RESUMO
Genetic predisposition and risk factors such as hypertension and smoking can instigate the development of thoracic aortic aneurysm (TAA), which can lead to highly lethal aortic wall dissection and/or rupture. Monogenic defects in multiple genes involved in the elastin-contractile unit and the TGFß signaling pathway have been associated with TAA in recent years, along with several genetic modifiers and risk-conferring polymorphisms. Advances in omics technology have also provided significant insights into the processes behind aortic wall degeneration: inflammation, epigenetics, vascular smooth muscle phenotype change and depletion, reactive oxygen species generation, mitochondrial dysfunction, and angiotensin signaling dysregulation. These recent advances and findings might pave the way for a therapy that is capable of stopping and perhaps even reversing aneurysm progression.
Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Dissecção Aórtica/genética , Dissecção Aórtica/metabolismo , Animais , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , FenótipoRESUMO
Importin 8, encoded by IPO8, is a ubiquitously expressed member of the importin-ß protein family that translocates cargo molecules such as proteins, RNAs, and ribonucleoprotein complexes into the nucleus in a RanGTP-dependent manner. Current knowledge of the cargoes of importin 8 is limited, but TGF-ß signaling components such as SMAD1-4 have been suggested to be among them. Here, we report that bi-allelic loss-of-function variants in IPO8 cause a syndromic form of thoracic aortic aneurysm (TAA) with clinical overlap with Loeys-Dietz and Shprintzen-Goldberg syndromes. Seven individuals from six unrelated families showed a consistent phenotype with early-onset TAA, motor developmental delay, connective tissue findings, and craniofacial dysmorphic features. A C57BL/6N Ipo8 knockout mouse model recapitulates TAA development from 8-12 weeks onward in both sexes but most prominently shows ascending aorta dilatation with a propensity for dissection in males. Compliance assays suggest augmented passive stiffness of the ascending aorta in male Ipo8-/- mice throughout life. Immunohistological investigation of mutant aortic walls reveals elastic fiber disorganization and fragmentation along with a signature of increased TGF-ß signaling, as evidenced by nuclear pSmad2 accumulation. RT-qPCR assays of the aortic wall in male Ipo8-/- mice demonstrate decreased Smad6/7 and increased Mmp2 and Ccn2 (Ctgf) expression, reinforcing a role for dysregulation of the TGF-ß signaling pathway in TAA development. Because importin 8 is the most downstream TGF-ß-related effector implicated in TAA pathogenesis so far, it offers opportunities for future mechanistic studies and represents a candidate drug target for TAA.
Assuntos
Aneurisma da Aorta Torácica/etiologia , Mutação com Perda de Função , Perda de Heterozigosidade , Fenótipo , beta Carioferinas/genética , Adulto , Animais , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linhagem , Transdução de Sinais , Síndrome , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Adulto Jovem , beta Carioferinas/metabolismoRESUMO
Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and ß-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of ß-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg/kg/day and 5 mg/kg/day) with barbadin, a ß-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Aneurisma Aórtico , Losartan , Síndrome de Marfan , Transdução de Sinais , Camundongos , Síndrome de Marfan/tratamento farmacológico , Síndrome de Marfan/patologia , Modelos Animais de Doenças , Aneurisma Aórtico/tratamento farmacológico , Aneurisma Aórtico/prevenção & controle , Oligopeptídeos/administração & dosagem , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Pirimidinas/administração & dosagem , Combinação de Medicamentos , Losartan/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Humanos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagemRESUMO
PURPOSE OF REVIEW: Structural genomic variants have emerged as a relevant cause for several disorders, including intellectual disability, neuropsychiatric disorders, cancer and congenital heart disease. In this review, we will discuss the current knowledge about the involvement of structural genomic variants and, in particular, copy number variants in the development of thoracic aortic and aortic valve disease. RECENT FINDINGS: There is a growing interest in the identification of structural variants in aortopathy. Copy number variants identified in thoracic aortic aneurysms and dissections, bicuspid aortic valve related aortopathy, Williams-Beuren syndrome and Turner syndrome are discussed in detail. Most recently, the first inversion disrupting FBN1 has been reported as a cause for Marfan syndrome. SUMMARY: During the past 15âyears, the knowledge on the role of copy number variants as a cause for aortopathy has grown significantly, which is partially due to the development of novel technologies including next-generation sequencing. Although copy number variants are now often investigated on a routine basis in diagnostic laboratories, more complex structural variants such as inversions, which require the use of whole genome sequencing, are still relatively new to the field of thoracic aortic and aortic valve disease.
Assuntos
Doenças da Aorta , Doença da Válvula Aórtica Bicúspide , Humanos , Doenças da Aorta/genética , Valva Aórtica/anormalidades , Genômica , Doenças das Valvas Cardíacas/genéticaRESUMO
Different pathogenic variants in the fibrillin-1 gene (FBN1) cause Marfan syndrome and acromelic dysplasias. Whereas the musculoskeletal features of Marfan syndrome involve tall stature, arachnodactyly, joint hypermobility, and muscle hypoplasia, acromelic dysplasia patients present with short stature, brachydactyly, stiff joints, and hypermuscularity. Similarly, pathogenic variants in the fibrillin-2 gene (FBN2) cause either a Marfanoid congenital contractural arachnodactyly or a FBN2-related acromelic dysplasia that most prominently presents with brachydactyly. The phenotypic and molecular resemblances between both the FBN1 and FBN2-related disorders suggest that reciprocal pathomechanistic lessons can be learned. In this review, we provide an updated overview and comparison of the phenotypic and mutational spectra of both the "tall" and "short" fibrillinopathies. The future parallel functional study of both FBN1/2-related disorders will reveal new insights into how pathogenic fibrillin variants differently affect the fibrillin microfibril network and/or growth factor homeostasis in clinically opposite syndromes. This knowledge may eventually be translated into new therapeutic approaches by targeting or modulating the fibrillin microfibril network and/or the signaling pathways under its control.
Assuntos
Fibrilina-1 , Fibrilina-2 , Síndrome de Marfan , Anormalidades Musculoesqueléticas/genética , Braquidactilia , Fibrilina-1/genética , Fibrilina-2/genética , Humanos , Síndrome de Marfan/genética , FenótipoRESUMO
Pathogenic variants in JAG1 are known to cause Alagille syndrome (ALGS), a disorder that primarily affects the liver, lung, kidney, and skeleton. Whereas cardiac symptoms are also frequently observed in ALGS, thoracic aortic aneurysms have only been reported sporadically in postmortem autopsies. We here report two families with segregating JAG1 variants that present with isolated aneurysmal disease, as well as the first histological evaluation of aortic aneurysm tissue of a JAG1 variant carrier. Our observations shed more light on the pathomechanisms behind aneurysm formation in JAG1 variant harboring individuals and underline the importance of cardiovascular imaging in the clinical follow-up of such individuals.
Assuntos
Síndrome de Alagille , Humanos , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Síndrome de Alagille/genética , Coração , Proteínas de Ligação ao CálcioRESUMO
The class I small leucine-rich proteoglycan biglycan is a crucial structural extracellular matrix component that interacts with a wide range of extracellular matrix molecules. In addition, biglycan is involved in sequestering growth factors such as transforming growth factor-ß and bone morphogenetic proteins and thereby regulating pathway activity. Biglycan consists of a 42-kDa core protein linked to two glycosaminoglycan side chains and both are involved in protein interactions. Biglycan is encoded by the BGN gene located on the X-chromosome and is expressed in various tissues, including vascular tissue, skin, brain, kidney, lung, the immune system, and the musculoskeletal system. Although an increasing amount of data on the biological function of biglycan in the vasculature has been produced, its role in thoracic aortic aneurysms is still not fully elucidated. This review focuses on the role of biglycan in the healthy thoracic aorta and the development of thoracic aortic aneurysm and dissections in both mice and humans.
Assuntos
Aorta Torácica , Fator de Crescimento Transformador beta , Animais , Aorta Torácica/metabolismo , Biglicano/genética , Biglicano/metabolismo , Proteínas Morfogenéticas Ósseas , Proteínas da Matriz Extracelular/genética , Camundongos , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
PURPOSE: In a large cohort of 373 pediatric patients with Marfan syndrome (MFS) with a severe cardiovascular phenotype, we explored the proportion of patients with MFS with a pathogenic FBN1 variant and analyzed whether the type/location of FBN1 variants was associated with specific clinical characteristics and response to treatment. Patients were recruited on the basis of the following criteria: aortic root z-score > 3, age 6 months to 25 years, no prior or planned surgery, and aortic root diameter < 5 cm. METHODS: Targeted resequencing and deletion/duplication testing of FBN1 and related genes were performed. RESULTS: We identified (likely) pathogenic FBN1 variants in 91% of patients. Ectopia lentis was more frequent in patients with dominant-negative (DN) variants (61%) than in those with haploinsufficient variants (27%). For DN FBN1 variants, the prevalence of ectopia lentis was highest in the N-terminal region (84%) and lowest in the C-terminal region (17%). The association with a more severe cardiovascular phenotype was not restricted to DN variants in the neonatal FBN1 region (exon 25-33) but was also seen in the variants in exons 26 to 49. No difference in the therapeutic response was detected between genotypes. CONCLUSION: Important novel genotype-phenotype associations involving both cardiovascular and extra-cardiovascular manifestations were identified, and existing ones were confirmed. These findings have implications for prognostic counseling of families with MFS.
Assuntos
Ectopia do Cristalino , Síndrome de Marfan , Variação Biológica da População , Criança , Ectopia do Cristalino/complicações , Ectopia do Cristalino/genética , Fibrilina-1/genética , Fibrilinas/genética , Genótipo , Humanos , Síndrome de Marfan/genética , Mutação , FenótipoRESUMO
PURPOSE: CTR9 is a subunit of the PAF1 complex (PAF1C) that plays a crucial role in transcription regulation by binding CTR9 to RNA polymerase II. It is involved in transcription-coupled histone modification through promoting H3K4 and H3K36 methylation. We describe the clinical and molecular studies in 13 probands, harboring likely pathogenic CTR9 missense variants, collected through GeneMatcher. METHODS: Exome sequencing was performed in all individuals. CTR9 variants were assessed through 3-dimensional modeling of the activated human transcription complex Pol II-DSIF-PAF-SPT6 and the PAF1/CTR9 complex. H3K4/H3K36 methylation analysis, mitophagy assessment based on tetramethylrhodamine ethyl ester perchlorate immunofluorescence, and RNA-sequencing in skin fibroblasts from 4 patients was performed. RESULTS: Common clinical findings were variable degrees of intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, and autism spectrum disorder. Mild dysmorphism and cardiac anomalies were less frequent. For 11 CTR9 variants, de novo occurrence was shown. Three-dimensional modeling predicted a likely disruptive effect of the variants on local CTR9 structure and protein interaction. Additional studies in fibroblasts did not unveil the downstream functional consequences of the identified variants. CONCLUSION: We describe a neurodevelopmental disorder caused by (mainly) de novo variants in CTR9, likely affecting PAF1C function.
Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Fosfoproteínas , Fatores de Transcrição , Regulação da Expressão Gênica , Heterozigoto , Humanos , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Fosfoproteínas/genética , Fatores de Transcrição/genéticaRESUMO
Meester-Loeys syndrome is an X-linked form of syndromic thoracic aortic aneurysm, characterized by the involvement of multiple organ systems. More specifically, the cardiovascular, skeletal, craniofacial, cutaneous and neurological systems are affected. Clear clinical overlap with Marfan syndrome and Loeys-Dietz syndrome is observed. Aortic dissections occur typically at young ages and are most often observed in males. Meester-Loeys syndrome is caused by loss-of-function mutations in BGN, encoding the small leucine-rich proteoglycan biglycan. Although functional consequences of these mutations remain largely elusive, increased TGF-ß signaling has been observed. Novel insights will provide opportunities for preventive therapeutic interventions.
Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Síndrome de Loeys-Dietz , Síndrome de Marfan , Humanos , Síndrome de Loeys-Dietz/diagnóstico , Síndrome de Loeys-Dietz/genética , Masculino , MutaçãoRESUMO
Thoracic aortic aneurysm and dissection (TAAD) is a major cause of cardiovascular morbidity and mortality. Loss-of-function variants in LOX, encoding the extracellular matrix crosslinking enzyme lysyl oxidase, have been reported to cause familial TAAD. Using a next-generation TAAD gene panel, we identified five additional probands carrying LOX variants, including two missense variants affecting highly conserved amino acids in the LOX catalytic domain and three truncating variants. Connective tissue manifestations are apparent in a substantial fraction of the variant carriers. Some LOX variant carriers presented with TAAD early in life, while others had normal aortic diameters at an advanced age. Finally, we identified the first patient with spontaneous coronary artery dissection carrying a LOX variant. In conclusion, our data demonstrate that loss-of-function LOX variants cause a spectrum of aortic and arterial aneurysmal disease, often combined with connective tissue findings.
Assuntos
Aneurisma da Aorta Torácica/genética , Proteína-Lisina 6-Oxidase/genética , Adulto , Dissecção Aórtica/genética , Dissecção Aórtica/fisiopatologia , Aorta/metabolismo , Aneurisma da Aorta Torácica/fisiopatologia , Artérias/metabolismo , Tecido Conjuntivo/metabolismo , Doenças do Tecido Conjuntivo/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Proteína-Lisina 6-Oxidase/metabolismoRESUMO
OBJECTIVE: To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. STUDY DESIGN: In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. RESULTS: Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status. CONCLUSIONS: In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.
Assuntos
Atenolol/uso terapêutico , Citocromo P-450 CYP2C9/genética , Regulação da Expressão Gênica , Losartan/uso terapêutico , Síndrome de Marfan/tratamento farmacológico , Receptores Adrenérgicos beta 1/genética , Adolescente , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Adulto , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Criança , Pré-Escolar , Citocromo P-450 CYP2C9/biossíntese , DNA/genética , Feminino , Seguimentos , Genótipo , Humanos , Lactente , Masculino , Síndrome de Marfan/genética , Síndrome de Marfan/metabolismo , Receptores Adrenérgicos beta 1/biossíntese , Estudos Retrospectivos , Adulto JovemRESUMO
Adams-Oliver syndrome (AOS) is a rare congenital disease characterized by aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). It shows significant genetic heterogeneity and can be transmitted by autosomal dominant or recessive inheritance. Recessive inheritance is associated with mutations of DOCK6 or EOGT; however, only few cases have been published so far. We present two families with EOGT-associated AOS. Due to pseudodominance in one family, the recognition of the recessive inheritance pattern was difficult. We identified two novel AOS-causing mutations (c.404G>A/p.Cys135Tyr and c.311+1G>T). The phenotype in the presented families was dominated by large ACC, whereas TTLD were mostly subtle or even absent and no major malformations occured. Our observations along with the previously published cases indicate that the two types of recessive AOS (EOGT- vs. DOCK6-associated) differ significanty regarding the frequency of neurologic or ocular deficits.
Assuntos
Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/genética , Mutação , N-Acetilglucosaminiltransferases/genética , Dermatoses do Couro Cabeludo/congênito , Criança , Consanguinidade , Éxons , Estudos de Associação Genética/métodos , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Linhagem , Fenótipo , Dermatoses do Couro Cabeludo/diagnóstico , Dermatoses do Couro Cabeludo/genéticaRESUMO
Adams-Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort. Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next-generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients. Taken together with previous reports, these findings bring the total number of reported disease variants to 63, with a diagnostic yield of 36% in familial cases. NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort. We confirm the relevance of genetic screening across the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype-phenotype correlations. This cohort offers potential for further gene identification to address missing heritability.
Assuntos
Displasia Ectodérmica/genética , Deformidades Congênitas dos Membros/genética , Dermatoses do Couro Cabeludo/congênito , Proteínas rho de Ligação ao GTP/genética , Displasia Ectodérmica/fisiopatologia , Extremidades/fisiopatologia , Feminino , Estudos de Associação Genética , Humanos , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Mutação , Linhagem , Receptores Notch/genética , Couro Cabeludo/fisiopatologia , Dermatoses do Couro Cabeludo/genética , Dermatoses do Couro Cabeludo/fisiopatologiaRESUMO
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.
Assuntos
Estudos de Associação Genética , Síndrome de Loeys-Dietz/genética , Mutação/genética , Proteína Smad2/genética , Proteína Smad3/genética , Fator de Crescimento Transformador beta2/genética , Fator de Crescimento Transformador beta3/genética , Animais , Modelos Animais de Doenças , Humanos , Síndrome de Loeys-Dietz/diagnóstico , Camundongos , Transdução de Sinais/genéticaRESUMO
Adams-Oliver syndrome (AOS) is a rare developmental disorder characterized by the presence of aplasia cutis congenita (ACC) of the scalp vertex and terminal limb-reduction defects. Cardiovascular anomalies are also frequently observed. Mutations in five genes have been identified as a cause for AOS prior to this report. Mutations in EOGT and DOCK6 cause autosomal-recessive AOS, whereas mutations in ARHGAP31, RBPJ, and NOTCH1 lead to autosomal-dominant AOS. Because RBPJ, NOTCH1, and EOGT are involved in NOTCH signaling, we hypothesized that mutations in other genes involved in this pathway might also be implicated in AOS pathogenesis. Using a candidate-gene-based approach, we prioritized DLL4, a critical NOTCH ligand, due to its essential role in vascular development in the context of cardiovascular features in AOS-affected individuals. Targeted resequencing of the DLL4 gene with a custom enrichment panel in 89 independent families resulted in the identification of seven mutations. A defect in DLL4 was also detected in two families via whole-exome or genome sequencing. In total, nine heterozygous mutations in DLL4 were identified, including two nonsense and seven missense variants, the latter encompassing four mutations that replace or create cysteine residues, which are most likely critical for maintaining structural integrity of the protein. Affected individuals with DLL4 mutations present with variable clinical expression with no emerging genotype-phenotype correlations. Our findings demonstrate that DLL4 mutations are an additional cause of autosomal-dominant AOS or isolated ACC and provide further evidence for a key role of NOTCH signaling in the etiology of this disorder.
Assuntos
Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/patologia , Mutação/genética , Dermatoses do Couro Cabeludo/congênito , Transdução de Sinais/genética , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Sequência de Bases , Proteínas de Ligação ao Cálcio , Heterozigoto , Humanos , Dados de Sequência Molecular , Linhagem , Receptores Notch/genética , Dermatoses do Couro Cabeludo/genética , Dermatoses do Couro Cabeludo/patologia , Análise de Sequência de DNARESUMO
PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families. METHODS: We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed. RESULTS: We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-ß signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture. CONCLUSION: In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-ß signaling.Genet Med 19 4, 386-395.
Assuntos
Aneurisma da Aorta Torácica/genética , Dissecção Aórtica/genética , Biglicano/genética , Mutação , Dissecção Aórtica/metabolismo , Aneurisma da Aorta Torácica/metabolismo , Biglicano/metabolismo , Células Cultivadas , Feminino , Genes Ligados ao Cromossomo X , Predisposição Genética para Doença , Humanos , Masculino , Linhagem , Análise de Sequência de DNA/métodos , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismoRESUMO
Marfan syndrome is an autosomal dominant connective tissue disorder, predominantly affecting the ocular, skeletal and cardiovascular systems. Here, we present the results of the first genetic testing in 40 Ukrainian Marfan (-like) patients and 10 relatives. We applied a targeted next generation sequencing panel comprising FBN1 and 13 thoracic aortic aneurysm genes. We identified 27 causal mutations in FBN1, obtaining a mutation yield of 67·5%. A significant difference in age at aortic surgery between mutation positive and negative patients was observed. Thus, we conclude that genetic testing is important to identify patients at higher risk for developing life-threatening cardiovascular complications.
Assuntos
Fibrilina-1/genética , Síndrome de Marfan/genética , Mutação/genética , Adulto , Alcaloides de Berberina , Estudos de Coortes , Feminino , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/cirurgia , Fenantridinas , Adulto JovemRESUMO
At least 14 causative genes have been identified for both syndromic and nonsyndromic forms of thoracic aortic aneurysm/dissection (TAA), an important cause of death in the industrialized world. Molecular confirmation of the diagnosis is increasingly important for gene-tailored patient management but consecutive, conventional molecular TAA gene screening is expensive and labor-intensive. To circumvent these problems, we developed a TAA gene panel for next-generation sequencing of 14 TAA genes. After validation, we applied the assay to 100 Marfan patients. We identified 90 FBN1 mutations, 44 of which were novel. In addition, Multiplex ligation-dependent probe amplification identified large deletions in six of the remaining samples, whereas false-negative results were excluded by Sanger sequencing of FBN1, TGFBR1, and TGFBR2 in the last four samples. Subsequently, we screened 55 syndromic and nonsyndromic TAA patients. We identified causal mutations in 15 patients (27%), one in each of the six following genes: ACTA2, COL3A1, TGFBR1, MYLK, SMAD3, SLC2A10 (homozygous), two in NOTCH1, and seven in FBN1. We conclude that our approach for TAA genetic testing overcomes the intrinsic hurdles of consecutive Sanger sequencing of all candidate genes and provides a powerful tool for the elaboration of clinical phenotypes assigned to different genes.