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1.
Artigo em Inglês | MEDLINE | ID: mdl-30905418

RESUMO

OBJECTIVES: This study aimed to review the clinical results of young adult patients with aortic disease associated with mutations in the fibrillin-1 gene (FBN1) and disclose the histologic differences between the ascending and descending aortas. METHODS: Between 2012 and 2015, 94 patients aged less than 50 years underwent surgery for thoracic aortic diseases. Forty-two patients (44.7%) had FBN-1 mutations. Of these, 40 patients (42.5%) with surgical specimens for histologic evaluation were included in the study. With the histologic results including the specimen sampled at their previous operations, cystic medial necrosis was classified into 3 grades according to the degree of the cystic area. RESULTS: Thirty-nine patients (97.5%) had aortic root dilatation (Z ≥2), and 13 patients (32.5%) had ectopia lentis. Thirty-nine patients (97.5%) fulfilled the diagnostic criteria for Marfan syndrome. There were no in-hospital deaths. The majority (27/29: 93.1%) of the specimens of the ascending aorta revealed cystic medial necrosis pattern. With grade III being the most severe condition, these cases were classified into grade I (n = 2), grade II (n = 5), and grade III (n = 20). In contrast, only 6 specimens (6/17: 35.3%) of the descending aorta showed a cystic medial necrosis pattern that was classified into grade I (n = 2) and grade III (n = 4), (P < .00001). CONCLUSIONS: Fewer specimens of the descending aorta revealed cystic medial necrosis compared with those of the ascending aorta. This difference might influence the characteristic aortic disease in Marfan syndrome associated with FBN-1 mutations.

2.
J Am Coll Cardiol ; 72(6): 605-615, 2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30071989

RESUMO

BACKGROUND: Thoracic aortic aneurysms progressively enlarge and predispose to acute aortic dissections. Up to 25% of individuals with thoracic aortic disease harbor an underlying Mendelian pathogenic variant. An evidence-based strategy for selection of genes to test in hereditary thoracic aortic aneurysm and dissection (HTAAD) helps inform family screening and intervention to prevent life-threatening thoracic aortic events. OBJECTIVES: The purpose of this study was to accurately identify genes that predispose to HTAAD using the Clinical Genome Resource (ClinGen) framework. METHODS: We applied the semiquantitative ClinGen framework to assess presumed gene-disease relationships between 53 candidate genes and HTAAD. Genes were classified as causative for HTAAD if they were associated with isolated thoracic aortic disease and were clinically actionable, triggering routine aortic surveillance, intervention, and family cascade screening. All gene-disease assertions were evaluated by a pre-defined curator-expert pair and subsequently discussed with an expert panel. RESULTS: Genes were classified based on the strength of association with HTAAD into 5 categories: definitive (n = 9), strong (n = 2), moderate (n = 4), limited (n = 15), and no reported evidence (n = 23). They were further categorized by severity of associated aortic disease and risk of progression. Eleven genes in the definitive and strong groups were designated as "HTAAD genes" (category A). Eight genes were classified as unlikely to be progressive (category B) and 4 as low risk (category C). The remaining genes were recent genes with an uncertain classification or genes with no evidence of association with HTAAD. CONCLUSIONS: The ClinGen framework is useful to semiquantitatively assess the strength of gene-disease relationships for HTAAD. Gene categories resulting from the curation may inform clinical laboratories in the development, interpretation, and subsequent clinical implications of genetic testing for patients with aortic disease.

3.
J Mol Diagn ; 20(5): 572-582, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29953964

RESUMO

There is significant debate within the diagnostics community regarding the accuracy of variant identification by next-generation sequencing and the necessity of confirmatory testing of detected variants. Because the quality threshold to discriminate false positives depends on the workflow, no regulatory standard regarding this matter has yet been published. The goal of this study was to empirically determine the threshold to perform additional Sanger sequencing and to reduce the experimental cost to a practical level. Using 278 model genes, a hybridization capture-based protocol was examined to meet the clinical requirements of low cost, high efficiency, and high-quality data. To reduce excessive false-positive detection, filtering processes were introduced to remove mismapped reads and strand-biased detection to a published best-practices pipeline. With seven samples from the 1000 Genomes Project, 2750 single-nucleotide polymorphisms and 142 insertions/deletions were identified by our designed workflow. Compared with variants registered in the single nucleotide polymorphism database (dbSNP), a zero false-positive threshold value was determined (quality score > 1000). The variants satisfying these criteria accounted for 95.6% of single-nucleotide polymorphisms and 50.7% of insertions/deletions. Except for deletions located within the highly repeated sequences, the workflow achieved 100% sensitivity. The established threshold allowed us to discriminate between convincing variants and those requiring validation, a design that reconciles the competing objectives of cost minimization and quality maximization of clinical gene panel testing.

4.
Hum Mutat ; 39(5): 621-634, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29392890

RESUMO

The Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-ß (TGF-ß) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-ß signaling. More recently, TGF-ß ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-ß pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF-ß signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.

5.
Genet Med ; 20(10): 1206-1215, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29300374

RESUMO

PURPOSE: Smooth muscle dysfunction syndrome (SMDS) due to heterozygous ACTA2 arginine 179 alterations is characterized by patent ductus arteriosus, vasculopathy (aneurysm and occlusive lesions), pulmonary arterial hypertension, and other complications in smooth muscle-dependent organs. We sought to define the clinical history of SMDS to develop recommendations for evaluation and management. METHODS: Medical records of 33 patients with SMDS (median age 12 years) were abstracted and analyzed. RESULTS: All patients had congenital mydriasis and related pupillary abnormalities at birth and presented in infancy with a patent ductus arteriosus or aortopulmonary window. Patients had cerebrovascular disease characterized by small vessel disease (hyperintense periventricular white matter lesions; 95%), intracranial artery stenosis (77%), ischemic strokes (27%), and seizures (18%). Twelve (36%) patients had thoracic aortic aneurysm repair or dissection at median age of 14 years and aortic disease was fully penetrant by the age of 25 years. Three (9%) patients had axillary artery aneurysms complicated by thromboembolic episodes. Nine patients died between the ages of 0.5 and 32 years due to aortic, pulmonary, or stroke complications, or unknown causes. CONCLUSION: Based on these data, recommendations are provided for the surveillance and management of SMDS to help prevent early-onset life-threatening complications.

6.
J Cardiothorac Surg ; 12(1): 97, 2017 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-29169363

RESUMO

BACKGROUND: A retrospective analysis was performed to determine the impact of genetically diagnosed connective tissue disease (CTD) on the early and late outcomes of surgical treatment for aortic dissection in patients having aortic pathology associated with cystic medial necrosis (CMN). METHODS: Between 2003 and 2013, a total of 43 patients (37 ± 12.8 years old, 23 men, 20 women) who had undergone surgery for aortic dissection associated with CMN in the aortic wall underwent genetic examinations. Subsequently, there were 30 patients with CTD (CTD group) and 13 without CTD (non-CTD group). RESULTS: There were no early or late deaths (the follow-up rate was 100% for 57.1 ± 43.0 months). The median age was significantly lower in the CTD group (p = 0.030). The rate of elastic fiber loss was significantly higher in the CTD group (p = 0.014). In the long-term follow-up, there were no significant differences in the incidences of re-dissection (p = 0.332). However, re-operations were required more frequently in the CTD group (p = 0.037). CONCLUSIONS: In patients with CTD as well as CMN, the onset of aortic dissection tends to be earlier, which would result in higher rates of re-operation, compared with the non-CTD group. Closer and stricter follow-up with medication and adequate surgical treatments with appropriate timing are mandatory for such high-risk patients.


Assuntos
Aneurisma Dissecante/cirurgia , Aneurisma da Aorta Torácica/cirurgia , Cistos/complicações , Procedimentos Cirúrgicos Vasculares/métodos , Adulto , Aneurisma Dissecante/etiologia , Aneurisma da Aorta Torácica/complicações , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/etiologia , Cistos/diagnóstico , Cistos/cirurgia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
7.
PLoS One ; 12(8): e0183225, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28817660

RESUMO

Cardiac progenitor cells have a limited proliferative capacity. The CREB-binding protein/p300-interacting transactivator, with the Glu/Asp-rich carboxy-terminal domain (Cited) gene family, regulates gene transcription. Increased expression of the Cited4 gene in an adult mouse is associated with exercise-induced cardiomyocyte hypertrophy and proliferation. However, the expression patterns and functional roles of the Cited4 gene during cardiogenesis are largely unknown. Therefore, in the present study, we investigated the expression patterns and functional roles of the Cited4 gene during in vitro cardiogenesis. Using embryoid bodies formed from mouse embryonic stem cells, we evaluated the expression patterns of the Cited4 gene by quantitative reverse transcriptase-polymerase chain reaction. Cited4 gene expression levels increased and decreased during the early and late phases of cardiogenesis, respectively. Moreover, Cited4 gene levels were significantly high in the cardiac progenitor cell population. A functional assay of the Cited4 gene in cardiac progenitor cells using flow cytometry indicated that overexpression of the Cited4 gene significantly increased the cardiac progenitor cell population compared with the control and knockdown groups. A cell proliferation assay, with 5-ethynyl-2'-deoxyuridine incorporation and Ki67 expression during the late phase of cardiogenesis, indicated that the number of troponin T-positive embryonic stem cell-direived cardiomyocytes with proliferative capacity was significantly greater in the overexpression group than in the control and knockdown groups. Our study results suggest that the Cited4 gene is related to cardiac differentiation and maintenance of proliferation capacity of embryonic stem cell-derived cardiomyocytes during in vitro cardiogenesis. Therefore, manipulation of Cited4 gene expression may be of great interest for cardiac regeneration.


Assuntos
Proliferação de Células , Células-Tronco Embrionárias/citologia , Coração/embriologia , Miócitos Cardíacos/citologia , Fatores de Transcrição/metabolismo , Animais , Separação Celular , Células Cultivadas , Células-Tronco Embrionárias/metabolismo , Citometria de Fluxo , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Miócitos Cardíacos/metabolismo , Fatores de Transcrição/genética
8.
Gen Thorac Cardiovasc Surg ; 65(12): 686-691, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28808903

RESUMO

OBJECTIVES: Actin, alpha-2, smooth muscle, aorta (ACTA2) mutations are one of the major causes of familial thoracic aortic aneurysms and dissections. The aim of this study was to review our clinical results of young adult patients with aortic disease caused by ACTA2 mutations. METHODS: We reviewed the medical records of 251 patients (<50 years old) who underwent surgery for thoracic aortic diseases between 2004 and 2014. Among them, nine patients (3.5%) had ACTA2 mutations. Their average age was 35 years (range 22-47) and two patients (22.2%) were males. No patients fulfilled the diagnostic criteria for Marfan syndrome. Preoperative diagnoses included annulo-aortic ectasia (n = 2), localized dissection of the sinus of Valsalva (n = 2), acute type B aortic dissection (n = 1), and chronic type B (n = 4). Eight patients (88.9%) had hypertension. RESULTS: A thoracoabdominal aortic replacement was required in three patients who had descending replacement for residual chronic type B aortic dissection. A patient who had thoracic endovascular aortic repair for complicated acute type B aortic dissection showed no aortic dilatation for 7 years after TEVAR. Histological results revealed cystic medial necrosis (CMN) in most cases (7/8; 87.5%). CONCLUSION: Surgical outcomes for patients with ACTA2 mutations were satisfactory. CMN was a major histological finding and family history of aortic event was detected in only half of the patients with ACTA2 mutations. Despite no characteristic physical findings besides hypertension, connective tissue disease including ACTA2 mutations should be considered for aortic dissection in young adult patients.


Assuntos
Actinas/genética , Aneurisma Dissecante/cirurgia , Aneurisma da Aorta Torácica/cirurgia , Implante de Prótese Vascular/métodos , DNA/genética , Procedimentos Endovasculares/métodos , Mutação , Actinas/metabolismo , Adulto , Aneurisma Dissecante/diagnóstico , Aneurisma Dissecante/genética , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/genética , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Sci Rep ; 7(1): 7168, 2017 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-28769032

RESUMO

Skeletal muscle is composed of heterogeneous populations of myofibers that are classified as slow- and fast-twitch fibers. The muscle fiber-type is regulated in a coordinated fashion by multiple genes, including transcriptional factors and microRNAs (miRNAs). However, players involved in this regulation are not fully elucidated. One of the members of the Vestigial-like factors, Vgll2, is thought to play a pivotal role in TEA domain (TEAD) transcription factor-mediated muscle-specific gene expression because of its restricted expression in skeletal muscles of adult mice. Here, we generated Vgll2 null mice and investigated Vgll2 function in adult skeletal muscles. These mice presented an increased number of fast-twitch type IIb fibers and exhibited a down-regulation of slow type I myosin heavy chain (MyHC) gene, Myh7, which resulted in exercise intolerance. In accordance with the decrease in Myh7, down-regulation of miR-208b, encoded within Myh7 gene and up-regulation of targets of miR-208b, Sox6, Sp3, and Purß, were observed in Vgll2 deficient mice. Moreover, we detected the physical interaction between Vgll2 and TEAD1/4 in neonatal skeletal muscles. These results suggest that Vgll2 may be both directly and indirectly involved in the programing of slow muscle fibers through the formation of the Vgll2-TEAD complex.

10.
Mol Genet Metab Rep ; 13: 23-29, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28765812

RESUMO

A high intake of products containing fructose is known to mediate insulin resistance. In the liver, AMPD2, an isoform of AMPD, has important glucose metabolic homeostasis functions including maintenance of AMP-activated protein kinase (AMPK). We speculated that AMPD2 induces impaired glucose tolerance in individuals who consume a high-fructose diet. We gave either a normal-chow (NCD) or high-fructose (HFrD) diet for 40 days to 8-week-old male wild-type (WT) and Ampd2 -/- homozygote (A2 -/-) C57BL/6 mice. A glucose tolerance test (GTT) and pyruvate tolerance test (PTT) were used to evaluate glucose metabolism. In addition, gluconeogenesis and glycolysis enzymes, and AMPK phosphorylation in the liver were investigated. With consumption of the HFrD, A2 -/- mice showed enhanced glucose tolerance in GTT and PTT results as compared to the WT mice, which were independent of changes in body weight. Also, the levels of phosphoenolpyruvate carboxy kinase and glucose-6-phosphatase (hepatic gluconeogenic enzymes) were significantly reduced in A2 -/- as compared to WT mice. The hepatic glycolytic enzymes glucokinase, phosphofructokinase, and pyruvate kinase were also examined, though there were no significant differences between genotypes in regard to both mRNA expression and protein expression under HFrD. Surprisingly, hepatic AMPK phosphorylation resulted in no changes in the A2 -/- as compared to WT mice under these conditions. Our results indicated that Ampd2-deficient mice are protected from high fructose diet-induced glycemic dysregulation, mainly because of gluconeogenesis inhibition, and indicate a novel therapeutic target for type 2 diabetes mellitus.

11.
Pulm Circ ; 7(3): 734-740, 2017 Jul-Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28660794

RESUMO

Left main coronary artery (LMCA) disease due to external compression by a dilated main pulmonary artery (MPA) is an uncommon clinical entity. Here, we describe a 52-year-old woman with pulmonary arterial hypertension (PAH) and anteroseptal old myocardial infarction (OMI). The cause of the OMI was external compression of the LMCA by the dilated MPA and aneurysm of the left coronary sinus of Valsalva. The patient's sister (aged 56 years) had also been diagnosed with PAH and both women had a novel heterozygous splicing mutation, IVS2-2A > G (c.374-2A > G in NM_001456), in the filamin A ( FLNA) gene. To our knowledge, this is the first report of HPAH which is likely to be due to FLNA mutation and compression of the LMCA between a dilated MPA and aneurysm of the left coronary sinus of Valsalva.

12.
Nucleosides Nucleotides Nucleic Acids ; 35(10-12): 543-549, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27906636

RESUMO

Renal hypouricemia (RHUC) is a hereditary disease characterized by a low level of plasma urate but with normal urinary urate excretion. RHUC type 1 is caused by mutations of the urate transporter URAT1 gene (SLC22A12). However, the plasma urate levels of URAT1 knockout mice are no different from those of wild-type mice. In the present study, a double knockout mouse, in which the URAT1 and uricase (Uox) genes were deleted (Urat1-Uox-DKO), were used as an experimental animal model of RHUC type 1 to investigate RHUC and excise-induced acute kidney injury (EIAKI). Mice were given a variable content of allopurinol for one week followed by HPLC measurement of urate and creatinine concentrations in spot urine and blood from the tail. The urinary excretion of urate in Urat1-Uox-DKO mice was approximately 25 times higher than those of humans. With allopurinol, the plasma urate levels of Urat1-Uox-DKO mice were lower than those of Uox-KO mice. There were no differences in the urinary urate excretions between Urat1-Uox-DKO and Uox-KO mice administered with 9 mg allopurinol /100 g feed. In the absence of allopurinol, plasma creatinine levels of some Urat1-Uox-DKO mice were higher than those of Uox-KO mice. Consequently, hypouricemia and normouricosuria may indicate that the Urat1-Uox-DKO mouse administered with allopurinol may represent a suitable animal model of RHUC type 1. Urat1-Uox-DKO mice without allopurinol exhibited acute kidney injury, thus providing additional benefit as a potential animal model for EIAKI. Finally, our data indicate that allopurinol appears to provide prophylactic effects for EIAKI.


Assuntos
Lesão Renal Aguda/genética , Transportadores de Ânions Orgânicos/genética , Erros Inatos do Transporte Tubular Renal/genética , Urato Oxidase/genética , Cálculos Urinários/genética , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/metabolismo , Alopurinol/farmacologia , Alopurinol/uso terapêutico , Animais , Creatinina/sangue , Modelos Animais de Doenças , Supressores da Gota/farmacologia , Supressores da Gota/uso terapêutico , Masculino , Camundongos Knockout , Transportadores de Ânions Orgânicos/metabolismo , Condicionamento Físico Animal , Erros Inatos do Transporte Tubular Renal/tratamento farmacológico , Erros Inatos do Transporte Tubular Renal/metabolismo , Urato Oxidase/metabolismo , Ácido Úrico/urina , Cálculos Urinários/tratamento farmacológico , Cálculos Urinários/metabolismo
13.
Circ Cardiovasc Genet ; 9(6): 548-558, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27879313

RESUMO

BACKGROUND: The natural history of aortic diseases in patients with TGFBR1 or TGFBR2 mutations reported by different investigators has varied greatly. In particular, the current recommendations for the timing of surgical repair of the aortic root aneurysms may be overly aggressive. METHODS AND RESULTS: The Montalcino Aortic Consortium, which includes 15 centers worldwide that specialize in heritable thoracic aortic diseases, was used to gather data on 441 patients from 228 families, with 176 cases harboring a mutation in TGBR1 and 265 in TGFBR2. Patients harboring a TGFBR1 mutation have similar survival rates (80% survival at 60 years), aortic risk (23% aortic dissection and 18% preventive aortic surgery), and prevalence of extra-aortic features (29% hypertelorism, 53% cervical arterial tortuosity, and 27% wide scars) when compared with patients harboring a TGFBR2 mutation. However, TGFBR1 males had a greater aortic risk than females, whereas TGFBR2 males and females had a similar aortic risk. Additionally, aortic root diameter prior to or at the time of type A aortic dissection tended to be smaller in patients carrying a TGFBR2 mutation and was ≤45 mm in 6 women with TGFBR2 mutations, presenting with marked systemic features and low body surface area. Aortic dissection was observed in 1.6% of pregnancies. CONCLUSIONS: Patients with TGFBR1 or TGFBR2 mutations show the same prevalence of systemic features and the same global survival. Preventive aortic surgery at a diameter of 45 mm, lowered toward 40 in females with low body surface area, TGFBR2 mutation, and severe extra-aortic features may be considered.


Assuntos
Aorta Torácica , Doenças da Aorta/genética , Heterozigoto , Mutação , Complicações Cardiovasculares na Gravidez/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/cirurgia , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/mortalidade , Doenças da Aorta/cirurgia , Austrália/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Japão/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Fenótipo , Gravidez , Complicações Cardiovasculares na Gravidez/diagnóstico por imagem , Complicações Cardiovasculares na Gravidez/mortalidade , Complicações Cardiovasculares na Gravidez/cirurgia , Prevalência , Modelos de Riscos Proporcionais , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Estados Unidos/epidemiologia , Procedimentos Cirúrgicos Vasculares
14.
Am J Med Genet A ; 170(7): 1924-7, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27080061

RESUMO

Sporadic and familial elastin mutations can occur in large vessel stenosis such as supravalvular aortic stenosis and narrowing of the descending aorta. However, there are very few reports regarding the arteriopathy of cerebral, pulmonary or abdominal arteries in elastin mutations. We herein report the case of a Japanese female patient presenting with multiple arteriopathy including moyamoya disease, a tortuosity of abdominal arteries and pulmonary hypertension due to peripheral pulmonary artery stenosis. This case suggests the possible progression of cerebral arteriopathy including moyamoya disease in patients with elastin mutations. © 2016 Wiley Periodicals, Inc.


Assuntos
Artérias/anormalidades , Constrição Patológica/genética , Elastina/genética , Instabilidade Articular/genética , Doença de Moyamoya/genética , Dermatopatias Genéticas/genética , Malformações Vasculares/genética , Adulto , Artérias/fisiopatologia , Constrição Patológica/fisiopatologia , Feminino , Humanos , Instabilidade Articular/fisiopatologia , Doença de Moyamoya/fisiopatologia , Mutação , Fenótipo , Dermatopatias Genéticas/fisiopatologia , Malformações Vasculares/fisiopatologia
15.
J Hum Genet ; 61(2): 157-62, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26490186

RESUMO

Congenital heart disease (CHD) is the most common birth defect occurring in humans and some transcriptional factors have been identified as causative. However, additional mutation analysis of these genes is necessary to develop effective diagnostic and medical treatment methods. We conducted sequence analysis of the coding regions of NKX2.5, GATA4, TBX1, TBX5, TBX20, CFC1 and ZIC3 in 111 Japanese patients with non-syndromic CHD and 9 of their relatives. All patient samples were also analyzed by multiplex ligation-dependent probe amplification using probes involved in chromosome deletion related to CHD. Five novel variations of TBX5, GATA4 and TBX20 were detected in 6 of the patients, whereas none were found in 200 controls. The TBX5 variation p.Pro108Thr, located in the T-box domain, was identified in a patient with tricuspid atresia, an exon-intron boundary variation of GATA4 (IVS4+5G>A) was detected in a Tetralogy of Fallot patient and an 8p23 microdeletion was detected in one patient with atrioventricular septal defect and psychomotor delay. A total of seven non-synonymous polymorphisms were found in the patients and controls. Accumulation of novel variations of genes involving the cardiac development may be required for better understanding of CHD.


Assuntos
Cardiopatias Congênitas/genética , Mutação , Deleção Cromossômica , Análise Mutacional de DNA , Fator de Transcrição GATA4/genética , Humanos , Japão , Polimorfismo Genético , Proteínas com Domínio T/genética
16.
J Hum Genet ; 61(1): 21-6, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26446364

RESUMO

Recent progress in the study of hereditary large vessel diseases such as Marfan syndrome (MFS) have not only identified responsible genes but also provided better understanding of the pathophysiology and revealed possible new therapeutic targets. Genes identified for these diseases include FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3, SKI, EFEMP2, COL3A1, FLNA, ACTA2, MYH11, MYLK and SLC2A10, as well as others. Their dysfunction disrupts the function of transforming growth factor-ß (TGF-ß) signaling pathways, as well as that of the extracellular matrix and smooth muscle contractile apparatus, resulting in progression of structural damage to large vessels, including aortic aneurysms and dissections. Notably, it has been shown that the TGF-ß signaling pathway has a key role in the pathogenesis of MFS and related disorders, which may be important for development of strategies for medical and surgical treatment of thoracic aortic aneurysms and dissections.


Assuntos
Aneurisma Dissecante/genética , Aneurisma da Aorta Torácica/genética , Síndrome de Marfan/genética , Aneurisma Dissecante/tratamento farmacológico , Aneurisma Dissecante/etiologia , Aneurisma da Aorta Torácica/tratamento farmacológico , Aneurisma da Aorta Torácica/etiologia , Síndrome de Ehlers-Danlos/genética , Fibrilina-1/genética , Humanos , Síndrome de Loeys-Dietz/genética , Mutação , Transdução de Sinais/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/fisiologia
17.
Eur J Hum Genet ; 24(3): 408-14, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26059841

RESUMO

Loss-of-function mutations in filamin A (FLNA) cause an X-linked dominant disorder with multiple organ involvement. Affected females present with periventricular nodular heterotopia (PVNH), cardiovascular complications, thrombocytopenia and Ehlers-Danlos syndrome. These mutations are typically lethal to males, and rare male survivors suffer from failure to thrive, PVNH, and severe cardiovascular and gastrointestinal complications. Here we report two surviving male siblings with a loss-of-function mutation in FLNA. They presented with multiple complications, including valvulopathy, intestinal malrotation and chronic intestinal pseudo-obstruction (CIPO). However, these siblings had atypical clinical courses, such as a lack of PVNH and a spontaneous improvement of CIPO. Trio-based whole-exome sequencing revealed a 4-bp deletion in exon 40 that was predicted to cause a lethal premature protein truncation. However, molecular investigations revealed that the mutation induced in-frame skipping of the mutated exon, which led to the translation of a mutant FLNA missing an internal region of 41 amino acids. Functional analyses of the mutant protein suggested that its binding affinity to integrin, as well as its capacity to induce focal adhesions, were comparable to those of the wild-type protein. These results suggested that exon skipping of FLNA partially restored its protein function, which could contribute to amelioration of the siblings' clinical courses. This study expands the diversity of the phenotypes associated with loss-of-function mutations in FLNA.


Assuntos
Éxons/genética , Filaminas/genética , Filaminas/metabolismo , Mutação/genética , Adulto , Células Sanguíneas/metabolismo , Criança , Pré-Escolar , Feminino , Imunofluorescência , Células HEK293 , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Fenótipo , Adulto Jovem
19.
Am J Med Genet A ; 167A(10): 2435-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26096872

RESUMO

Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder, caused by heterozygous mutations in TGFBR1 or TGFBR2 and characterized by vascular complications (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections) and skeletal manifestations. We here report the first patient with LDS presenting with reversible cerebral vasoconstriction syndrome (RCVS), a clinico-radiological condition characterized by recurrent thunderclap headaches, with or without neurological symptoms, and reversible vasoconstriction of cerebral arteries. The patient was a 9-year-old boy with a heterozygous TGFBR2 mutation, manifesting camptodactyly, talipes equinovarus, and lamboid craniosynostosis. He complained of severe recurrent headaches 2 months after total aortic replacement for aortic root dilatation and a massive Stanford type B aortic dissection. A thoracic CT scan revealed a left subclavian artery dissection. Brain MRI and MRA detected bilateral internal carotid artery constriction along with a cortical subarachnoid hemorrhage without intracranial aneurysms. Subsequently, he developed visual disturbance and a generalized seizure associated with multiple legions of cortical and subcortical increased signals including the left posterior lobe, consistent with posterior reversible encephalopathy syndrome (PRES), a condition characterized by headaches, visual disorders, seizures, altered mentation, consciousness disturbances, focal neurological signs, and vasogenic edema predominantly in the white matter of the posterior lobe. Vasoconstriction of the internal carotid artery was undetectable 2 months later, and he was diagnosed as having RCVS. Endothelial dysfunction, associated with impaired TGF-ß signaling, might have been attributable to the development of RCVS and PRES.


Assuntos
Aneurisma Dissecante/genética , Síndrome de Loeys-Dietz/genética , Síndrome da Leucoencefalopatia Posterior/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Hemorragia Subaracnóidea/genética , Vasoconstrição , Aneurisma Dissecante/sangue , Aneurisma Dissecante/patologia , Artérias Cerebrais/metabolismo , Artérias Cerebrais/patologia , Criança , Expressão Gênica , Heterozigoto , Humanos , Síndrome de Loeys-Dietz/sangue , Síndrome de Loeys-Dietz/patologia , Masculino , Mutação , Síndrome da Leucoencefalopatia Posterior/sangue , Síndrome da Leucoencefalopatia Posterior/patologia , Proteínas Serina-Treonina Quinases/sangue , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/sangue , Transdução de Sinais , Hemorragia Subaracnóidea/sangue , Hemorragia Subaracnóidea/patologia
20.
J Am Coll Cardiol ; 65(13): 1324-1336, 2015 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-25835445

RESUMO

BACKGROUND: Aneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture. Investigations of the pathogenic mechanisms involved in syndromic types of thoracic aortic aneurysms, such as Marfan and Loeys-Dietz syndromes, have revealed an important contribution of disturbed transforming growth factor (TGF)-ß signaling. OBJECTIVES: This study sought to discover a novel gene causing syndromic aortic aneurysms in order to unravel the underlying pathogenesis. METHODS: We combined genome-wide linkage analysis, exome sequencing, and candidate gene Sanger sequencing in a total of 470 index cases with thoracic aortic aneurysms. Extensive cardiological examination, including physical examination, electrocardiography, and transthoracic echocardiography was performed. In adults, imaging of the entire aorta using computed tomography or magnetic resonance imaging was done. RESULTS: Here, we report on 43 patients from 11 families with syndromic presentations of aortic aneurysms caused by TGFB3 mutations. We demonstrate that TGFB3 mutations are associated with significant cardiovascular involvement, including thoracic/abdominal aortic aneurysm and dissection, and mitral valve disease. Other systemic features overlap clinically with Loeys-Dietz, Shprintzen-Goldberg, and Marfan syndromes, including cleft palate, bifid uvula, skeletal overgrowth, cervical spine instability and clubfoot deformity. In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-ß signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up-regulation of both canonical and noncanonical TGF-ß signaling in association with up-regulation of the expression of TGF-ß ligands. CONCLUSIONS: Our findings emphasize the broad clinical variability associated with TGFB3 mutations and highlight the importance of early recognition of the disease because of high cardiovascular risk.


Assuntos
Aneurisma Dissecante/genética , Aneurisma Aórtico/genética , Mutação , Fator de Crescimento Transformador beta3/genética , Adulto , Idoso , Eletrocardiografia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Linhagem , Análise de Sequência de DNA
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