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1.
Genet Med ; 24(10): 2112-2122, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36053285

RESUMO

PURPOSE: Heterozygous pathogenic/likely pathogenic (P/LP) variants in the ACTA2 gene confer a high risk for thoracic aortic aneurysms and aortic dissections. This retrospective multicenter study elucidates the clinical outcome of ACTA2-related vasculopathies. METHODS: Index patients and relatives with a P/LP variant in ACTA2 were included. Data were collected through retrospective review of medical records using a standardized questionnaire. RESULTS: A total of 49 individuals from 28 families participated in our study. In total, 20 different ACTA2 variants were detected. Aortic events occurred in 65% of the cases (78.6% index patients and 47.6% relatives). Male sex and hypertension emerged as significantly associated with aortic events. Of 20 individuals, 5 had an aortic diameter of <45 mm (1.77 inches) at the time of the type A dissection. Mean age at first aortic event was 49.0 ± 12.4 years. Severe surgical complications for type A and type B dissection occurred in 25% and 16.7% of the cases and in-hospital mortality rates were 9.5% and 0%, respectively. CONCLUSION: P/LP ACTA2 variants are associated with an increased risk for an aortic event and age-related penetrance, which emphasizes the importance of early recognition of the disease. Caregivers should be aware of the risk for aortic dissections, even in individuals with aortic diameters within the normal range.


Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Actinas/genética , Adulto , Dissecção Aórtica/genética , Aorta , Aneurisma da Aorta Torácica/epidemiologia , Aneurisma da Aorta Torácica/genética , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
2.
Clin Genet ; 97(5): 723-730, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31898322

RESUMO

Disease-causing variants in TGFB3 cause an autosomal dominant connective tissue disorder which is hard to phenotypically delineate because of the small number of identified cases. The purpose of this retrospective cross-sectional multicenter study is to elucidate the genotype and phenotype in an international cohort of TGFB3 patients. Eleven (eight novel) TGFB3 disease-causing variants were identified in 32 patients (17 families). Aortic root dilatation and mitral valve disease represented the most common cardiovascular findings, reported in 29% and 32% of patients, respectively. Dissection involving distal aortic segments occurred in two patients at age 50 and 52 years. A high frequency of systemic features (65% high-arched palate, 63% arachnodactyly, 57% pectus deformity, 52% joint hypermobility) was observed. In familial cases, incomplete penetrance and variable clinical expressivity were noted. Our cohort included the first described homozygous patient, who presented with a more severe phenotype compared to her heterozygous relatives. In conclusion, TGFB3 variants were associated with a high percentage of systemic features and aortic disease (dilatation/dissection) in 35% of patients. No deaths occurred from cardiovascular events or pregnancy-related complications. Nevertheless, homozygosity may be driving a more severe phenotype.


Assuntos
Aracnodactilia/genética , Doenças do Tecido Conjuntivo/genética , Síndrome de Loeys-Dietz/genética , Fator de Crescimento Transformador beta3/genética , Adolescente , Adulto , Aracnodactilia/patologia , Criança , Pré-Escolar , Doenças do Tecido Conjuntivo/patologia , Feminino , Predisposição Genética para Doença , Genótipo , Heterozigoto , Homozigoto , Humanos , Síndrome de Loeys-Dietz/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Fenótipo , Fator de Crescimento Transformador beta3/deficiência , Adulto Jovem
3.
Clin Genet ; 97(6): 890-901, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32266967

RESUMO

Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.


Assuntos
Anormalidades Múltiplas/genética , Calcinose/genética , Otopatias/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Megalencefalia/genética , Atrofia Muscular/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , 3-Hidroxiacil-CoA Desidrogenases/genética , Anormalidades Múltiplas/patologia , Acetil-CoA C-Aciltransferase/genética , Adolescente , Adulto , Calcinose/patologia , Isomerases de Ligação Dupla Carbono-Carbono/genética , Criança , Pré-Escolar , Otopatias/patologia , Enoil-CoA Hidratase/genética , Face/anormalidades , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Megalencefalia/patologia , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/patologia , Atrofia Muscular/patologia , Mutação , Mutação de Sentido Incorreto/genética , Fenótipo , Racemases e Epimerases/genética , Neoplasias Testiculares , Adulto Jovem
4.
Am J Med Genet A ; 182(5): 1201-1208, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32100459

RESUMO

Homozygosity for nonsense variants in CEP55 has been associated with a lethal condition characterized by multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly (MARCH syndrome) also known as Meckel-like syndrome. Missense variants in CEP55 have not previously been reported in association with disease. Here we describe seven living individuals from five families with biallelic CEP55 variants. Four unrelated individuals with microcephaly, speech delays, and bilateral toe syndactyly all have a common CEP55 variant c.70G>A p.(Glu24Lys) in trans with nonsense variants. Three siblings are homozygous for a consensus splice site variant near the end of the gene. These affected girls all have severely delayed development, microcephaly, and varying degrees of lissencephaly/pachygyria. Here we compare our seven patients with three previously reported families with a prenatal lethal phenotype (MARCH syndrome/Meckel-like syndrome) due to homozygous CEP55 nonsense variants. Our series suggests that individuals with compound heterozygosity for nonsense and missense variants in CEP55 have a different viable phenotype. We show that homozygosity for a splice variant near the end of the CEP55 gene is also compatible with life.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Síndrome de Dandy-Walker/genética , Predisposição Genética para Doença , Malformações do Sistema Nervoso/genética , Cisto Pancreático/genética , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Cerebelo/patologia , Criança , Pré-Escolar , Síndrome de Dandy-Walker/epidemiologia , Síndrome de Dandy-Walker/patologia , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Feminino , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/epidemiologia , Microcefalia/genética , Microcefalia/patologia , Mutação , Mutação de Sentido Incorreto , Malformações do Sistema Nervoso/epidemiologia , Malformações do Sistema Nervoso/patologia , Cisto Pancreático/epidemiologia , Cisto Pancreático/patologia , Linhagem , Fenótipo , Gravidez , Adulto Jovem
6.
Hum Mutat ; 39(9): 1173-1192, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29907982

RESUMO

Simultaneous analysis of multiple genes using next-generation sequencing (NGS) technology has become widely available. Copy-number variations (CNVs) in disease-associated genes have emerged as a cause for several hereditary disorders. CNVs are, however, not routinely detected using NGS analysis. The aim of this study was to assess the diagnostic yield and the prevalence of CNVs using our panel of Hereditary Thoracic Aortic Disease (H-TAD)-associated genes. Eight hundred ten patients suspected of H-TAD were analyzed by targeted NGS analysis of 21 H-TAD associated genes. In addition, the eXome hidden Markov model (XHMM; an algorithm to identify CNVs in targeted NGS data) was used to detect CNVs in these genes. A pathogenic or likely pathogenic variant was found in 66 of 810 patients (8.1%). Of these 66 pathogenic or likely pathogenic variants, six (9.1%) were CNVs not detectable by routine NGS analysis. These CNVs were four intragenic (multi-)exon deletions in MYLK, TGFB2, SMAD3, and PRKG1, respectively. In addition, a large duplication including NOTCH1 and a large deletion encompassing SCARF2 were detected. As confirmed by additional analyses, both CNVs indicated larger chromosomal abnormalities, which could explain the phenotype in both patients. Given the clinical relevance of the identification of a genetic cause, CNV analysis using a method such as XHMM should be incorporated into the clinical diagnostic care for H-TAD patients.


Assuntos
Aorta Torácica/patologia , Aneurisma da Aorta Torácica/genética , Doenças da Aorta/genética , Variações do Número de Cópias de DNA/genética , Adulto , Aneurisma da Aorta Torácica/patologia , Doenças da Aorta/patologia , Aberrações Cromossômicas , Proteína Quinase Dependente de GMP Cíclico Tipo I/genética , Exoma/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Receptor Notch1/genética , Receptores Depuradores Classe F/genética
7.
Hum Mutat ; 38(4): 439-450, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28074631

RESUMO

Mutations in genes encoding proteins of the smooth muscle cell (SMC) contractile apparatus contribute to familial aortic aneurysms. To investigate the pathogenicity of these mutations, SMC are required. We demonstrate a novel method to generate SMC-like cells from human dermal fibroblasts by transdifferentiation to study the effect of variants in genes encoding proteins of the SMC contractile apparatus (ACTA2 and MYH11) in patients with aortic aneurysms. Dermal fibroblasts from seven healthy donors and cells from seven patients with MYH11 or ACTA2 variants were transdifferentiated into SMC-like cells within a 2-week duration using 5 ng/ml TGFß1 on a scaffold containing collagen and elastin. The induced SMC were comparable to primary human aortic SMC in mRNA expression of SMC markers which was confirmed on the protein level by immunofluorescence quantification analysis and Western blotting. In patients with MYH11 or ACTA2 variants, the effect of intronic variants on splicing was demonstrated on the mRNA level in the induced SMC, allowing classification into pathogenic or nonpathogenic variants. In conclusion, direct conversion of human dermal fibroblasts into SMC-like cells is a highly efficient method to investigate the pathogenicity of variants in proteins of the SMC contractile apparatus.


Assuntos
Actinas/genética , Aneurisma Aórtico/genética , Transdiferenciação Celular/genética , Fibroblastos/metabolismo , Mutação , Miócitos de Músculo Liso/metabolismo , Cadeias Pesadas de Miosina/genética , Adulto , Idoso , Aneurisma Aórtico/patologia , Transdiferenciação Celular/efeitos dos fármacos , Células Cultivadas , Derme/citologia , Proteínas da Matriz Extracelular/farmacologia , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Miócitos de Músculo Liso/citologia , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Crescimento Transformador beta/farmacologia
8.
Haematologica ; 101(9): 1018-27, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27247322

RESUMO

Ankyrin-R provides a key link between band 3 and the spectrin cytoskeleton that helps to maintain the highly specialized erythrocyte biconcave shape. Ankyrin deficiency results in fragile spherocytic erythrocytes with reduced band 3 and protein 4.2 expression. We use in vitro differentiation of erythroblasts transduced with shRNAs targeting ANK1 to generate erythroblasts and reticulocytes with a novel ankyrin-R 'near null' human phenotype with less than 5% of normal ankyrin expression. Using this model, we demonstrate that absence of ankyrin negatively impacts the reticulocyte expression of a variety of proteins, including band 3, glycophorin A, spectrin, adducin and, more strikingly, protein 4.2, CD44, CD47 and Rh/RhAG. Loss of band 3, which fails to form tetrameric complexes in the absence of ankyrin, alongside GPA, occurs due to reduced retention within the reticulocyte membrane during erythroblast enucleation. However, loss of RhAG is temporally and mechanistically distinct, occurring predominantly as a result of instability at the plasma membrane and lysosomal degradation prior to enucleation. Loss of Rh/RhAG was identified as common to erythrocytes with naturally occurring ankyrin deficiency and demonstrated to occur prior to enucleation in cultures of erythroblasts from a hereditary spherocytosis patient with severe ankyrin deficiency but not in those exhibiting milder reductions in expression. The identification of prominently reduced surface expression of Rh/RhAG in combination with direct evaluation of ankyrin expression using flow cytometry provides an efficient and rapid approach for the categorization of hereditary spherocytosis arising from ankyrin deficiency.


Assuntos
Anquirinas/deficiência , Proteínas Sanguíneas/metabolismo , Eritroblastos/metabolismo , Membrana Eritrocítica/metabolismo , Lisossomos/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteína 1 de Troca de Ânion do Eritrócito/química , Proteína 1 de Troca de Ânion do Eritrócito/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Citoesqueleto/genética , Citoesqueleto/metabolismo , Eritroblastos/química , Eritroblastos/citologia , Eritropoese/genética , Regulação da Expressão Gênica , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Modelos Biológicos , Mutação , Ligação Proteica , Multimerização Proteica , Proteólise , Esferocitose Hereditária/genética , Esferocitose Hereditária/metabolismo
9.
Am J Med Genet A ; 170(7): 1874-80, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27109146

RESUMO

Mutations in RIT1, involved in the RAS-MAPK pathway, have recently been identified as a cause for Noonan syndrome. We present two patients with Noonan syndrome caused by a RIT1 mutation with novel phenotypic manifestations, severe bilateral lower limb lymphedema starting during puberty, and fetal hydrops resulting in intrauterine fetal death, respectively. Including our patients, a total of 52 patients have been reported with Noonan syndrome caused by a RIT1 mutation. Our report contributes to the delineation of the phenotype associated with RIT1 mutations and underlines that lymphatic involvement is part of this spectrum. In addition, we provide an overview of the currently described Noonan syndrome patients with RIT1 mutations in literature. © 2016 Wiley Periodicals, Inc.


Assuntos
Hidropisia Fetal/genética , Síndrome de Noonan/genética , Proteínas ras/genética , Feminino , Humanos , Hidropisia Fetal/fisiopatologia , Extremidade Inferior/fisiopatologia , Masculino , Mutação de Sentido Incorreto , Síndrome de Noonan/fisiopatologia , Fenótipo
10.
Hum Mutat ; 36(12): 1145-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26247899

RESUMO

We report three families with arterial aneurysms and dissections in which variants predicted to be pathogenic were identified in SMAD2. Moreover, one variant occurred de novo in a proband with unaffected parents. SMAD2 is a strong candidate gene for arterial aneurysms and dissections given its role in the TGF-ß signaling pathway. Furthermore, although SMAD2 and SMAD3 probably have functionally distinct roles in cell signaling, they are structurally very similar. Our findings indicate that SMAD2 mutations are associated with arterial aneurysms and dissections and are in accordance with the observation that patients with pathogenic variants in genes encoding proteins involved in the TGF-ß signaling pathway exhibit arterial aneurysms and dissections as key features.


Assuntos
Aneurisma/genética , Dissecção Aórtica/genética , Artérias/metabolismo , Artérias/patologia , Mutação , Proteína Smad2/genética , Adulto , Alelos , Aneurisma/diagnóstico , Aneurisma/metabolismo , Dissecção Aórtica/diagnóstico , Dissecção Aórtica/metabolismo , Biologia Computacional/métodos , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Domínios e Motivos de Interação entre Proteínas , Análise de Sequência de DNA , Proteína Smad2/química , Adulto Jovem
12.
Circ Genom Precis Med ; 17(3): e003978, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38623759

RESUMO

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder with a high risk for arterial, bowel, and uterine rupture, caused by heterozygous pathogenic variants in COL3A1. The aim of this cohort study is to provide further insights into the natural history of vEDS and describe genotype-phenotype correlations in a Dutch multicenter cohort to optimize patient care and increase awareness of the disease. METHODS: Individuals with vEDS throughout the Netherlands were included. The phenotype was charted by retrospective analysis of molecular and clinical data, combined with a one-time physical examination. RESULTS: A total of 142 individuals (50% female) participated the study, including 46 index patients (32%). The overall median age at genetic diagnosis was 41.0 years. More than half of the index patients (54.3%) and relatives (53.1%) had a physical appearance highly suggestive of vEDS. In these individuals, major events were not more frequent (P=0.90), but occurred at a younger age (P=0.01). A major event occurred more often and at a younger age in men compared with women (P<0.001 and P=0.004, respectively). Aortic aneurysms (P=0.003) and pneumothoraces (P=0.029) were more frequent in men. Aortic dissection was more frequent in individuals with a COL3A1 variant in the first quarter of the collagen helical domain (P=0.03). CONCLUSIONS: Male sex, type and location of the COL3A1 variant, and physical appearance highly suggestive of vEDS are risk factors for the occurrence and early age of onset of major events. This national multicenter cohort study of Dutch individuals with vEDS provides a valuable basis for improving guidelines for the diagnosing, follow-up, and treatment of individuals with vEDS.


Assuntos
Colágeno Tipo III , Síndrome de Ehlers-Danlos , Humanos , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/epidemiologia , Feminino , Masculino , Países Baixos/epidemiologia , Adulto , Colágeno Tipo III/genética , Pessoa de Meia-Idade , Estudos Retrospectivos , Estudos de Coortes , Fenótipo , Adolescente , Estudos de Associação Genética , Adulto Jovem , Idoso , Síndrome de Ehlers-Danlos Tipo IV
13.
NPJ Genom Med ; 9(1): 22, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38531898

RESUMO

Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females). The identified BGN variants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence of BGN and the 5' untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPase ATP2B3 (normally repressed in skin fibroblasts) driven by the remnant BGN promotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identified BGN missense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants in BGN.

15.
J Trauma ; 69(3): 589-94; discussion 594, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20838130

RESUMO

OBJECTIVES: Mobile medical teams (MMTs) provide specialized care on-scene with the purpose to improve outcome. However, this additional care could prolong the on-scene time (OST), which is related to mortality. The purpose of this study was to assess the effects of MMT involvement on the mortality rate and on the OST, in a Dutch consecutive cohort of Level I trauma patients. METHODS: All patients who required presentation in the trauma resuscitation room in an urban Level I trauma center were included in this prospective study during the period of November 2005 till November 2007. For data collection, we used both pre- and in-hospital registration systems. Outcome measures were 30-day mortality and OST. RESULTS: In total, 1,054 patients were analyzed. In 172 (16%) patients, the MMT was involved. Mortality was significantly higher in the MMT group compared with patients treated without MMT involvement; 9.9% versus 2.7%, respectively (p < 0.001). Significantly higher Injury Severity Scores, intervention rates, and a significantly lower Triage Revised Trauma Score were found in patients treated by MMT. After adjustment for patient and injury characteristics, no association could be found between MMT involvement and higher mortality (95% CI, 0.581-3.979; p = 0.394). In patients with severe traumatic brain injury (GCS score ≤ 8) in whom a MMT was involved, the mortality was 25.5%, compared with 32.7% in those without MMT involvement (p = 0.442). The mean OST was prolonged (2.7 minutes) when MMT was involved (26.1 vs. 23.4 minutes; p = 0.003). CONCLUSIONS: In this study, OSTs were long compared with PHTLS recommendations. MMT involvement slightly prolonged the OST. Trauma patients with MMT involvement had a high mortality, but after correction for patient and injury characteristics, the mortality rate did not significantly differ from patients without MMT involvement.


Assuntos
Ambulâncias/estatística & dados numéricos , Ferimentos e Lesões/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Lesões Encefálicas/mortalidade , Lesões Encefálicas/terapia , Criança , Pré-Escolar , Serviços Médicos de Emergência/estatística & dados numéricos , Feminino , Humanos , Lactente , Escala de Gravidade do Ferimento , Masculino , Pessoa de Meia-Idade , Países Baixos , Estudos Prospectivos , Fatores de Tempo , Ferimentos e Lesões/terapia , Ferimentos Penetrantes/mortalidade , Ferimentos Penetrantes/terapia , Adulto Jovem
16.
Mol Genet Genomic Med ; 7(2): e00518, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30485715

RESUMO

BACKGROUND: Pathogenic variants in FBN1 cause autosomal dominant Marfan syndrome but can also be found in patients presenting with apparently isolated features of Marfan syndrome. Moreover, several families with autosomal recessive Marfan syndrome caused by pathogenic variants in FBN1 have been described. The aim of this report was to underline the clinical variability that can be associated with the pathogenic variant c.1453C>T, p.(Arg485Cys) in FBN1. METHODS: We provide the clinical details of two autosomal dominant families with this specific FBN1 variant, which was previously associated with autosomal recessive Marfan syndrome. RESULTS: Clinical data of 14 individuals carrying this variant from these two families were collected retrospectively. In both families, the diagnosis of autosomal dominant Marfan syndrome was established based on the characteristics of the variant and the phenotype which includes aortic aneurysms and dissections. Of interest, in one of the families, multiple relatives were diagnosed with early onset abdominal aortic aneurysms. CONCLUSION: In conclusion, FBN1 variant c.1453C>T, p.(Arg485Cys) is a pathogenic variant that can cause autosomal dominant Marfan syndrome characterized by a high degree of clinical variability and apparently isolated early onset familial abdominal aortic aneurysms.


Assuntos
Fibrilina-1/genética , Síndrome de Marfan/genética , Adulto , Feminino , Genes Dominantes , Humanos , Masculino , Síndrome de Marfan/patologia , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Fenótipo
17.
J Clin Invest ; 129(12): 5374-5380, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31513549

RESUMO

Myocardin (MYOCD) is the founding member of a class of transcriptional coactivators that bind the serum-response factor to activate gene expression programs critical in smooth muscle (SM) and cardiac muscle development. Insights into the molecular functions of MYOCD have been obtained from cell culture studies, and to date, knowledge about in vivo roles of MYOCD comes exclusively from experimental animals. Here, we defined an often lethal congenital human disease associated with inheritance of pathogenic MYOCD variants. This disease manifested as a massively dilated urinary bladder, or megabladder, with disrupted SM in its wall. We provided evidence that monoallelic loss-of-function variants in MYOCD caused congenital megabladder in males only, whereas biallelic variants were associated with disease in both sexes, with a phenotype additionally involving the cardiovascular system. These results were supported by cosegregation of MYOCD variants with the phenotype in 4 unrelated families by in vitro transactivation studies in which pathogenic variants resulted in abrogated SM gene expression and by the finding of megabladder in 2 distinct mouse models with reduced Myocd activity. In conclusion, we have demonstrated that variants in MYOCD result in human disease, and the collective findings highlight a vital role for MYOCD in mammalian organogenesis.


Assuntos
Mutação , Proteínas Nucleares/genética , Transativadores/genética , Bexiga Urinária/anormalidades , Adulto , Animais , Feminino , Variação Genética , Humanos , Masculino , Camundongos , Músculo Liso/metabolismo , Proteínas Nucleares/fisiologia , Transativadores/fisiologia
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