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1.
J Immunol Res ; 2020: 7509608, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32090130

RESUMO

Peroxisome proliferator-activated receptors (PPAR gamma-2) and beta-3-adrenergic receptors (ADRB3) are involved in the risk of hypertension. But their exact role in blood pressure modulation in patients with connective tissue diseases (CTD) is still not well defined. In this study, 104 patients with CTD and 103 gender- and age-matched controls were genotyped for Pro12Ala and C1431T polymorphisms of the PPAR gamma-2 gene and Trp64Arg polymorphism of the ADRB gene. Anthropometric and biochemical measurements were evaluated, followed by genotyping using TaqMan® SNP genotyping assays and polymerase chain reaction-restriction fragment length polymorphism. The prevalence of analyzed genotypes and alleles was comparable between patients with CTD and the control group, as well as hypertensive and normotensive subjects. Patients with CTD have lower body fat and higher body water amount, serum glucose, and triglyceride (TG) levels. Hypertensive subjects are older and have higher body mass, BMI, waist circumference (WC), body water content, glucose, and TG concentration. The multivariate analysis revealed that hypertensive subjects with Ala12/X or Trp64Trp have higher body mass and WC when compared to normotensive subjects. Trp64Trp polymorphism was also characterized by a higher TG level, while T1431/X subjects had higher WC. The presence of CTD, visceral fat distribution, and increased age are the predictors of hypertension development. Hypertensive patients with CTD and Trp64Trp polymorphism have an increased risk of visceral obesity development and metabolic complications, which in turn affects the value of blood pressure. In addition, either Ala12/X or T1431/X predicts the visceral body fat distribution in hypertensive subjects.


Assuntos
Doenças do Tecido Conjuntivo/complicações , Doenças do Tecido Conjuntivo/genética , Patrimônio Genético , Predisposição Genética para Doença , Hipertensão/etiologia , Alelos , Biomarcadores , Pesos e Medidas Corporais , Doenças do Tecido Conjuntivo/patologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Razão de Chances , Fatores de Risco
2.
BMC Med Genet ; 21(1): 27, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32039712

RESUMO

BACKGROUND: Stickler syndrome is the most common genetic cause of rhegmatogenous retinal detachment (RRD) in children, and has a high risk of blindness. Type I (STL1) is the most common subtype, caused by COL2A1 mutations. This study aims to analyze the mutation spectrum of COL2A1 and further elucidate the genotype-phenotype relationships in the East Asian populations with STL1, which is poorly studied at present. METHODS: By searching MEDLINE, Web of Science, CNKI, Wanfang Data, HGMD and Clinvar, all publications associated with STL1 were collected. Then, they were carefully screened to obtain all reported STL1-related variants in COL2A1 and clinical features in East Asian patients with STL1. RESULTS: There were 274 COL2A1 variants identified in 999 patients with STL1 from 466 unrelated families, and more than half of them were truncation mutations. Of the 107 STL1 patients reported in the East Asian population, it was found that patients with truncation mutations had milder systemic phenotypes, whereas patients with splicing mutations had severer phenotypes. In addition, several recurrent variants (c.3106C > T, c.1833 + 1G > A, c.2710C > T and c.1693C > T) were found. CONCLUSIONS: Genotype-phenotype correlations should certainly be studied carefully, contributed to making personalized follow-up plans and predicting prognosis of this disorder. Genome editing holds great potential for treating inherited diseases caused by pathogenic mutations. In this study, several recurrent variants were found, providing potential candidate targets for genetic manipulation in the future.


Assuntos
Artrite/genética , Doenças do Tecido Conjuntivo/genética , Análise Mutacional de DNA , Perda Auditiva Neurossensorial/genética , Mutação/genética , Descolamento Retiniano/genética , Artrite/epidemiologia , Artrite/patologia , Doenças do Tecido Conjuntivo/epidemiologia , Doenças do Tecido Conjuntivo/patologia , Oftalmopatias Hereditárias , Estudos de Associação Genética , Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/patologia , Humanos , Fenótipo , Descolamento Retiniano/epidemiologia , Descolamento Retiniano/patologia
3.
Neurology ; 93(22): e2007-e2020, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31719132

RESUMO

OBJECTIVES: To determine the frequency of rare and pertinent disease-causing variants in small vessel disease (SVD)-associated genes (such as NOTCH3, HTRA1, COL4A1, COL4A2, FOXC1, TREX1, and GLA) in cerebral SVD, we performed targeted gene sequencing in 950 patients with younger-onset apparently sporadic SVD stroke using a targeted sequencing panel. METHODS: We designed a high-throughput sequencing panel to identify variants in 15 genes (7 known SVD genes, 8 SVD-related disorder genes). The panel was used to screen a population of 950 patients with younger-onset (≤70 years) MRI-confirmed SVD stroke, recruited from stroke centers across the United Kingdom. Variants were filtered according to their frequency in control databases, predicted effect, presence in curated variant lists, and combined annotation dependent depletion scores. Whole genome sequencing and genotyping were performed on a subset of patients to provide a direct comparison of techniques. The frequency of known disease-causing and pertinent variants of uncertain significance was calculated. RESULTS: We identified previously reported variants in 14 patients (8 cysteine-changing NOTCH3 variants in 11 patients, 2 HTRA1 variants in 2 patients, and 1 missense COL4A1 variant in 1 patient). In addition, we identified 29 variants of uncertain significance in 32 patients. CONCLUSION: Rare monogenic variants account for about 1.5% of younger onset lacunar stroke. Most are cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy variants, but the second most common gene affected is HTRA1. A high-throughput sequencing technology platform is an efficient, reliable method to screen for such mutations.


Assuntos
Doenças de Pequenos Vasos Cerebrais/genética , Acidente Vascular Cerebral Lacunar/genética , Idade de Início , Idoso , CADASIL/genética , Angiopatia Amiloide Cerebral Familiar/genética , Doenças do Tecido Conjuntivo/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Enxaqueca com Aura/genética , Mutação
4.
Yi Chuan ; 41(10): 919-927, 2019 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-31624054

RESUMO

Fibrillin-2 (FBN2) is an important component of microfibers which are involved in the formation of elastic fibers in connective tissue throughout the human body. Hereditary connective tissue diseases may result from genetic mutations of FBN2 causing heterogeneity of fibrin. Genetic mutations of FBN2 are associated with a variety of hereditary connective tissue diseases including Congenital Contractural Arachnodactyl (CCA), Macular Degeneration (MD), and myopathy. Studies have shown that the FBN2 gene is recognized as the only pathogenic gene related to CCA and that CCA patients have different clinical presentations depending on the identified genetic mutations at different FBN2 sites. In this review, we summarize the roles of FBN2, its mutations and impact on the physiological and pathological processes of many hereditary connective tissue diseases. We include brief descriptions of clinical manifestations of these diseases providing a basis for further exploration of the specific molecular mechanism of FBN2 gene mutation pathogenesis which provides a theoretical basis for the therapy and medications for refractory diseases caused by FBN2 gene mutation.


Assuntos
Doenças do Tecido Conjuntivo/genética , Fibrilina-2/genética , Humanos , Mutação
5.
Genet Test Mol Biomarkers ; 23(11): 783-790, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31638417

RESUMO

Aims: This quality analysis study was designed to review the indications, reports, and clinical consequences of 438 diagnostic next-generation sequencing (NGS) gene panel analyses for hereditary connective tissue disorders (HCTD). Methods: Molecular analyses were retrieved from laboratory databases and patient records, and compared to the clinical information in the requisition and classified according to the Human Phenotype Ontology. Results: In 123 of 438 NGS analyses, 156 sequence variants were reported in 33 of 54 genes analyzed. NGS analyses and, in some cases, postanalytic assessment resulted in identification of pathogenic variants in 40 (9%) of patients, and variants of uncertain significance were identified in 83 (19%) of cases analyzed. While cardiovascular abnormalities were the most common phenotype noted in the requisitions, no specific organ system could be identified in which the reported symptoms provided an actionable indication for the analysis. Certain health issues recorded in the patients' records were found to be frequently left out of requisitions. Conclusions: The interpretation of genetic sequence variants continues to be a significant challenge in HCTD. Although not associated with the highest diagnostic yield, cardiovascular disease and family history may be suitable indications for NGS due to the clinical consequences of the identification of a known or likely causative sequence variant for a vascular HCTD in patients and relatives.


Assuntos
Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Tecido Conjuntivo/metabolismo , Tecido Conjuntivo/fisiopatologia , Bases de Dados Genéticas , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Humanos
6.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340433

RESUMO

Lysyl oxidase like 3 (LOXL3) is a copper-dependent amine oxidase responsible for the crosslinking of collagen and elastin in the extracellular matrix. LOXL3 belongs to a family including other members: LOX, LOXL1, LOXL2, and LOXL4. Autosomal recessive mutations are rare and described in patients with Stickler syndrome, early-onset myopia and non-syndromic cleft palate. Along with an essential function in embryonic development, multiple biological functions have been attributed to LOXL3 in various pathologies related to amino oxidase activity. Additionally, various novel roles have been described for LOXL3, such as the oxidation of fibronectin in myotendinous junction formation, and of deacetylation and deacetylimination activities of STAT3 to control of inflammatory response. In tumors, three distinct roles were described: (1) LOXL3 interacts with SNAIL and contributes to proliferation and metastasis by inducing epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma cells; (2) LOXL3 is localized predominantly in the nucleus associated with invasion and poor gastric cancer prognosis; (3) LOXL3 interacts with proteins involved in DNA stability and mitosis completion, contributing to melanoma progression and sustained proliferation. Here we review the structure, function and activity of LOXL3 in normal and pathological conditions and discuss the potential of LOXL3 as a therapeutic target in various diseases.


Assuntos
Aminoácido Oxirredutases/genética , Artrite/genética , Fissura Palatina/genética , Doenças do Tecido Conjuntivo/genética , Matriz Extracelular/genética , Perda Auditiva Neurossensorial/genética , Miopia/genética , Neoplasias/genética , Descolamento Retiniano/genética , Aminoácido Oxirredutases/química , Aminoácido Oxirredutases/metabolismo , Artrite/enzimologia , Artrite/patologia , Fissura Palatina/enzimologia , Fissura Palatina/patologia , Colágeno/química , Colágeno/genética , Colágeno/metabolismo , Doenças do Tecido Conjuntivo/enzimologia , Doenças do Tecido Conjuntivo/patologia , Elastina/química , Elastina/genética , Elastina/metabolismo , Transição Epitelial-Mesenquimal/genética , Matriz Extracelular/química , Matriz Extracelular/enzimologia , Regulação da Expressão Gênica , Perda Auditiva Neurossensorial/enzimologia , Perda Auditiva Neurossensorial/patologia , Humanos , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Miopia/enzimologia , Miopia/patologia , Neoplasias/enzimologia , Neoplasias/patologia , Especificidade de Órgãos , Descolamento Retiniano/enzimologia , Descolamento Retiniano/patologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo
7.
Arch Gynecol Obstet ; 300(3): 491-493, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31250196

RESUMO

Ehlers-Danlos syndromes (EDS) are a genetically heterogeneous group of inherited connective tissue disorders classified into six major types with a variable collection of findings and different inheritance patterns. Although complications occur in about one-half of pregnancies in women with EDS, the majority can have a good outcome if managed appropriately. Classic EDS is characterized by joint hypermobility, loose skin with poor healing and easy bruising, musculoskeletal problems with chronic pain and at risk for pre-term delivery. In addition, the vascular form of EDS can have cardiac anomalies, aneurysms, gastrointestinal perforation and uterine rupture during pregnancy. Due to overlapping features among the connective tissue disorders, it is difficult to categorize the disorder into specific types without detailed genetic testing which is now available through advanced genomic technology using next-generation DNA sequencing, searching genomic databases and bioinformatics approach. Therefore, obstetrical complications are variable but relate to specific connective tissue disorders requiring an exact diagnosis. There are several dozen genes causing connective tissue disorders that are currently available for testing using next-generation sequencing and bioinformatics to provide pertinent care, treatment and surveillance of the affected pregnant woman but also for her at-risk fetus related to the specific heritable condition.


Assuntos
Colágeno/genética , Tecido Conjuntivo/fisiopatologia , Síndrome de Ehlers-Danlos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Complicações na Gravidez/diagnóstico , Pele/patologia , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/genética , Síndrome de Ehlers-Danlos/diagnóstico , Feminino , Testes Genéticos , Humanos , Instabilidade Articular/etiologia , Mutação/genética , Gravidez , Complicações na Gravidez/genética , Diagnóstico Pré-Natal , Análise de Sequência de DNA
8.
Subcell Biochem ; 91: 281-310, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30888657

RESUMO

We begin this chapter by describing normal characteristics of several pertinent connective tissue components, and some of the basic changes they undergo with ageing. These alterations are not necessarily tied to any specific disease or disorders, but rather an essential part of the normal ageing process. The general features of age-induced changes, such as skin wrinkles, in selected organs with high content of connective or soft tissues are discussed in the next part of the chapter. This is followed by a section dealing with age-related changes in specific diseases that fall into at least two categories. The first category encompasses common diseases with high prevalence among mostly ageing populations where both genetic and environmental factors play roles. They include but may not be limited to atherosclerosis and coronary heart disease, type II diabetes, osteopenia and osteoporosis, osteoarthritis, tendon dysfunction and injury, age-related disorders of spine and joints. Disorders where genetics plays the primary role in pathogenesis and progression include certain types of progeria, such as Werner syndrome and Hutchinson-Gilford progeria belong to the second category discussed in this chapter. These disorders are characterized by accelerated signs and symptoms of ageing. Other hereditary diseases or syndromes that arise from mutations of genes encoding for components of connective tissue and are less common than diseases included in the first group will be discussed briefly as well, though they may not be directly associated with ageing, but their connective tissue undergoes some changes compatible with ageing. Marfan and Ehlers-Danlos syndromes are primary examples of such disorders. We will probe the role of specific components of connective tissue and extracellular matrix if not in each of the diseases, then at least in the main representatives of these disorders.


Assuntos
Envelhecimento/patologia , Doenças do Tecido Conjuntivo/patologia , Envelhecimento/genética , Tecido Conjuntivo/metabolismo , Tecido Conjuntivo/patologia , Doenças do Tecido Conjuntivo/genética , Humanos , Progéria/genética , Progéria/patologia
9.
Am J Med Genet A ; 179(4): 552-560, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30706611

RESUMO

We describe a data repository on heritable disorders of connective tissue (HDCT) assembled by the National Institutes of Health's National Institute on Aging (NIA) Intramural Research Program between 2001 and 2013. Participants included affected persons with a wide range of heritable connective tissue phenotypes, and unaffected family members. Elements include comprehensive history and physical examination, standardized laboratory data, physiologic measures and imaging, standardized patient-reported outcome measures, and an extensive linked biorepository. The NIA made a commitment to make the repository available to extramural investigators and deposited samples at Coriell Tissue Repository (N = 126) and GenTAC registry (N = 132). The clinical dataset was transferred to Penn State University College of Medicine Clinical and Translational Science Institute in 2016, and data elements inventoried. The consented cohort of 1,009 participants averaged 39 ± 18 years (mean ± SD, range 2-95) at consent; gender distribution is 71% F and 83% self-report Caucasian ethnicity. Diagnostic categories include Ehlers-Danlos syndrome (classical N = 50, hypermobile N = 99, vascular N = 101, rare types and unclassified N = 178), Marfan syndrome (N = 33), Stickler syndrome (N = 60), fibromuscular dysplasia (N = 135), Other HDCT (N = 72). Unaffected family members (N = 218) contributed DNA for the molecular archive only. We aim to develop further discrete data from unstructured elements, analyze multisymptom HDCT manifestations, encourage data use by other researchers and thereby better understand the complexity of these high-morbidity conditions and their multifaceted effects on affected persons.


Assuntos
Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/patologia , Sistema de Registros/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite/genética , Artrite/patologia , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patologia , Feminino , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Síndrome de Marfan/genética , Síndrome de Marfan/patologia , Pessoa de Meia-Idade , National Institutes of Health (U.S.) , Fenótipo , Descolamento Retiniano/genética , Descolamento Retiniano/patologia , Anormalidades da Pele/genética , Anormalidades da Pele/patologia , Estados Unidos , Adulto Jovem
10.
Genet Med ; 21(8): 1832-1841, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30675029

RESUMO

PURPOSE: Heritable factors play an important etiologic role in connective tissue disorders (CTD) with vascular involvement, and a genetic diagnosis is getting increasingly important for gene-tailored, personalized patient management. METHODS: We analyzed 32 disease-associated genes by using targeted next-generation sequencing and exome sequencing in a clinically relevant cohort of 199 individuals. We classified and refined sequence variants according to their likelihood for pathogenicity. RESULTS: We identified 1 pathogenic variant (PV; in FBN1 or SMAD3) in 15 patients (7.5%) and ≥1 likely pathogenic variant (LPV; in COL3A1, FBN1, FBN2, LOX, MYH11, SMAD3, TGFBR1, or TGFBR2) in 19 individuals (9.6%), together resulting in 17.1% diagnostic yield. Thirteen PV/LPV were novel. Of PV/LPV-negative patients 47 (23.6%) showed ≥1 variant of uncertain significance (VUS). Twenty-five patients had concomitant variants. In-depth evaluation of reported/calculated variant classes resulted in reclassification of 19.8% of variants. CONCLUSION: Variant classification and refinement are essential for shaping mutational spectra of disease genes, thereby improving clinical sensitivity. Obligate stringent multigene analysis is a powerful tool for identifying genetic causes of clinically related CTDs. Nonetheless, the relatively high rate of PV/LPV/VUS-negative patients underscores the existence of yet unknown disease loci and/or oligogenic/polygenic inheritance.


Assuntos
Aorta/fisiopatologia , Doenças do Tecido Conjuntivo/genética , Sequenciamento de Nucleotídeos em Larga Escala , Síndrome de Marfan/genética , Adulto , Aorta/metabolismo , Biomarcadores/metabolismo , Estudos de Coortes , Tecido Conjuntivo/metabolismo , Tecido Conjuntivo/patologia , Doenças do Tecido Conjuntivo/fisiopatologia , Feminino , Testes Genéticos , Humanos , Masculino , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/fisiopatologia
12.
Eur J Hum Genet ; 27(3): 369-377, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30568244

RESUMO

Stickler syndrome is a genetic disorder that can lead to joint problems, hearing difficulties and retinal detachment. Genes encoding collagen types II, IX and XI are usually responsible, but some families have no causal variant identified. We investigate a variant in the gene encoding growth factor BMP4 in a family with Stickler syndrome with associated renal dysplasia. Next generation sequencing of the coding region of COL2A1, COL11A1 and a panel of genes associated with congenital anomalies of the kidney and urinary tract (CAKUT) was performed. A novel heterozygous BMP4 variant causing a premature stop codon, c. 130G>T, p.(Gly44Ter), which segregated with clinical features of Stickler syndrome in multiple family members, was identified. No variant affecting gene function was detected in COL2A1 or COL11A1. Skin fibroblasts were cultured with and without emetine, and the mRNA extracted and analysed by Sanger sequencing to assess whether the change was causing nonsense-mediated decay. Nonsense-mediated decay was not observed from the extracted BMP4 mRNA. BMP4 is a growth factor known to contribute to eye development in animals, and gene variants in humans have been linked to microphthalmia/anophthalmia as well as CAKUT. The variant identified here further demonstrates the importance of BMP4 in eye development. This is the first report of a BMP4 DNA variant causing Stickler syndrome, and we suggest BMP4 be added to standard diagnostic gene panels for this condition.


Assuntos
Artrite/genética , Proteína Morfogenética Óssea 4/genética , Doenças do Tecido Conjuntivo/genética , Perda Auditiva Neurossensorial/genética , Rim/anormalidades , Mutação com Perda de Função , Descolamento Retiniano/genética , Adulto , Artrite/patologia , Proteína Morfogenética Óssea 4/metabolismo , Células Cultivadas , Doenças do Tecido Conjuntivo/patologia , Feminino , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Linhagem , Fenótipo , Descolamento Retiniano/patologia
13.
Am J Med Genet A ; 179(1): 50-56, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30548383

RESUMO

Biallelic variants in the AEBP1 gene cause a novel autosomal-recessive connective tissue disorder (CTD) reminiscent of Ehlers-Danlos Syndrome (EDS). The four previously reported individuals show considerable clinical variability. Unbiased high-throughput sequencing enables the rapid identification of additional cases for such rare entities. We identified the homozygous nonsense variant c.917dup, p.Tyr306* in AEBP1 using clinical exome sequencing in a female individual with previously unsolved CTD. Segregation testing confirmed homozygosity in the clinically affected brother and heterozygous carrier status in the healthy mother. Chromosomal microarray showed that the variant lies in a run of homozygosity, suggesting a common origin of this genomic segment. RT-PCR analysis in the mother revealed a monoallelic expression of the normal transcript supporting a nonsense-mediated mRNA decay and functional nullizygosity as disease mechanism. We describe two individuals from a fourth family with AEBP1-associated CTD. Our results further verify that autosomal-recessive inherited LOF variants in the AEBP1 gene cause clinical features of different EDS subtypes, but also of the marfanoid spectrum. As identification of further individuals is necessary to inform the clinical characterization, we stress the added value of exome sequencing for such rare diseases.


Assuntos
Carboxipeptidases/genética , Doenças do Tecido Conjuntivo/genética , Síndrome de Ehlers-Danlos/genética , Predisposição Genética para Doença , Proteínas Repressoras/genética , Adulto , Códon sem Sentido/genética , Tecido Conjuntivo/metabolismo , Tecido Conjuntivo/patologia , Doenças do Tecido Conjuntivo/fisiopatologia , Síndrome de Ehlers-Danlos/fisiopatologia , Exoma/genética , Feminino , Genes Recessivos , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Mutação com Perda de Função/genética , Masculino , Linhagem , Fenótipo , Irmãos
14.
Clin Genet ; 95(2): 325-328, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30362103

RESUMO

Stickler syndrome is a collagenopathy that is typically inherited as autosomal dominant disease caused by monoallelic mutations in COL2A1, COL11A2, and COL11A1. Rarely, biallelic mutations in COL9A1, COL9A2, and COL9A3 cause an autosomal recessive Stickler syndrome. One previous report described two siblings with Stickler syndrome and a homozygous mutation in LOXL3, suggesting that biallelic mutations in LOXL3 can also cause autosomal recessive Stickler syndrome. LOXL3 is a member of the lysyl oxidase family of genes which encode enzymes oxidizing the side chain of peptidyl lysine permitting the covalent crosslinking of collagen and elastin chains. Therefore, LOXL3 deficiency is expected to result in collagen defect. Furthermore, Loxl3 deficient mouse model demonstrated features overlapping with Stickler syndrome. In this report, we describe a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. This report not only supports that biallelic LOXL3 mutations cause autosomal recessive Stickler syndrome, but also further delineates the phenotype associated with LOXL3 mutations. In addition, the family described here shows an interesting example for pseudodominance, which can be observed in recessive diseases when one parent is affected and the other is heterozygous carrier.


Assuntos
Aminoácido Oxirredutases/genética , Artrite/diagnóstico , Artrite/genética , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/genética , Genes Recessivos , Estudos de Associação Genética , Predisposição Genética para Doença , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Mutação , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/genética , Adulto , Alelos , Substituição de Aminoácidos , Criança , Feminino , Genótipo , Humanos , Masculino , Linhagem , Fenótipo
15.
Semin Cell Dev Biol ; 89: 100-108, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30312775

RESUMO

Collagens are the most abundant vertebrate extracellular matrix proteins. They form a superfamily of 28 members that show a remarkable diversity in molecular and supramolecular organization, tissue distribution and function and mutations in collagen genes result in a wide range of inherited connective tissue diseases. In the recent years, unexpected and very diverse regulatory and mechanical collagen functions have been reported. But the structural and functional landscape of the collagen superfamily is still far from being complete. Zebrafish has emerged over the last decades as a powerful model to interrogate gene function and there are numerous advantages of using zebrafish for collagen research, including recent advances in genome editing technologies and the characterization of the zebrafish matrisome. One can confidently predict that zebrafish will rapidly become a popular vertebrate model to investigate the role of collagens in development, disease and regeneration as discussed in this chapter.


Assuntos
Colágeno/genética , Doenças do Tecido Conjuntivo/genética , Proteínas da Matriz Extracelular/genética , Regeneração/genética , Animais , Doenças do Tecido Conjuntivo/patologia , Matriz Extracelular/genética , Humanos , Modelos Animais , Mutação/genética , Peixe-Zebra/genética
16.
Rev Med Chil ; 146(8): 938-942, 2018 Aug.
Artigo em Espanhol | MEDLINE | ID: mdl-30534875

RESUMO

Ehlers Danlos Syndrome comprises a heterogeneous group of genetic disorders of the connective tissue, due to defects in collagen or its modifying enzymes. We report a 21 years old male presenting with translucent skin revealing the subcutaneous venous pattern. He had a thin face, large-appearing eyes, thin lips, thin nose, joint hypermotility and history of hip dysplasia. A vascular Ehlers Danlos Syndrome was suspected. However, the genetic study to confirm the diagnosis was not done.


Assuntos
Síndrome de Ehlers-Danlos/diagnóstico , Adulto , Doenças do Tecido Conjuntivo/diagnóstico por imagem , Doenças do Tecido Conjuntivo/genética , Síndrome de Ehlers-Danlos/genética , Heterogeneidade Genética , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Adulto Jovem
17.
BMC Med Genet ; 19(1): 212, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30541462

RESUMO

BACKGROUND: Dwarfism is a common severe growth disorder, but the etiology is unclear in the majority of cases. Recombinant human growth hormone may be a treatment option, but it has limited efficacy. The currently known laboratory assays do not meet the precision requirements for clinical diagnosis. Here, we have constructed a targeted next-generation sequencing (NGS) panel of selected genes that are suspected to be associated with dwarfism for genetic screening. METHODS: Genetic screening of 91 children with short stature of unknown etiology was performed with the help of the NGS panel. All the coding regions and exon-intron boundaries of 166 genes were included in the panel. To clarify the pathogenicity of these mutations, their clinical data were reviewed and analyzed. RESULTS: The assay identified p.A72G, p.I282V, and p.P491S variants of the PTPN11 gene and a p.I437T variant of the SOS1 gene in 4 cases with Noonan syndrome. A frameshift mutation (p.D2407fs) of the ACAN gene was identified in a case of idiopathic short stature with moderately advanced bone age. A p.R904C variant of the COL2A1 gene was found in a patient, who was accordingly diagnosed with Stickler syndrome. Severe short stature without limb deformity was associated with a p.G11A variant of HOXD13. In addition, we evaluated evidence that a p.D401N variant of the COMP gene may cause multiple epiphyseal dysplasia. CONCLUSIONS: Our findings suggest that syndromes, particularly Noonan syndrome, may be overlooked due to atypical clinical features. This gene panel has been verified to be effective for the rapid screening of genetic etiologies associated with short stature and for guiding precision medicine-based clinical management.


Assuntos
Artrite/genética , Doenças do Tecido Conjuntivo/genética , Nanismo/genética , Perda Auditiva Neurossensorial/genética , Mutação , Síndrome de Noonan/genética , Osteocondrodisplasias/genética , Descolamento Retiniano/genética , Adolescente , Agrecanas/genética , Artrite/diagnóstico , Artrite/etnologia , Artrite/patologia , Grupo com Ancestrais do Continente Asiático , Proteína de Matriz Oligomérica de Cartilagem/genética , Criança , Pré-Escolar , Colágeno Tipo II/genética , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/etnologia , Doenças do Tecido Conjuntivo/patologia , Nanismo/diagnóstico , Nanismo/etnologia , Nanismo/patologia , Feminino , Expressão Gênica , Testes Genéticos/métodos , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/etnologia , Perda Auditiva Neurossensorial/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/genética , Humanos , Masculino , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/etnologia , Síndrome de Noonan/patologia , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/etnologia , Osteocondrodisplasias/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/etnologia , Descolamento Retiniano/patologia , Proteína SOS1/genética , Fatores de Transcrição/genética
18.
Am J Hum Genet ; 103(6): 976-983, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30449416

RESUMO

We have investigated a distinct disorder with progressive corneal neovascularization, keloid formation, chronic skin ulcers, wasting of subcutaneous tissue, flexion contractures of the fingers, and acro-osteolysis. In six affected individuals from four families, we found one of two recurrent variants in discoidin domain receptor tyrosine kinase 2 (DDR2): c.1829T>C (p.Leu610Pro) or c.2219A>G (p.Tyr740Cys). DDR2 encodes a collagen-responsive receptor tyrosine kinase that regulates connective-tissue formation. In three of the families, affected individuals comprise singleton adult individuals, and parental samples were not available for verification of the de novo occurrence of the DDR2 variants. In the fourth family, a mother and two of her children were affected, and the c.2219A>G missense variant was proven to be de novo in the mother. Phosphorylation of DDR2 was increased in fibroblasts from affected individuals, suggesting reduced receptor autoinhibition and ligand-independent kinase activation. Evidence for activation of other growth-regulatory signaling pathways was not found. Finally, we found that the protein kinase inhibitor dasatinib prevented DDR2 autophosphorylation in fibroblasts, suggesting an approach to treatment. We propose this progressive, fibrotic condition should be designated as Warburg-Cinotti syndrome.


Assuntos
Doenças do Tecido Conjuntivo/genética , Receptor com Domínio Discoidina 2/genética , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Colágeno/genética , Doenças do Tecido Conjuntivo/tratamento farmacológico , Feminino , Fibroblastos/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/genética , Alinhamento de Sequência , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
19.
Am J Med Genet A ; 176(12): 2887-2891, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30450842

RESUMO

Stickler syndrome is a connective tissue disorder characterized by hearing loss, ocular anomalies, palatal defects, and skeletal abnormalities. The autosomal dominant form is the most common, but autosomal recessive forms have also been described. We report the second case of autosomal recessive Stickler syndrome due to homozygosity for a loss of function mutation in COL9A3, which encodes the α3 chain of type IX procollagen. The clinical features were similar to the previously described COL9A3 Stickler syndrome family, including moderate to severe sensorineural hearing loss, high myopia, and both tibial and femoral bowing at birth. Radiographs demonstrated abnormal capital femoral epiphyses and mild irregularities of the vertebral endplates. This case further establishes the phenotype associated with mutations in this gene. We suggest that loss of the α3 chain of type IX collagen results in a Stickler syndrome phenotype similar to that of the other autosomal recessive forms caused by mutations in genes encoding the α1 and α2 chains of type IX collagen.


Assuntos
Artrite/diagnóstico , Artrite/genética , Colágeno Tipo IX/genética , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/genética , Genes Recessivos , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Mutação , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/genética , Criança , Análise Mutacional de DNA , Homozigoto , Humanos , Recém-Nascido , Fenótipo , Radiografia , Sequenciamento Completo do Exoma
20.
Mol Vis ; 24: 560-573, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30181686

RESUMO

Purpose: Our previous study reported that 5.5% of probands with early-onset high myopia (eoHM) had mutations in COL2A1 or COL11A1. Why were the probands initially considered to have eoHM but not Stickler syndrome (STL)? Methods: Probands and family members with eoHM and mutations in COL2A1 or COL11A1 were followed up and reexamined based on the criteria for STL. Further comprehensive examinations were conducted for patients with eoHM and mutations in COL2A1 or COL11A1 and controls with eoHM without mutations in COL2A1 or COL11A1. We performed comparisons between probands, affected family members with mutations in COL2A1 or COL11A1, and controls with eoHM without mutations in COL2A1 or COL11A1. Results: Twelve probands (8.91±4.03 years) and 14 affected family members (37.00±11.18 years) with eoHM and mutations in COL2A1 or COL11A1, as well as 30 controls with eoHM but without mutations in COL2A1 or COL11A1, were recruited. Among them, 25.0% of probands and 50.0% of affected family members met the diagnostic criteria for STL after reexamination. Posterior vitreous detachment/foveal hypoplasia (PVD/FH), hypermobility of the elbow joint (HJ), and vitreous opacity were more frequent in patients with eoHM with mutations in COL2A1 or COL11A1 than in the controls (p = 1.40 × 10-5, 3.72 × 10-4, 2.30× 10-3, respectively). HJ was more common in the probands than in the affected family members (11/12 versus 3/14; p = 3.42 × 10-4), suggesting age-dependent manifestation. EoHM presented in all the probands and in 11/14 affected family members, suggesting that it is a more common indicator of STL than the previously described vitreoretinal abnormalities, especially in children. The rate of STL diagnosis could increase from 25.0% to 66.7% for probands and from 50.0% to 92.9% for affected family members if eoHM, PVD/FH, and HJ are added to the diagnostic criteria. Conclusions: In summary, it is not easy to differentiate STL from eoHM with routine ocular examination in outpatient clinics. Awareness of atypical phenotypes and newly recognized signs may be of help in identifying atypical STL, especially in children at eye clinics.


Assuntos
Artrite/diagnóstico , Artrite/genética , Colágeno Tipo II/genética , Colágeno Tipo XI/genética , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Mutação , Miopia Degenerativa/diagnóstico , Miopia Degenerativa/genética , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/genética , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Diagnóstico Precoce , Feminino , Seguimentos , Estudos de Associação Genética , Humanos , Masculino , Linhagem , Fenótipo , Adulto Jovem
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