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1.
J Hum Genet ; 64(9): 885-890, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31270375

RESUMO

Pediatric hypertension can cause hypertensive emergencies, including hemorrhagic stroke, contributing to rare but serious childhood morbidity and mortality. Renovascular hypertension (RVH) is one of the major causes of secondary hypertension in children. Grange syndrome (MIM#602531) is a rare disease characterized by multiple stenosis or occlusion of the renal, abdominal, coronary, and cerebral arteries, which can cause phenotypes of RVH and fibromuscular dysplasia (MIM#135580). We report the case of a 7-year-old girl with Grange syndrome who showed RVH and multiple seizure episodes. At 1 year of age, she experienced seizures and sequential hemiparesis caused by a left thalamic hemorrhage without cerebral vascular anomalies. Chronic hypertension was observed, and abdominal computed tomography angiography showed characteristic bilateral renal artery stenosis. Whole-exome sequencing revealed a novel homozygous pathogenic variant in the YY1AP1 gene (NM_001198903.1: c.1169del: p.Lys390Argfs*12). Biallelic YY1AP1 mutations are known to cause Grange syndrome. Unlike previously reported patients, our patient presented with intracerebral hemorrhagic stroke without anomalous brain artery or bone fragility. The phenotype in our patient may help better understand this ultra-rare syndrome. Grange syndrome should be considered in patients presenting with childhood-onset hypertension and/or hemorrhagic stroke for early clinical intervention.


Assuntos
Sequência de Aminoácidos , Arteriopatias Oclusivas/genética , Osso e Ossos/anormalidades , Braquidactilia/genética , Proteínas de Ciclo Celular/genética , Cardiopatias Congênitas/genética , Hipertensão Renovascular/genética , Hipertensão/genética , Hemorragias Intracranianas/genética , Deleção de Sequência , Acidente Vascular Cerebral/genética , Sindactilia/genética , Fatores de Transcrição/genética , Arteriopatias Oclusivas/patologia , Arteriopatias Oclusivas/fisiopatologia , Osso e Ossos/patologia , Osso e Ossos/fisiopatologia , Braquidactilia/patologia , Braquidactilia/fisiopatologia , Criança , Feminino , Cardiopatias Congênitas/patologia , Cardiopatias Congênitas/fisiopatologia , Homozigoto , Humanos , Hipertensão/patologia , Hipertensão/fisiopatologia , Hipertensão Renovascular/patologia , Hipertensão Renovascular/fisiopatologia , Hemorragias Intracranianas/patologia , Hemorragias Intracranianas/fisiopatologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Sindactilia/patologia , Sindactilia/fisiopatologia
2.
Eur J Med Genet ; 62(7): 103648, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30998997

RESUMO

CANAC1C encodes for the main cardiac L-type calcium channel and mutations on it lead to a prolonged QT interval in Timothy Syndrome (TS). We provide a new de novo constitutional heterozygote missense variation in CACNA1C in a living adult woman, also carrier of the known c.2146-1G>C heterozygous variation of PKP2 inherited from her father. To our knowledge, this patient is the first to have the two variations in these genes. Theses clinical and molecular findings expand the clinical and molecular spectrum of TS and show the interest of next generation sequencing or whole exome sequencing in rare disorders, atypical or novel phenotype.


Assuntos
Transtorno Autístico/genética , Canais de Cálcio Tipo L/genética , Síndrome do QT Longo/genética , Fenótipo , Sindactilia/genética , Adulto , Transtorno Autístico/patologia , Feminino , Heterozigoto , Humanos , Síndrome do QT Longo/patologia , Mutação , Placofilinas/genética , Sindactilia/patologia
3.
JAAPA ; 32(4): 32-37, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30913147

RESUMO

Although congenital hand anomalies associated with finger nubbins may be produced by amniotic band disruption sequence (ABDS), symbrachydactyly should be considered in the differential diagnosis. ABDS usually affects more than one limb but symbrachydactyly largely is limited to one upper extremity, and has five distinct clinical presentations: short-fingered, atypical cleft, monodactylous, peromelic, and a forearm proximal transverse deficiency. This article discusses the diagnosis of symbrachydactyly compared with ABDS and outlines plans for managing patients with symbrachydactyly.


Assuntos
Síndrome de Bandas Amnióticas , Dedos/anormalidades , Sindactilia/diagnóstico , Dedos do Pé/anormalidades , Feminino , Deformidades Congênitas da Mão/classificação , Humanos , Lactente , Radiografia , Sindactilia/etiologia , Sindactilia/patologia , Sindactilia/cirurgia
5.
Eur J Med Genet ; 62(4): 278-281, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30107244

RESUMO

Mesoaxial syndactyly is characterized by fusion of the central digits. The disorder segregates in autosomal recessive pattern and mapped on human chromosome 17p13.3. Homozygous missense mutations in the BHLHA9 have been reported to cause mesoaxial synostotic syndactyly with phalangeal reduction (MSSD). In the present study, we have investigated a family segregating mesoaxial synostotic syndactyly with phalangeal reduction (MSSD) in autosomal recessive manner. Genotyping using microsatellite markers followed by Sanger sequencing revealed a homozygous deletion and insertion mutation (NM_001164405: c.252_270delinsGCA; p.(Phe85Glufs*108)) in the BHLHA9 gene in affected individuals of the family. This study reports the first frameshift mutation in the BHLHA9 causing mesoaxial synostotic syndactyly and phalangeal reduction.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Dedos/anormalidades , Mutação INDEL , Polidactilia/genética , Sindactilia/genética , Dedos do Pé/anormalidades , Adulto , Criança , Feminino , Dedos/patologia , Mutação da Fase de Leitura , Humanos , Masculino , Linhagem , Polidactilia/patologia , Sindactilia/patologia , Dedos do Pé/patologia
6.
Bone ; 116: 321-332, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30077757

RESUMO

Sclerosteosis (SOST) refers to two extremely rare yet similar skeletal dysplasias featuring a diffusely radiodense skeleton together with congenital syndactyly. SOST1 is transmitted as an autosomal recessive (AR) trait and to date caused by ten homozygous loss-of-function mutations within the gene SOST that encodes the inhibitor of Wnt-mediated bone formation, sclerostin. SOST2 is transmitted as an autosomal dominant (AD) or AR trait and to date caused by one heterozygous or two homozygous loss-of-function mutation(s), respectively, within the gene LRP4 that encodes the sclerostin interaction protein, low-density lipoprotein receptor-related protein 4 (LRP4). Herein, we investigated two teenagers and one middle-aged man with SOST in three families living in the state of Tamil Nadu in southern India. Next generation sequencing of their genomic DNA using our high bone density gene panel revealed SOST1 in the teenagers caused by a unique homozygous nonsense SOST mutation (c.129C > G, p.Tyr43X) and SOST2 in the man caused by homozygosity for one of the two known homozygous missense LRP4 mutations (c.3508C > T, p.Arg1170Trp). He becomes the fourth individual and the first non-European recognized with SOST2. His clinical course was milder than the life-threatening SOST1 demonstrated by the teenagers who suffered blindness, deafness, and raised intracranial pressure, yet his congenital syndactyly was more striking by featuring bony fusion of digits. All three patients were from consanguineous families and heterozygosity for the SOST mutation was documented in the mothers of both teenagers. Thus, on the endogamous genetic background of Indian Tamils, SOST1 from sclerostin deficiency compared to SOST2 from LRP4 deactivation is a more severe and life-threatening disorder featuring complications due to osteosclerosis of especially the skull. In contrast, the syndactyly of SOST2 is particularly striking by involving bony fusion of some digits. Both the SOST and LRP4 mutations in this ethnic population likely reflect genetic founders.


Assuntos
Hiperostose/patologia , Sindactilia/patologia , Adolescente , Sequência de Bases , Proteínas Morfogenéticas Ósseas/genética , Osso e Ossos/metabolismo , Análise Mutacional de DNA , Família , Feminino , Marcadores Genéticos/genética , Humanos , Hiperostose/diagnóstico por imagem , Hiperostose/genética , Índia , Proteínas Relacionadas a Receptor de LDL/genética , Masculino , Pessoa de Meia-Idade , Minerais/metabolismo , Linhagem , Sindactilia/diagnóstico por imagem , Sindactilia/genética
7.
Glia ; 66(11): 2324-2339, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30151840

RESUMO

To study the role of L-type voltage-gated Ca++ channels in oligodendrocyte development, we used a mouse model of Timothy syndrome (TS) in which a gain-of-function mutation in the α1 subunit of the L-type Ca++ channel Cav1.2 gives rise to an autism spectrum disorder (ASD). Oligodendrocyte progenitor cells (OPCs) isolated from the cortex of TS mice showed greater L-type Ca++ influx and displayed characteristics suggestive of advanced maturation compared to control OPCs, including a more complex morphology and higher levels of myelin protein expression. Consistent with this, expression of Cav1.2 channels bearing the TS mutation in wild-type OPCs triggered process formation and promoted oligodendrocyte-neuron interaction via the activation of Ca++ /calmodulin-dependent protein kinase II. To ascertain whether accelerated OPC maturation correlated with functional enhancements, we examined myelination in the TS brain at different postnatal time points. The expression of myelin proteins was significantly higher in the corpus callosum, cortex and striatum of TS animals, and immunohistochemical analysis for oligodendrocyte stage-specific markers revealed an increase in the density of myelinating oligodendrocytes in several areas of the TS brain. Along the same line, electron microscopy studies in the corpus callosum of TS animals showed significant increases both in the percentage of myelinated axons and in the thickness of myelin sheaths. In summary, these data indicate that OPC development and oligodendrocyte myelination is enhanced in the brain of TS mice, and suggest that this mouse model of a syndromic ASD is a useful tool to explore the role of L-type Ca++ channels in myelination.


Assuntos
Transtorno Autístico/complicações , Transtorno Autístico/patologia , Diferenciação Celular/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Síndrome do QT Longo/complicações , Síndrome do QT Longo/patologia , Proteínas da Mielina/metabolismo , Oligodendroglia/fisiologia , Sindactilia/complicações , Sindactilia/patologia , Animais , Animais Recém-Nascidos , Transtorno Autístico/genética , Proteínas Relacionadas à Autofagia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cálcio/metabolismo , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Células Cultivadas , Córtex Cerebral/citologia , Técnicas de Cocultura , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Síndrome do QT Longo/genética , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Transgênicos , Mutação/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neurônios/ultraestrutura , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Células Precursoras de Oligodendrócitos/metabolismo , Células Precursoras de Oligodendrócitos/patologia , Oligodendroglia/patologia , Oligodendroglia/ultraestrutura , Potássio/farmacologia , Sindactilia/genética
8.
JCI Insight ; 3(11)2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29875318

RESUMO

The WNT pathway has become an attractive target for skeletal therapies. High-bone-mass phenotypes in patients with loss-of-function mutations in the LRP5/6 inhibitor Sost (sclerosteosis), or in its downstream enhancer region (van Buchem disease), highlight the utility of targeting Sost/sclerostin to improve bone properties. Sclerostin-neutralizing antibody is highly osteoanabolic in animal models and in human clinical trials, but antibody-based inhibition of another potent LRP5/6 antagonist, Dkk1, is largely inefficacious for building bone in the unperturbed adult skeleton. Here, we show that conditional deletion of Dkk1 from bone also has negligible effects on bone mass. Dkk1 inhibition increases Sost expression, suggesting a potential compensatory mechanism that might explain why Dkk1 suppression lacks anabolic action. To test this concept, we deleted Sost from osteocytes in, or administered sclerostin neutralizing antibody to, mice with a Dkk1-deficient skeleton. A robust anabolic response to Dkk1 deletion was manifest only when Sost/sclerostin was impaired. Whole-body DXA scans, µCT measurements of the femur and spine, histomorphometric measures of femoral bone formation rates, and biomechanical properties of whole bones confirmed the anabolic potential of Dkk1 inhibition in the absence of sclerostin. Further, combined administration of sclerostin and Dkk1 antibody in WT mice produced a synergistic effect on bone gain that greatly exceeded individual or additive effects of the therapies, confirming the therapeutic potential of inhibiting multiple WNT antagonists for skeletal health. In conclusion, the osteoanabolic effects of Dkk1 inhibition can be realized if sclerostin upregulation is prevented. Anabolic therapies for patients with low bone mass might benefit from a strategy that accounts for the compensatory milieu of WNT inhibitors in bone tissue.


Assuntos
Anabolizantes/administração & dosagem , Glicoproteínas/antagonistas & inibidores , Hiperostose/tratamento farmacológico , Osteogênese/efeitos dos fármacos , Sindactilia/tratamento farmacológico , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Anticorpos Neutralizantes/administração & dosagem , Proteínas Morfogenéticas Ósseas/genética , Modelos Animais de Doenças , Feminino , Fêmur/citologia , Fêmur/diagnóstico por imagem , Fêmur/patologia , Marcadores Genéticos/genética , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Hiperostose/diagnóstico por imagem , Hiperostose/genética , Hiperostose/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação com Perda de Função , Masculino , Camundongos , Osteócitos , Coluna Vertebral/citologia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/patologia , Sindactilia/diagnóstico por imagem , Sindactilia/genética , Sindactilia/patologia , Resultado do Tratamento , Regulação para Cima/efeitos dos fármacos , Microtomografia por Raio-X
9.
Am J Med Genet A ; 176(7): 1657-1661, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29736926

RESUMO

Timothy syndrome is characterized by a unique combination of a prolongation of the corrected QT interval of the electrocardiogram and bilateral cutaneous syndactyly of the fingers and the toes and is caused by heterozygous mutations in CACNA1C, a gene encoding a calcium channel. After the discovery of the CACNA1C gene as the causative gene for Timothy syndrome, patients with CACNA1C mutations with QT prolongation but without syndactyly were described. Here, we report a 5-year-old female patient with cutaneous syndactyly, developmental delay, and pulmonary hypertension. Exome analysis showed a previously undescribed de novo heterozygous mutation in the CACNA1C gene, p.Arg1024Gly. To our knowledge, this patient is the first to exhibit syndactyly and to carry a CACNA1C mutation but to not have QT prolongation, which has long been considered an obligatory feature of Timothy syndrome.


Assuntos
Transtorno Autístico/patologia , Canais de Cálcio Tipo L/genética , Deficiências do Desenvolvimento/patologia , Hipertensão Pulmonar/patologia , Síndrome do QT Longo/patologia , Mutação , Sindactilia/patologia , Transtorno Autístico/genética , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Hipertensão Pulmonar/genética , Recém-Nascido , Síndrome do QT Longo/genética , Fenótipo , Sindactilia/genética
10.
PLoS One ; 13(5): e0197535, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29771958

RESUMO

The elaborate anatomy of hands and feet is shaped by coordinated formation of digits and regression of the interdigital mesenchyme (IM). A failure of this process causes persistence of interdigital webbing and consequently cutaneous syndactyly. Bone morphogenetic proteins (BMPs) are key inductive factors for interdigital cell death (ICD) in vivo. NOGGIN (NOG) is a major BMP antagonist that can interfere with BMP-induced ICD when applied exogenously, but its in vivo role in this process is unknown. We investigated the physiological role of NOG in ICD and found that Noggin null mice display cutaneous syndactyly and impaired interdigital mesenchyme specification. Failure of webbing regression was caused by lack of cell cycle exit and interdigital apoptosis. Unexpectedly, Noggin null mutants also exhibit increased Indian hedgehog (Ihh) expression within cartilage condensations that leads to aberrant extension of IHH downstream signaling into the interdigital mesenchyme. A converse phenotype with increased apoptosis and reduced cell proliferation was found in the interdigital mesenchyme of Ihh mutant embryos. Our data point towards a novel role for NOG in balancing Ihh expression in the digits impinging on digit-interdigit cross talk. This suggests a so far unrecognized physiological role for IHH in interdigital webbing biology.


Assuntos
Apoptose/fisiologia , Proteínas Morfogenéticas Ósseas/fisiologia , Proteínas de Transporte/fisiologia , Proteínas Hedgehog/fisiologia , Mesoderma/embriologia , Transdução de Sinais/fisiologia , Sindactilia/fisiopatologia , Animais , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Proteínas de Transporte/genética , Cartilagem/embriologia , Ciclo Celular , Ectoderma/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/deficiência , Proteínas Hedgehog/genética , Mesoderma/citologia , Mesoderma/patologia , Camundongos , Camundongos Knockout , Transdução de Sinais/genética , Organismos Livres de Patógenos Específicos , Sindactilia/embriologia , Sindactilia/patologia , Dedos do Pé/embriologia
11.
J Cell Sci ; 131(9)2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29618634

RESUMO

Given the importance of connexin43 (Cx43, encoded by GJA1) function in the central nervous system and sensory organ processing, we proposed that it would also be crucial in auditory function. To that end, hearing was examined in two mouse models of oculodentodigital dysplasia that globally express GJA1 mutations resulting in mild or severe loss of Cx43 function. Although Cx43I130T/+ mutant mice, with ∼50% Cx43 channel function, did not have any hearing loss, Cx43G60S/+ mutant mice, with ∼20% Cx43 channel function, had severe hearing loss. There was no evidence of inner ear sensory hair cell loss, suggesting that the mechanism for Cx43-linked hearing loss lies downstream in the auditory pathway. Since evidence suggests that Cx26 function is essential for hearing and may be protective against noise-induced hearing loss, we challenged Cx43I130T/+ mice with a loud noise and found that they had a similar susceptibility to noise-induced hearing loss to that found in controls, suggesting that decreased Cx43 function does not sensitize the mice for environmentally induced hearing loss. Taken together, this study suggests that Cx43 plays an important role in baseline hearing and is essential for auditory processing.This article has an associated First Person interview with the first author of the paper.


Assuntos
Conexina 43/genética , Anormalidades Craniofaciais/complicações , Anormalidades Craniofaciais/genética , Anormalidades do Olho/complicações , Anormalidades do Olho/genética , Deformidades Congênitas do Pé/complicações , Deformidades Congênitas do Pé/genética , Perda Auditiva/etiologia , Perda Auditiva/genética , Mutação , Sindactilia/complicações , Sindactilia/genética , Anormalidades Dentárias/complicações , Anormalidades Dentárias/genética , Animais , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Cóclea/metabolismo , Cóclea/patologia , Conexina 43/metabolismo , Anormalidades Craniofaciais/metabolismo , Anormalidades Craniofaciais/patologia , Modelos Animais de Doenças , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Deformidades Congênitas do Pé/metabolismo , Deformidades Congênitas do Pé/patologia , Células Ciliadas Auditivas Internas/metabolismo , Células Ciliadas Auditivas Internas/patologia , Perda Auditiva/patologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sindactilia/metabolismo , Sindactilia/patologia , Anormalidades Dentárias/metabolismo , Anormalidades Dentárias/patologia
12.
J Hum Genet ; 63(7): 851-855, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29703962

RESUMO

3-hydroxyisobutryl-CoA hydrolase (HIBCH) deficiency is a rare inborn error of valine metabolism characterized by neurodegenerative symptoms and caused by recessive mutations in the HIBCH gene. In this study, utilizing whole exome sequencing, we identified two novel splicing mutations of HIBCH (c.304+3A>G; c.1010_1011+3delTGGTA) in a Chinese patient with characterized neurodegenerative features of HIBCH deficiency and bilateral syndactyly which was not reported in previous studies. Functional tests showed that both of these two mutations destroyed the normal splicing and reduced the expression of HIBCH protein. Through a literature review, a potential phenotype-genotype correlation was found that patients carrying truncating mutations tended to have more severe phenotypes compared with those with missense mutations. Our findings would widen the mutation spectrum of HIBCH causing HIBCH deficiency and the phenotypic spectrum of the disease. The potential genotype-phenotype correlation would be profitable for the treatment and management of patients with HIBCH deficiency.


Assuntos
Anormalidades Múltiplas/genética , Erros Inatos do Metabolismo dos Aminoácidos/genética , Mutação , Sindactilia/genética , Tioléster Hidrolases/deficiência , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/enzimologia , Anormalidades Múltiplas/patologia , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico por imagem , Erros Inatos do Metabolismo dos Aminoácidos/enzimologia , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Sequência de Bases , Feminino , Expressão Gênica , Genes Recessivos , Estudos de Associação Genética , Humanos , Lactente , Masculino , Linhagem , Processamento de RNA , Sindactilia/diagnóstico por imagem , Sindactilia/enzimologia , Sindactilia/patologia , Tioléster Hidrolases/genética , Sequenciamento Completo do Exoma
13.
Metabolism ; 80: 38-47, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29080811

RESUMO

Sclerosteosis and van Buchem disease (VBD) are two rare autosomal recessive disorders that results from osteoblast hyperactivity, in which progressive bone overgrowth leads to very dense bones, distortion of the face, and entrapment of cranial nerves. Sclerosteosis is caused by loss-of-function mutations in the SOST gene which encodes a secreted glycoprotein, sclerostin. VBD is caused by a noncoding deletion that removes a SOST-specific regulatory element in bone. In bone, SOST is expressed predominantly by osteocytes and sclerostin suppresses bone formation by inhibiting the canonical Wnt signaling pathway. Here we describe how human genetics studies in sclerosteosis and VBD patients, in combination with the generation of transgenic and knockout mice, has led to a better understanding of the role of sclerostin in bone metabolism.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Marcadores Genéticos/genética , Hiperostose/genética , Osteocondrodisplasias/genética , Sindactilia/genética , Animais , Modelos Animais de Doenças , Humanos , Hiperostose/patologia , Osteocondrodisplasias/patologia , Sindactilia/patologia
14.
Am J Med Genet A ; 173(12): 3226-3230, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29088509

RESUMO

The STAR syndrome is a rare X-linked dominant developmental disorder caused by point mutations in the single FAM58A gene or deletions involving FAM58A and its flanking genes. The STAR phenotype is characterized by a rather homogeneous constellation of facial dysmorphisms and malformations summarized by its acronym, Syndactyly, Telecanthus, Anogenital, and Renal malformations. Here we describe a female patient with STAR syndrome and a 130 kb deletion at Xq28, including the FAM58A gene. She presented with cleft lip palate, omphalocele, and cerebral malformations not previously considered part of the phenotypic spectrum of this syndrome. She died at 6 weeks from respiratory failure.


Assuntos
Canal Anal/anormalidades , Fissura Palatina/genética , Ciclinas/genética , Hipertelorismo/genética , Rim/anormalidades , Sindactilia/genética , Dedos do Pé/anormalidades , Anormalidades Urogenitais/genética , Canal Anal/patologia , Bandeamento Cromossômico , Fissura Palatina/diagnóstico , Fissura Palatina/patologia , Evolução Fatal , Feminino , Humanos , Hipertelorismo/diagnóstico , Hipertelorismo/patologia , Recém-Nascido , Cariotipagem , Rim/patologia , Mutação Puntual , Sindactilia/diagnóstico , Sindactilia/patologia , Dedos do Pé/patologia , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/patologia
15.
Medicine (Baltimore) ; 96(30): e7639, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28746226

RESUMO

Numerous techniques have been developed that use various flaps to treat syndactyly. Skin grafts have often been used to cover remaining surgical defects. The long-term aim of surgery is to find new methods of separating the digits without using skin grafts. This paper describes a new surgical technique for the correction of simple, incomplete, and complete syndactyly. The technique consists of a dorsal double-wing flap to cover the newly created web space and zigzag incisions in the fingers, thus avoiding the use of skin grafts in this space. Overall, 35 web spaces in 24 patients were treated using this technique. Patient follow-up ranged from 6 months to nearly 5 years. There were no complications such as hematoma, infection or flap necrosis, and no fingers needed skin grafts after separation. The average operative time for each web space was approximately 45 minutes. Ninety-seven percent of patients treated with the dorsal double-wing flap procedure achieved good function, and superior cosmetic results following a single surgery. The technique is simple, rapid, safe, and easily performed and does not require the use of skin grafts.


Assuntos
Dedos/cirurgia , Procedimentos Cirúrgicos Reconstrutivos , Retalhos Cirúrgicos , Sindactilia/cirurgia , Criança , Pré-Escolar , Feminino , Dedos/patologia , Humanos , Lactente , Masculino , Duração da Cirurgia , Estudos Retrospectivos , Retalhos Cirúrgicos/patologia , Sindactilia/patologia , Resultado do Tratamento
16.
Stem Cell Reports ; 9(1): 50-57, 2017 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-28648896

RESUMO

L-type calcium channel CaV1.2 plays an essential role in cardiac function. The gain-of-function mutations in CaV1.2 have been reported to be associated with Timothy syndrome, a disease characterized by QT prolongation and syndactyly. Previously we demonstrated that roscovitine, a cyclin-dependent kinase (CDK) inhibitor, could rescue the phenotypes in induced pluripotent stem cell-derived cardiomyocytes from Timothy syndrome patients. However, exactly how roscovitine rescued the phenotypes remained unclear. Here we report a mechanism potentially underlying the therapeutic effects of roscovitine on Timothy syndrome cardiomyocytes. Our results using roscovitine analogs and CDK inhibitors and constructs demonstrated that roscovitine exhibits its therapeutic effects in part by inhibiting CDK5. The outcomes of this study allowed us to identify a molecular mechanism whereby CaV1.2 channels are regulated by CDK5. This study provides insights into the regulation of cardiac calcium channels and the development of future therapeutics for Timothy syndrome patients.


Assuntos
Transtorno Autístico/tratamento farmacológico , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Síndrome do QT Longo/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Sindactilia/tratamento farmacológico , Transtorno Autístico/metabolismo , Transtorno Autístico/patologia , Canais de Cálcio Tipo L/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , Quinase 5 Dependente de Ciclina/metabolismo , Humanos , Síndrome do QT Longo/metabolismo , Síndrome do QT Longo/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Roscovitina , Sindactilia/metabolismo , Sindactilia/patologia
17.
Rom J Morphol Embryol ; 58(1): 277-280, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28523332

RESUMO

Apert syndrome - acrocephalosyndactyly - is a rare autosomal dominant disorder representing 1:65 000 cases of living newborns. Characteristic malformations of the Apert syndrome are early craniostenosis, microviscerocranium and II-V finger syndactyly of hand and toes with proximal phalanx of the bilateral thumb "in delta". It is difficult to determine prenatal diagnosis in the second quarter, when examining the morphology of fetal signs; the dysmorphism signs appeared in the third pregnancy quarter. We present here the case of a newborn with Apert syndrome that was born prematurely in our Clinic after a monitored pregnancy, where there was issued a suspicion of cranio-facial dysmorphism, malposition and malformation of the feet and hands in the third quarter of prenatal pregnancy. The diagnosis of Apert syndrome was placed on clinical signs, laboratory and genetic tests. The clinical outcome of the baby in the maternity was favorable, the therapeutic management being established by a multidisciplinary team. Immediate complications were due to the case of prematurity: respiratory distress syndrome and the characteristics of the syndrome: micrognathia and naso-facial dysmorphism, syndactyly, bilateral foot metatarsus adductus.


Assuntos
Acrocefalossindactilia/patologia , Acrocefalossindactilia/diagnóstico por imagem , Feminino , Humanos , Recém-Nascido , Gravidez , Reticulocitose , Sindactilia/diagnóstico por imagem , Sindactilia/patologia
18.
J Bone Miner Res ; 32(8): 1739-1749, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28477420

RESUMO

Sclerosteosis is a rare autosomal recessive bone disorder marked by hyperostosis of the skull and tubular bones. Initially, we and others reported that sclerosteosis was caused by loss-of-function mutations in SOST, encoding sclerostin. More recently, we identified disease-causing mutations in LRP4, a binding partner of sclerostin, in three sclerosteosis patients. Upon binding to sclerostin, LRP4 can inhibit the canonical WNT signaling that is known to be an important pathway in the regulation of bone formation. To further investigate the role of LRP4 in the bone formation process, we generated an Lrp4 mutated sclerosteosis mouse model by introducing the p.Arg1170Gln mutation in the mouse genome. Extensive analysis of the bone phenotype of the Lrp4R1170Q/R1170Q knock-in (KI) mouse showed the presence of increased trabecular and cortical bone mass as a consequence of increased bone formation by the osteoblasts. In addition, three-point bending analysis also showed that the increased bone mass results in increased bone strength. In contrast to the human sclerosteosis phenotype, we could not observe syndactyly in the forelimbs or hindlimbs of the Lrp4 KI animals. Finally, we could not detect any significant changes in the bone formation and resorption markers in the serum of the mutant mice. However, the serum sclerostin levels were strongly increased and the level of sclerostin in the tibia was decreased in Lrp4R1170Q/R1170Q mice, confirming the role of LRP4 as an anchor for sclerostin in bone. In conclusion, the Lrp4R1170Q/R1170Q mouse is a good model for the human sclerosteosis phenotype caused by mutations in LRP4 and can be used in the future for further investigation of the mechanism whereby LRP4 regulates bone formation. © 2017 American Society for Bone and Mineral Research.


Assuntos
Glicoproteínas/metabolismo , Homozigoto , Hiperostose , Mutação de Sentido Incorreto , Receptores de LDL , Sindactilia , Tíbia/metabolismo , Via de Sinalização Wnt , Substituição de Aminoácidos , Animais , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Glicoproteínas/genética , Humanos , Hiperostose/genética , Hiperostose/metabolismo , Hiperostose/patologia , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , Camundongos Knockout , Receptores de LDL/genética , Receptores de LDL/metabolismo , Sindactilia/genética , Sindactilia/metabolismo , Sindactilia/patologia , Tíbia/patologia
19.
Nature ; 545(7652): 54-59, 2017 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-28445465

RESUMO

The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome-a neurodevelopmental disorder that is caused by mutations in the CaV1.2 calcium channel-interneurons display abnormal migratory saltations. We also show that after migration, interneurons functionally integrate with glutamatergic neurons to form a microphysiological system. We anticipate that this approach will be useful for studying neural development and disease, and for deriving spheroids that resemble other brain regions to assemble circuits in vitro.


Assuntos
Neurônios/citologia , Prosencéfalo/citologia , Prosencéfalo/crescimento & desenvolvimento , Esferoides Celulares/citologia , Transtorno Autístico/genética , Transtorno Autístico/patologia , Linhagem Celular , Movimento Celular , Células Cultivadas , Feminino , Neurônios GABAérgicos/citologia , Ácido Glutâmico/metabolismo , Humanos , Interneurônios/citologia , Interneurônios/patologia , Síndrome do QT Longo/genética , Síndrome do QT Longo/patologia , Masculino , Modelos Biológicos , Neurogênese , Neurônios/patologia , Células-Tronco Pluripotentes/citologia , Prosencéfalo/anatomia & histologia , Sinapses/fisiologia , Sindactilia/genética , Sindactilia/patologia
20.
J Bone Miner Res ; 32(6): 1368-1385, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28177159

RESUMO

We present for the first time the generation of induced pluripotent stem cells (iPSCs) from a patient with a connexin-linked disease. The importance of gap junctional intercellular communication in bone homeostasis is exemplified by the autosomal dominant developmental disorder oculodentodigital dysplasia (ODDD), which is linked to mutations in the GJA1 (Cx43) gene. ODDD is characterized by craniofacial malformations, ophthalmic deficits, enamel hypoplasia, and syndactyly. In addition to harboring a Cx43 p.V216L mutation, ODDD iPSCs exhibit reduced Cx43 mRNA and protein abundance when compared to control iPSCs and display impaired channel function. Osteogenic differentiation involved an early, and dramatic downregulation of Cx43 followed by a slight upregulation during the final stages of differentiation. Interestingly, osteoblast differentiation was delayed in ODDD iPSCs. Moreover, Cx43 subcellular localization was altered during chondrogenic differentiation of ODDD iPSCs compared to controls and this may have contributed to the more compact cartilage pellet morphology found in differentiated ODDD iPSCs. These studies highlight the importance of Cx43 expression and function during osteoblast and chondrocyte differentiation, and establish a potential mechanism for how ODDD-associated Cx43 mutations may have altered cell lineages involved in bone and cartilage development. © 2017 American Society for Bone and Mineral Research.


Assuntos
Diferenciação Celular , Conexina 43/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Mutação/genética , Condrogênese , Colágeno/metabolismo , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Derme/patologia , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Fibroblastos/metabolismo , Deformidades Congênitas do Pé/genética , Deformidades Congênitas do Pé/patologia , Junções Comunicantes/metabolismo , Humanos , Osteogênese , Sindactilia/genética , Sindactilia/patologia , Anormalidades Dentárias/genética , Anormalidades Dentárias/patologia
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