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1.
Gene ; 733: 144369, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-31972311

RESUMO

MAP2K1 encodes mitogen-activated protein kinase 1 (MEK1). Mutations in MAP2K1 lead to continuous activation of MEK/ERK signaling pathway, giving rise to cardio-facio-cutaneous syndrome (CFCS). However, the molecular mechanisms of abnormal activation of MEK/ERK signaling pathway and the role of autophagy, if any, in manifesting CFCS in MAP2K mutants remain unclear. Here, we report three Chinese children with CFCS having MAP2K1 pathogenic variants, identified by exome sequencing. They presented with dysmorphic facial features, seizures, psychomotor retardation, and short stature. Additionally, the third child showed pulmonary valve stenosis, multiple skeletal deformities, and osteoporosis. Whole exome sequencing revealed two heterozygous missense mutations in exon 3 of MAP2K1 (c.383G>T; p.Gly128Val and c.389A>G; p.Tyr130Cys), as well as a novel heterozygous missense variant (c.170A>T; p.Lys57Met) in exon 2 of MAP2K1. In SH-SY5Y cells, we identified, for the first time, that MAP2K1 mutations can activate the p-ERK-dependent cell cycle progression and autophagy, and cause CFCS. Our results extended the mutational spectrum of MAP2K1, examined the role of MEK1 protein in nerve cell functions, and demonstrated, for the first time, that autophagy may mediate the altered MAP2K1 function, leading to CFCS phenotypes.


Assuntos
Autofagia , Displasia Ectodérmica/patologia , Insuficiência de Crescimento/patologia , Cardiopatias Congênitas/patologia , MAP Quinase Quinase 1/genética , Mutação , Adulto , Apoptose , Ciclo Celular , Movimento Celular , Proliferação de Células , Criança , Displasia Ectodérmica/genética , Displasia Ectodérmica/metabolismo , Facies , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/metabolismo , Feminino , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Humanos , Lactente , Sistema de Sinalização das MAP Quinases , Masculino , Fenótipo , Fosforilação , Células Tumorais Cultivadas
2.
Horm Res Paediatr ; 91(4): 223-240, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31195397

RESUMO

Based on a recent Dutch national guideline, we propose a structured stepwise diagnostic approach for children with growth failure (short stature and/or growth faltering), aiming at high sensitivity for pathologic causes at acceptable specificity. The first step is a detailed clinical assessment, aiming at obtaining relevant clinical clues from the medical history (including family history), physical examination (emphasising head circumference, body proportions and dysmorphic features) and assessment of the growth curve. The second step consists of screening: a radiograph of the hand and wrist (for bone age and assessment of anatomical abnormalities suggestive for a skeletal dysplasia) and laboratory tests aiming at detecting disorders that can present as isolated short stature (anaemia, growth hormone deficiency, hypothyroidism, coeliac disease, renal failure, metabolic bone diseases, renal tubular acidosis, inflammatory bowel disease, Turner syndrome [TS]). We advise molecular array analysis rather than conventional karyotyping for short girls because this detects not only TS but also copy number variants and uniparental isodisomy, increasing diagnostic yield at a lower cost. Third, in case of diagnostic clues for primary growth disorders, further specific testing for candidate genes or a hypothesis-free approach is indicated; suspicion of a secondary growth disorder warrants adequate further targeted testing.


Assuntos
Determinação da Idade pelo Esqueleto , Variações do Número de Cópias de DNA , Insuficiência de Crescimento , Hormônio do Crescimento Humano , Cariotipagem , Dissomia Uniparental , Criança , Pré-Escolar , Insuficiência de Crescimento/sangue , Insuficiência de Crescimento/diagnóstico , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Feminino , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/deficiência , Humanos , Masculino
3.
J Vet Diagn Invest ; 31(4): 601-603, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31006384

RESUMO

Six, 5-6-wk-old pigs, from 3 farms of the same company, with significant loss of body condition were submitted for postmortem evaluation. Macroscopically, the main lesion observed in all of the pigs was thymic atrophy. Microscopically, all of the pigs had thymic atrophy, superficial lymphocytic fundic gastritis, atrophic enteritis, superficial colitis, and neutrophilic and lymphocytic rhinitis, leading to a diagnosis of porcine periweaning failure-to-thrive syndrome. In the pigs from 2 of the farms, many of the thymic corpuscles had infiltrates of neutrophils and degenerate cells, in some cases infiltrating the surrounding parenchyma.


Assuntos
Insuficiência de Crescimento/veterinária , Doenças dos Suínos/diagnóstico , Timo/patologia , Animais , Insuficiência de Crescimento/diagnóstico , Insuficiência de Crescimento/patologia , Suínos , Doenças dos Suínos/patologia , Desmame
4.
J Hum Genet ; 64(5): 499-504, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30842599

RESUMO

The genotype-phenotype correlation in BRAF variant in cardio-facio-cutaneous (CFC) syndrome is not clearly defined. Here we report a case with a severe clinical phenotype and a novel BRAF variant, p.Leu485del. The present case showed severe intellectual disability, impaired awareness, hyperekplexia, involuntary movements, early onset refractory seizures, and delayed myelination on brain magnetic resonance imaging as well as a polycystic and dysplastic kidney, which are previously unreported anomalies in CFC or RAS/mitogen-activated protein kinase syndromes related to BRAF variant. CFC syndrome, especially caused by BRAF variant, should be included in the differential diagnosis of patients with developmental and epileptic encephalopathies and hyperekplexia. Furthermore, we need to keep in mind that missense variants or the deletion of Leucine-485 may be associated with severe symptoms.


Assuntos
Sequência de Aminoácidos , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , Cardiopatias Congênitas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Deleção de Sequência , Pré-Escolar , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/patologia , Cardiopatias Congênitas/patologia , Humanos , Leucina , Masculino , Índice de Gravidade de Doença
5.
Am J Med Genet C Semin Med Genet ; 181(2): 208-217, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30896080

RESUMO

RASopathies are a group of genetic disorders due to dysregulation of the RAS-MAPK signaling pathway, which is important in regulating cell growth, proliferation, and differentiation. These include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), cardiofaciocutaneous (CFC) syndrome, and Costello syndrome (CS), clinical manifestations include growth retardation, developmental delay, cardiac defects, and specific dysmorphic features. There were abundant publications describing the genotype and phenotype from the Western populations. However, detailed study of RASopathies in Chinese population is lacking. We present here the largest cohort of RASopathies ever reported in Chinese populations, detailing the mutation spectrum and clinical phenotypes of these patients. The Clinical Genetic Service, Department of Health, and Queen Mary Hospital are tertiary referral centers for genetic disorders in Hong Kong. We retrospectively reviewed all the genetically confirmed cases of RASopathies, including NS, NSML, CFC syndrome, and CS, over the past 29 years (from 1989 to 2017). Analyses of the mutation spectrum and clinical phenotypes were performed. One hundred and ninety-one ethnic Chinese patients with genetically confirmed RASopathies were identified, including 148 patients with NS, 23 NSML, 12 CFC syndrome, and eight CS. We found a lower incidence of hypertrophic cardiomyopathy in individuals with NSML (27.3%), and NS caused by RAF1 mutations (62.5%). Another significant finding was for those NS patients with myeloproliferative disorder, the mutations fall within Exon 3 of PTPN11 but not only restricted to the well-known hotspots, that is, p.Asp61 and p.Thr731, which suggested that re-evaluation of the current tumor surveillance recommendation maybe warranted.


Assuntos
Mutação , Fenótipo , Proteínas ras/genética , Síndrome de Costello/genética , Síndrome de Costello/patologia , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Feminino , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Hong Kong , Humanos , Síndrome LEOPARD/genética , Síndrome LEOPARD/patologia , Sistema de Sinalização das MAP Quinases/genética , Masculino , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Estudos Retrospectivos
6.
J Clin Res Pediatr Endocrinol ; 11(3): 293-300, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-30859796

RESUMO

Objective: Insulin like growth factors-1 (IGF-1) is essential for normal in utero and postnatal human growth. It mediates its effects through the IGF-1 receptor (IGF1R), a widely expressed cell surface tyrosine kinase receptor. The aim of the study was to analyze pre- and post-natal growth, clinical features and laboratory findings in a small for gestational age (SGA) girl in whom discordant postnatal growth persisted and her appropriate for gestational age (AGA) brother. Methods: A girl born with a low weight and length [-2.3 and -2.4 standard deviation (SD) score (SDS), respectively] but borderline low head circumference (-1.6 SD) presented with a height of -1.7 SDS, in contrast to a normal height twin brother (0.0 SDS). IGF-1 resistance was suspected because of elevated serum IGF-1 levels. Results: Sequencing revealed the presence of a previously described pathogenic heterozygous mutation (p.Glu1050Lys) in the SGA girl which was not present in the parents nor in the AGA twin brother. Conclusion: The pathogenic IGF1R mutation in this girl led to intrauterine growth retardation followed by partial postnatal catch-up growth. Height in mid-childhood was in the lower half of the reference range, but still 1.7 SD shorter than her twin brother.


Assuntos
Insuficiência de Crescimento/patologia , Retardo do Crescimento Fetal/patologia , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Mutação , Receptor IGF Tipo 1/genética , Estatura , Insuficiência de Crescimento/sangue , Insuficiência de Crescimento/genética , Feminino , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/genética , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional/sangue , Fator de Crescimento Insulin-Like I/análise , Masculino , Prognóstico , Gêmeos Dizigóticos
7.
Am J Med Genet A ; 179(4): 628-633, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30693654

RESUMO

Focal dermal hypoplasia (FDH) is a rare genetic disorder caused by mutations in the PORCN gene located on the X chromosome. Short stature was previously noted to be a common finding in FDH, however the etiology of this is unclear. The present study sought to elucidate specific causes for short stature by assessing growth charts, determining bone ages and auxologic measurements, examining laboratory data for the common causes of growth failure, assessing dietary intake, and performing a growth hormone stimulation test. Sixteen patients with FDH between the ages of 3 and 18 years of age consented to the study. While 11 out of 16 patients had short stature based on height less than 2 standard deviations below mid-parental target height percentile and bone age not suggestive of likely catch-up growth, only four had a BMI less than the 5th percentile for age. Laboratory studies did not support a gastrointestinal, allergy or autoimmune cause of growth failure. Three patients had results suggestive of possible growth hormone deficiency. Although short stature is a common feature in FDH, our data suggests that severe undernutrition is not common in this group and that there may be underlying treatable causes for this short stature in some patients.


Assuntos
Insuficiência de Crescimento/etiologia , Insuficiência de Crescimento/patologia , Hipoplasia Dérmica Focal/complicações , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Fenótipo
9.
Epileptic Disord ; 20(4): 313-318, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30078785

RESUMO

Mutation of the gene encoding ubiquitin-like modifier-activating enzyme 5 (UBA5) causes autosomal recessive early-onset epileptic encephalopathy. UBA5 acts as an E1-activating enzyme in the ubiquitin-fold modifier 1 pathway, which is important for unfolded protein elimination and regulation of apoptosis, and has been linked to human diseases. We identified biallelic mutations in UBA5 in a Japanese boy with intractable West syndrome, profound failure to thrive, and severe cerebral and cerebellar atrophy. The boy presented with epileptic spasms and hypsarrhythmia at the age of three months. He was diagnosed with West syndrome, however, treatments with adrenocorticotropic hormone and several antiepileptic drugs were ineffective. MRI findings were initially normal, but subsequently showed a progression of cerebellar and cerebral atrophy. By the age of seven years, he had not achieved any developmental milestones; he had daily epileptic spasms and tonic seizures and profound failure to thrive. Gene analysis revealed novel compound heterozygous mutations in UBA5; a microdeletion encompassing the entire UBA5 gene and a putative disease-causing missense mutation in the catalytic domain. These biallelic variants may have caused loss of function, accounting for the observed clinical symptoms. Intractable infantile epileptic spasms, failure to thrive, and severe neurological impairment may be characteristic of patients with UBA5 mutations.


Assuntos
Cerebelo/patologia , Cérebro/patologia , Insuficiência de Crescimento , Espasmos Infantis , Enzimas Ativadoras de Ubiquitina/genética , Atrofia/patologia , Cerebelo/diagnóstico por imagem , Cérebro/diagnóstico por imagem , Criança , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Insuficiência de Crescimento/fisiopatologia , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Mutação , Espasmos Infantis/genética , Espasmos Infantis/patologia , Espasmos Infantis/fisiopatologia
10.
Am J Med Genet A ; 176(7): 1670-1674, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29799162

RESUMO

Cardio-facio-cutaneous syndrome (CFCS), a rare congenital disorder of RASopathies, displays high phenotypic variability. Complications during pregnancy and in the perinatal period are commonly reported. Polyhydramnios is observed in over half of pregnancies and might occur with fetal macrocephaly, macrosomia, and/or heart defects. Premature birth is not uncommon and any complications like respiratory insufficiency, edema, and feeding difficulties are present and might delay accurate clinical diagnosis. Besides neonatal complications, CFCS newborns and later infants have distinctive dysmorphic features usually accompanied by neurological (hypotonia with motor delay, neurocognitive delay) findings. Also, heart defects usually present at birth. Herein, we present the case of a female baby born prematurely from a pregnancy complicated with polyhydramnios, presenting at birth with craniofacial features typical for RASopathies, heart defects, neurological abnormalities, and hyperkeratosis unusual for a neonatal period. Due to the presence of a heart defect and other complications related to premature birth, the course of the disease was severe with a fatal outcome at the age of 9 months. The RASopathy, particularly CFCS, clinical diagnosis was confirmed and de novo p.Phe57Ile mutation in MAP2K2 was identified.


Assuntos
Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , MAP Quinase Quinase 2/genética , Facies , Evolução Fatal , Feminino , Humanos , Recém-Nascido , Mutação , Fenótipo
11.
Am J Med Genet A ; 176(7): 1637-1640, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29704308

RESUMO

Cardiofaciocutaneous (CFC) syndrome is a RASopathy characterized by intellectual disability, congenital heart defects, a characteristic facial appearance, gastro-intestinal complications, ectodermal abnormalities and growth failure. The RASopathies result from germline mutations in the Ras/Mitogen-activated-protein-kinase (MAPK) pathway. CFC is associated with mutations in BRAF, KRAS, MEK1 and MEK2. CFC has been considered a "sporadic" disorder, with minimal recurrence risk to siblings. In recent years, vertical transmission of CFC has been seen in mutations involving the MEK2 and KRAS genes, but has not previously been reported with BRAF mutations. Two brothers with clinical features of CFC and mutations in BRAF (c.770A > G, p.Gln257Arg) are described. Neither parent (both phenotypically normal) had the BRAF mutation in their leukocyte DNA. Although this mutation is one of the most common mutations in CFC, to our knowledge, this is the first molecularly confirmed BRAF mutation causing CFC in siblings. This observation also likely represents the first description of germ cell mosaicism in CFC and so it is important to provide optimal genetic counselling to families regarding the risk of reoccurrence.


Assuntos
Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Gônadas/metabolismo , Gônadas/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Mosaicismo , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Facies , Feminino , Humanos , Recém-Nascido , Masculino , Pais , Fenótipo , Irmãos
12.
Sci Rep ; 8(1): 2421, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29402968

RESUMO

RASopathies are a group of heterogeneous conditions caused by germline mutations in RAS/MAPK signalling pathway genes. With next-generation sequencing (NGS), sequencing capacity is no longer a limitation to molecular diagnosis. Instead, the rising number of variants of unknown significance (VUSs) poses challenges to clinical interpretation and genetic counselling. We investigated the potential of an integrated pipeline combining NGS and the functional assessment of variants for the diagnosis of RASopathies. We included 63 Chinese patients with RASopathies that had previously tested negative for PTPN11 and HRAS mutations. In these patients, we performed a genetic analysis of genes associated with RASopathies using a multigene NGS panel and Sanger sequencing. For the VUSs, we evaluated evidence from genetic, bioinformatic and functional data. Twenty disease-causing mutations were identified in the 63 patients, providing a primary diagnostic yield of 31.7%. Four VUSs were identified in five patients. The functional assessment supported the pathogenicity of the RAF1 and RIT1 VUSs, while the significance of two VUSs in A2ML1 remained unclear. In summary, functional analysis improved the diagnostic yield from 31.7% to 36.5%. Although technically demanding and time-consuming, a functional genetic diagnostic analysis can ease the clinical translation of these findings to aid bedside interpretation.


Assuntos
Síndrome de Costello/genética , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , Cardiopatias Congênitas/genética , Neurofibromatose 1/genética , Síndrome de Noonan/genética , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas ras/genética , Adolescente , Animais , Bioensaio , Criança , Pré-Escolar , Biologia Computacional , Síndrome de Costello/patologia , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/patologia , Feminino , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mutação em Linhagem Germinativa , Cardiopatias Congênitas/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , MAP Quinase Quinase 1/genética , Masculino , Mutação de Sentido Incorreto , Neurofibromatose 1/patologia , Síndrome de Noonan/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína SOS1/genética , Peixe-Zebra , alfa-Macroglobulinas/genética
14.
Paediatr Int Child Health ; 38(4): 277-280, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-28557682

RESUMO

A 3-month-old boy presented with failure to thrive and a history of a prenatally detected unilateral hydroureteronephrosis which was confirmed after birth. His growth and developmental milestones had been normal during the first 2 months but in the third month his appetite was poor with reduced intake but no vomiting. At presentation, his temperature was normal, there was mild dehydration and there was weight loss (his weight had decreased by 270 g in the past month). Haemoglobin was 11.9 g/dL, total white cell count 20.2 × 109/L (7-15) [neutrophils 30% (39-75) and lymphocytes 61% (16-47)], platelets 702 × 109/L (150-450), BUN12.1 mmol/L (2.1-16.1), serum creatinine 35.4 µmol/L (15.0-37.1), sodium 126 mmol/L (135-144), potassium 6.8 mmol/L (3.6-4.8), chloride 88 mmol/L (98-106) and bicarbonate 14 mmol/L (19-24). Intravenous rehydration with sodium chloride 0.9% solution was commenced and he was transferred to the paediatric intensive care unit. A salt-wasting syndrome was suspected and a differential diagnosis included adrenal insufficiency, pseudohypoaldosteronism and congenital adrenal hyperplasia (owing to 21-hydroxylase deficiency). Urinalysis confirmed a urinary tract infection. Serum aldosterone was 3608 ng/dL (3.7-43.2), plasma renin activity > 38.9 pmol/L (<0.85), random cortisol 459 nmol/L (74-289), adrenocorticotropic hormone (ACTH) 6.01 pmol/L (1.32-6.60) and 17-hydroxyprogesterone 4.01 nmol/L (<3.2). Treatment of the urinary tract infection was followed by normalisation of serum electrolytes and other biochemical abnormalities, return of appetite and normal growth, which confirmed the diagnosis of transient pseudohypoaldosteronsim (TPHA). TPHA is discussed and insight provided to enable early recognition and adequate treatment of this rare clinical entity.


Assuntos
Insuficiência de Crescimento/etiologia , Hiperpotassemia/etiologia , Pseudo-Hipoaldosteronismo/complicações , Pseudo-Hipoaldosteronismo/diagnóstico , Glândulas Suprarrenais/patologia , Anti-Infecciosos/uso terapêutico , Análise Química do Sangue , Insuficiência de Crescimento/patologia , Humanos , Hiperpotassemia/patologia , Lactente , Masculino , Pseudo-Hipoaldosteronismo/patologia , Resultado do Tratamento , Urinálise , Infecções Urinárias/diagnóstico , Infecções Urinárias/tratamento farmacológico
15.
Mol Psychiatry ; 23(8): 1687-1698, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29158583

RESUMO

Ras/MAPK pathway signaling is a major participant in neurodevelopment, and evidence suggests that BRAF, a key Ras signal mediator, influences human behavior. We studied the role of the mutation BRAFQ257R, the most common cause of cardiofaciocutaneous syndrome (CFC), in an induced pluripotent stem cell (iPSC)-derived model of human neurodevelopment. In iPSC-derived neuronal cultures from CFC subjects, we observed decreased p-AKT and p-ERK1/2 compared to controls, as well as a depleted neural progenitor pool and rapid neuronal maturation. Pharmacological PI3K/AKT pathway manipulation recapitulated cellular phenotypes in control cells and attenuated them in CFC cells. CFC cultures displayed altered cellular subtype ratios and increased intrinsic excitability. Moreover, in CFC cells, Ras/MAPK pathway activation and morphological abnormalities exhibited cell subtype-specific differences. Our results highlight the importance of exploring specific cellular subtypes and of using iPSC models to reveal relevant human-specific neurodevelopmental events.


Assuntos
Displasia Ectodérmica/metabolismo , Insuficiência de Crescimento/metabolismo , Cardiopatias Congênitas/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Sistema de Sinalização das MAP Quinases , Neurogênese/fisiologia , Neurônios/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Técnicas de Cultura de Células , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/patologia , Cardiopatias Congênitas/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Mutação , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo
16.
Horm Res Paediatr ; 89(1): 38-46, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29161691

RESUMO

BACKGROUND/AIMS: Carney complex (CNC) is a rare syndrome associated with multiple tumors and several other unique manifestations. We describe the clinical, genetic, and laboratory findings in a cohort of patients with CNC and failure to thrive (FTT). METHODS: A retrospective case series of pediatric patients with CNC presenting with FTT. RESULTS: We describe a patient with infantile Cushing syndrome (CS) who presented with severe FTT and liver disease; the patient was subsequently diagnosed with CNC. This led to the realization that at least 10 other patients with CNC and FTT have been investigated in the last 22 years at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Four of those had primary pigmented nodular adrenocortical disease (PPNAD), 2 had cardiac myxomas, and 3 had liver disease. CONCLUSION: Pediatric patients with CNC may present with FTT whose primary cause is variable and includes CS due to PPNAD, hepatic involvement, and other manifestations of CNC. FTT due to liver disease and/or other causes is a unique new presentation of this rare syndrome with which clinicians need to be familiar.


Assuntos
Complexo de Carney , Insuficiência de Crescimento , Adolescente , Adulto , Complexo de Carney/diagnóstico , Complexo de Carney/genética , Complexo de Carney/patologia , Criança , Pré-Escolar , Insuficiência de Crescimento/diagnóstico , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos Retrospectivos
17.
Int J Mol Sci ; 18(12)2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29194391

RESUMO

Cardiofaciocutaneous (CFC) syndrome is a rare genetic disorder caused by mutations in the extracellular signal-regulated kinase (ERK) signaling. However, little is known about how aberrant ERK signaling is associated with the defective bone development manifested in most CFC syndrome patients. In this study, induced pluripotent stem cells (iPSCs) were generated from dermal fibroblasts of a CFC syndrome patient having rapidly accelerated fibrosarcoma kinase B (BRAF) gain-of-function mutation. CFC-iPSCs were differentiated into mesenchymal stem cells (CFC-MSCs) and further induced to osteoblasts in vitro. The osteogenic defects of CFC-MSCs were revealed by alkaline phosphatase activity assay, mineralization assay, quantitative real-time polymerase chain reaction (qRT-PCR), and western blotting. Osteogenesis of CFC-MSCs was attenuated compared to wild-type (WT)-MSCs. In addition to activated ERK signaling, increased p-SMAD2 and decreased p-SMAD1 were observed in CFC-MSCs during osteogenesis. The defective osteogenesis of CFC-MSCs was rescued by inhibition of ERK signaling and SMAD2 signaling or activation of SMAD1 signaling. Importantly, activation of ERK signaling and SMAD2 signaling or inhibition of SMAD1 signaling recapitulated the impaired osteogenesis in WT-MSCs. Our findings indicate that SMAD2 signaling and SMAD1 signaling as well as ERK signaling are responsible for defective early bone development in CFC syndrome, providing a novel insight on the pathological mechanism and therapeutic targets.


Assuntos
Displasia Ectodérmica/patologia , Insuficiência de Crescimento/patologia , Cardiopatias Congênitas/patologia , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Mesenquimais/citologia , Osteoblastos/citologia , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Diferenciação Celular , Linhagem Celular , Displasia Ectodérmica/genética , Displasia Ectodérmica/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Facies , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/metabolismo , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Mutação , Osteoblastos/metabolismo , Osteogênese , Fosforilação , Transdução de Sinais , Proteína Smad1/metabolismo , Proteína Smad2/metabolismo
18.
Hum Mol Genet ; 26(23): 4715-4727, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973166

RESUMO

Germline mutations in BRAF are a major cause of cardio-facio-cutaneous (CFC) syndrome, which is characterized by heart defects, characteristic craniofacial dysmorphology and dermatologic abnormalities. Patients with CFC syndrome also commonly show gastrointestinal dysfunction, including feeding and swallowing difficulties and gastroesophageal reflux. We have previously found that knock-in mice expressing a Braf Q241R mutation exhibit CFC syndrome-related phenotypes, such as growth retardation, craniofacial dysmorphisms, congenital heart defects and learning deficits. However, it remains unclear whether BrafQ241R/+ mice exhibit gastrointestinal dysfunction. Here, we report that BrafQ241R/+ mice have neonatal feeding difficulties and esophageal dilation. The esophagus tissues from BrafQ241R/+ mice displayed incomplete replacement of smooth muscle with skeletal muscle and decreased contraction. Furthermore, the BrafQ241R/+ mice showed hyperkeratosis and a thickened muscle layer in the forestomach. Treatment with MEK inhibitors ameliorated the growth retardation, esophageal dilation, hyperkeratosis and thickened muscle layer in the forestomach in BrafQ241R/+ mice. The esophageal dilation with aberrant skeletal-smooth muscle boundary in BrafQ241R/+ mice were recovered after treatment with the histone H3K27 demethylase inhibitor GSK-J4. Our results provide clues to elucidate the pathogenesis and possible treatment of gastrointestinal dysfunction and failure to thrive in patients with CFC syndrome.


Assuntos
Displasia Ectodérmica/enzimologia , Estenose Esofágica/enzimologia , Insuficiência de Crescimento/enzimologia , Hiperplasia Epitelial Focal/enzimologia , Cardiopatias Congênitas/enzimologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Gastropatias/enzimologia , Animais , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Estenose Esofágica/genética , Estenose Esofágica/patologia , Facies , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Feminino , Hiperplasia Epitelial Focal/genética , Mutação em Linhagem Germinativa , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Inibidores de Proteínas Quinases/farmacologia , Gastropatias/genética
19.
Hum Mutat ; 38(12): 1671-1683, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28779497

RESUMO

PAX7 encodes a transcription factor essential in neural crest formation, myogenesis, and pituitary lineage specification. Pax7 null mice fail to thrive and exhibit muscle weakness, dying within 3 weeks. We describe a human autosomal-recessive syndrome, with failure to thrive, severe global developmental delay, microcephaly, axial hypotonia, pyramidal signs, dystonic postures, seizures, irritability, and self-mutilation. Aside from low blood carnitine levels, biochemical and metabolic screen was normal, with growth hormone deficiency in one patient. Electromyography was normal, with no specific findings in brain MRI/MRS yet nondemonstrable neuropituitary, a finding of unclear significance. Muscle biopsy showed unaffected overall organization of muscle fibers, yet positive fetal alpha myosin staining, suggesting regeneration. Homozygosity mapping with whole-exome sequencing identified a single disease-associated mutation in PAX7, segregating as expected in the kindred with no homozygosity in 200 ethnically matched controls. Transfection experiments showed that the PAX7 splice-site mutation putatively causes nonsense-mediated mRNA decay affecting onlyPAX7 isoform 3. This isoform, expressed specifically in brain, skeletal muscle and testes, is the sole Pax7 variant normally found in mice. The human muscle phenotype is in line with that in conditional Pax7 null mutant mice, where initial aberrant histological findings resolve postnatally through muscle regeneration.


Assuntos
Deficiências do Desenvolvimento/genética , Insuficiência de Crescimento/genética , Hipotonia Muscular/genética , Doenças Neuromusculares/genética , Fator de Transcrição PAX7/genética , Sequência de Aminoácidos , Animais , Aberrações Cromossômicas , Deficiências do Desenvolvimento/patologia , Insuficiência de Crescimento/patologia , Genes Recessivos , Homozigoto , Humanos , Masculino , Camundongos , Camundongos Knockout , Desenvolvimento Muscular/genética , Hipotonia Muscular/patologia , Mutação , Doenças Neuromusculares/patologia , Degradação do RNAm Mediada por Códon sem Sentido , Fenótipo , Alinhamento de Sequência , Transcriptoma , Sequenciamento Completo do Exoma
20.
Am J Physiol Renal Physiol ; 313(4): F1026-F1037, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28701310

RESUMO

The renal collecting duct (CD) contains two major cell types, intercalated (ICs) and principal cells (PCs). A previous report showed that deletion of ß1-integrin in the entire renal CD causes defective CD morphogenesis resulting in kidney dysfunction. However, subsequent deletion of ß1-integrin specifically in ICs and PCs, respectively, did not cause any morphological defects in the CDs. The discrepancy between these studies prompts us to reinvestigate the role of ß1-integrin in CD cells, specifically in the PCs. We conditionally deleted ß1-integrin in mouse CD PCs using a specific aquaporin-2 (AQP2) promoter Cre-LoxP system. The resulting mutant mice, ß-1f/fAQP2-Cre+, had lower body weight, failed to thrive, and died around 8-12 wk. Their CD tubules were dilated, and some of them contained cellular debris. Increased apoptosis and proliferation of PCs were observed in the dilated CDs. Trichrome staining and electron microscopy revealed the presence of peritubular and interstitial fibrosis that is associated with increased production of extracellular matrix proteins including collagen type IV and fibronectin, as detected by immunoblotting. Further analysis revealed a significantly increased expression of transforming growth factor-ß (TGF-ß)-induced protein, fibronectin, and TGF-ß receptor-1 mRNAs and concomitantly increased phosphorylation of SMAD-2 that indicates the activation of the TGF-ß signaling pathway. Therefore, our data reveal that normal expression of ß1-integrin in PCs is a critical determinant of CD structural and functional integrity and further support the previously reported critical role of ß1-integrin in the development and/or maintenance of the CD structure and function.


Assuntos
Matriz Extracelular/metabolismo , Deleção de Genes , Integrina beta1/metabolismo , Medula Renal/metabolismo , Túbulos Renais Coletores/metabolismo , Poliúria/metabolismo , Insuficiência Renal/metabolismo , Fatores Etários , Animais , Apoptose , Aquaporina 2/genética , Proliferação de Células , Matriz Extracelular/ultraestrutura , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/metabolismo , Insuficiência de Crescimento/patologia , Fibrose , Predisposição Genética para Doença , Integrases/genética , Integrina beta1/genética , Medula Renal/ultraestrutura , Túbulos Renais Coletores/ultraestrutura , Camundongos Knockout , Fenótipo , Fosforilação , Poliúria/genética , Poliúria/patologia , Regiões Promotoras Genéticas , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Insuficiência Renal/genética , Insuficiência Renal/patologia , Transdução de Sinais , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta/metabolismo
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