns of several key genes involved in the development of these structures. Specifically, we show that the expression of pitx2, bmp4 and shh is altered in the eye, oral jaw, nasal pit and forebrain in these lens-ablated fish. Furthermore, for the first time, we show altered pitx2 expression in the cavefish, which also has altered eye and tooth phenotypes. We thus provide evidence for a genetic linkage between the eye and tooth modules in this fish species. Furthermore, the altered pitx2 expression pattern, together with the described morphological features of the lens-ablated fish suggests that Astyanax mexicanus could be considered as an alternative teleost model organism in which to study Axenfeld-Rieger syndrome (ARS), a rare autosomal dominant developmental disorder that is associated with PITX2 and which has both ocular and non-ocular abnormalities.


Assuntos
Caraciformes , Proteínas de Peixes , Regulação da Expressão Gênica no Desenvolvimento , Ligação Genética , Cristalino/embriologia , Dente/embriologia , Animais , Segmento Anterior do Olho/anormalidades , Segmento Anterior do Olho/embriologia , Caraciformes/embriologia , Caraciformes/genética , Modelos Animais de Doenças , Anormalidades do Olho/embriologia , Anormalidades do Olho/genética , Oftalmopatias Hereditárias , Proteínas de Peixes/biossíntese , Proteínas de Peixes/genética , Cristalino/patologia
20.
Cytogenet Genome Res ; 154(4): 181-186, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29902798

RESUMO

Oculodentodigital dysplasia (ODDD) is a rare condition characterized by a typical facial appearance and variable findings of the eyes, teeth, and fingers. ODDD is caused by mutations in the GJA1 gene in chromosome 6q22 and inherited in an autosomal dominant manner in the majority of the patients. However, in recent clinical reports, autosomal recessive ODDD cases due to by GJA1 mutations were also described. Here, we report on a 14-year-old boy with microphthalmia, microcornea, narrow nasal bridge, hypoplastic alae nasi, prominent columnella, hypodontia, dental caries, and partial syndactyly of the 2nd and 3rd toes. These clinical findings were concordant with the diagnosis of ODDD, and a novel homozygous mutation (c.442C>T, p.Arg148Ter) was determined in the GJA1 gene leading to a premature stop codon. His phenotypically normal parents were found to be carriers of the same mutation. This is the third family in the literature in which ODDD segregates in an autosomal recessive manner.


Assuntos
Anormalidades Craniofaciais/genética , Anormalidades do Olho/genética , Deformidades Congênitas do Pé/genética , Genes Recessivos , Sindactilia/genética , Anormalidades Dentárias/genética , Adolescente , Códon de Terminação/genética , Conexina 43/genética , Homozigoto , Humanos , Masculino , Mutação
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