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1.
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
Int J Mol Med ; 42(4): 1819-1826, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30015854

RESUMO

Stickler syndrome is a group of inherited connective tissue disorders characterized by distinctive facial and ocular abnormalities, hearing loss and early­onset arthritis. The aim of the present study was to investigate the genetic changes in two Chinese patients with Stickler syndrome, manifested as bilateral retinal detachment and peripheral retinal degeneration. Complete ophthalmic examinations, including best­corrected visual acuity, slit­lamp examination and fundus examination, were performed. Genomic DNA was extracted from leukocytes of the peripheral blood collected from the patients, their unaffected family members and 200 unrelated control subjects from the same population. Next­generation sequencing of established genes associated with ocular disease was performed. A heterozygous collagen type II α1 chain (COL2A1) mutation c.1310G>C (p.R437P) in exon 21 was identified in Family 1 and a heterozygous COL2A1 mutation c.2302­1G>A in intron 34 was identified in Family 2. The functional effects of the mutations were assessed by polymorphism phenotyping (PolyPhen) and sorting intolerant from tolerant (SIFT) analysis. The c.1310G>C mutation was predicted to damage protein structure and function, and the c.2302­1G>A mutation was predicted to result in a splicing defect. The findings of the current study expand the established mutation spectrum of COL2A1, and may facilitate genetic counseling and development of therapeutic strategies for patients with Stickler syndrome.


Assuntos
Artrite/genética , Colágeno Tipo II/genética , Doenças do Tecido Conjuntivo/genética , Perda Auditiva Neurossensorial/genética , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Polimorfismo Genético , Descolamento Retiniano/genética , Adulto , Família , Feminino , Humanos , Masculino
8.
Clin Interv Aging ; 13: 463-472, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29606859

RESUMO

Background: The aim of the research genetic study was to investigate the association between variants (C1431T and Pro12Ala) of the peroxisome proliferator-activated receptor (PPARgamma-2) gene, Trp64Arg polymorphism of the beta-3-adrenergic receptor gene and lipid profile in Polish population including group of 103 patients with connective tissue disease (CTD) and 103 sex-and age-matched controls in context of statin use. Methods: Anthropometric and biochemical parameters were measured by routine methods, followed by genotyping (TagMan® Genotyping Assays, PCR-restriction fragment length polymorphism analysis). Nearly 30% of CTD patients used statins and 10% of the control group. Results: Although there were no differences between alleles and genotypes prevalence between CTD vs control groups, interesting lipid-gene associations were noted in this study. A higher level of triglycerides (TAG) and TAG/high-density lipoprotein (HDL) ratios was observed in CTD patients compared to controls. Similar differences were noted in CTD and control groups without statin treatment. Atherogenic markers: the atherogenic index of plasma, TAG/HDL and low-density lipoprotein/HDL ratio were low in the analyzed groups. Of the six analyzed polymorphisms, the Pro12Pro or C14131C or Trp64Trp genotypes were related to higher TAG and TAG/HDL ratios in patients with CTD; however, the highest TAG values were observed in the presence of the Trp64Trp genotype. Conclusion: Lipid disorders were present in both groups independent of statin treatment (mixed dyslipidemia and hypercholesterolemia were observed in the CTD and control groups, respectively). The risk of dyslipidemia increases with age. The presence of Pro12Pro, C14131C and Trp64Trp genotypes is related to higher TAG level in CTDs, and of these the Trp64Trp variant most reliably predicts hypertriglyceridemia.


Assuntos
Doenças do Tecido Conjuntivo/genética , Dislipidemias/genética , PPAR gama/genética , Receptores Adrenérgicos beta 3/genética , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Doenças do Tecido Conjuntivo/complicações , Dislipidemias/complicações , Dislipidemias/tratamento farmacológico , Genótipo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Pessoa de Meia-Idade , Polônia , Polimorfismo Genético , Triglicerídeos/sangue
9.
Eur J Med Genet ; 61(7): 399-402, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29501612

RESUMO

We report a 29 week fetus with arthrogryposis multiplex congenita, multiple joint dislocations, scoliosis and dysmorphism who was detected to be double heterozygote for putatively pathogenic FBN1 (NM_000138.4:c.6004C > T; p.Pro2002Ser) and FBN2 (NM_001999.3:c.2945G > T; p.Cys982Phe) variants on exome sequencing. The de-novo status of these variants is not confirmed as parental genotypes could not be ascertained. A comparison of the post-mortem findings of the fetus with reported phenotypes of Beals and Marfan syndromes indicated overlapping clinical features suggestive of a blended phenotype.


Assuntos
Doenças do Tecido Conjuntivo/genética , Fibrilina-1/genética , Fibrilina-2/genética , Anormalidades Múltiplas/genética , Aracnodactilia/genética , Artrogripose/genética , Contratura/genética , Exoma/genética , Feto , Heterozigoto , Humanos , Luxações Articulares/genética , Fenótipo , Escoliose/genética , Análise de Sequência de DNA
10.
Wiad Lek ; 71(1 pt 1): 47-51, 2018.
Artigo em Polonês | MEDLINE | ID: mdl-29558351

RESUMO

The available data indicate that seropositive rheumatoid arthritis (RA) develops as a result of systemic, autoimmune reaction directed against a range of "self" peptides/proteins that have undergone specific forms of post-translational modification. The development and progress of autoimmunity may be triggered by non-specific, local inflammatory processes outside the joints, for example in the oral or respiratory mucous membrane. The disease occurs in genetically susceptible individuals under the influence of environmental risk factors that promote autoimmunity and consequently the inflammatory process. Smoking is particularly linked with RA pathogenesis. Synovitis of multiple, symmetrical, peripheral joints is the most typical feature of RA which results in irreversible damage to joints structure and as a consequence in disability of patients. However, the inflammatory process in the course of RA has a systemic, constitutional nature. Therefore, extra-articular symptoms with internal organ involvement may occur additionally to synovitis, what is an unfavorable prognostic factor. Extra-articular manifestations of RA are associated with the high disease activity both inflammatory and immunological. They occur in patients with severe form of the disease and contribute to a significant lifespan reduction. This is usually associated with progressive atherosclerosis and cardiovascular complications. The systemic inhibition of an abnormal immune system activity is the mainstay of the effective RA treatment. The currently used disease modifying antirheumatic drugs affect the activity and function of different constituents of the immune system, including B and T lymphocytes and the main pro-inflammatory cytokines, and contribute to autoimmune and inflammatory processes.


Assuntos
Artrite Reumatoide/etiologia , Autoimunidade , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genética , Doenças do Tecido Conjuntivo/etiologia , Doenças do Tecido Conjuntivo/genética , Predisposição Genética para Doença , Humanos , Inflamação , Fatores de Risco
12.
Clin Genet ; 93(1): 126-133, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28386937

RESUMO

Deletions encompassing TAK1-binding protein 2 (TAB2) associated with isolated and syndromic congenital heart defects. Rare missense variants are found in patients with a similar phenotype as well as in a single individual with frontometaphyseal dysplasia. We describe a family and an additional sporadic patient with polyvalvular heart disease, generalized joint hypermobility and related musculoskeletal complications, soft, velvety and hyperextensible skin, short limbs, hearing impairment, and facial dysmorphism. In the first family, whole-exome sequencing (WES) disclosed the novel TAB2 c.1398dup (p.Thr467Tyrfs*6) variant that eliminates the C-terminal zinc finger domain essential for activation of TAK1 (TGFß-activated kinase 1)-dependent signaling pathways. The sporadic case carryed a ~2 Mb de novo deletion including 28 genes also comprising TAB2. This study reveal an association between TAB2 mutations and a phenotype resembling Ehlers-Danlos syndrome with severe polyvalvular heart disease and subtle facial dysmorphism. Our findings support the existence of a wider spectrum of clinical phenotypes associated with TAB2 perturbations and emphasize the role of TAK1 signaling network in human development.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doenças do Tecido Conjuntivo/genética , Face/anormalidades , Cardiopatias Congênitas/genética , Mutação , Adolescente , Adulto , Saúde da Família , Feminino , Valvas Cardíacas/anormalidades , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem
13.
Cesk Slov Oftalmol ; 74(3): 108-111, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30650974

RESUMO

The authors present the ocular finding in a patient sent to the Department of Paediatric Ophthalmology at the Children's University Hospital - Faculty of Medicine, Comenius University in Bratislava at the age of 3 months, with congenital glaucoma in her right eye and bilateral high myopia. The family anamnesis of the patient shows repeated occurrence of stunted growth, myopia, facial dysmorphia and cataract. The child's mother had high myopia, the mother's brother underwent cataract surgery, the child's grandmother and her sisters and the child's great grandmother had high myopia and glaucoma, and probably underwent cataract surgery at a young age. The child's mother and grandmother underwent a genetic examination, with a conclusion of Marshall syndrome. Within the framework of neonatal screening, poor cortical auditory evoked potential, a defect of the interventricular septum and bifid uvula were diagnosed in the child. With regard to the overall finding in the patient and the genetic family history, we suspected Marshall syndrome. A genetic examination determined Stickler syndrome type 1 with the presence of mutation in the COL2A gene (variant c.2710C >T (p.Arg904Cys,rs121912882)). Due to high intraocular pressure with the impossibility of compensation by medication, bilateral trabuculectomy was performed on the patient. At present the patient has intraocular pressure compensated with adjuvant medicamentous therapy. With regard to high myopia and pronounced degenerative changes on the periphery of the retina in the sense of lattice degeneration, preventive cryopexy of the retinal periphery is planned. A molecular genetic analysis helped diagnose the pathology as Stickler syndrome type 1, which manifested phenotype symptoms of Marshall syndrome or Stickler syndrome type 2. Key words: Marshall syndrome, Stickler syndrome, mid-facial dysmorfism, myopia, glaucoma, cataract.


Assuntos
Artrite , Doenças do Tecido Conjuntivo , Perda Auditiva Neurossensorial , Descolamento Retiniano , Artrite/diagnóstico , Artrite/genética , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/genética , Feminino , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Humanos , Lactente , Masculino , Miopia , Linhagem , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/genética
14.
J Med Case Rep ; 11(1): 237, 2017 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-28841907

RESUMO

BACKGROUND: Stickler syndrome is a group of collagenopathies characterized by ophthalmic, skeletal, and orofacial abnormalities, with the degree of symptoms varying among patients. Mutations in the COL2A1, COL11A1, and COL11A2 procollagen genes cause Stickler syndrome. Marshall syndrome, caused by a COL11A1 mutation, has clinical overlap with Stickler syndrome. CASE PRESENTATION: A 2-year-old Japanese boy was presented to our hospital with short stature (79.1 cm, -2.52 standard deviation). His past medical history was significant for soft cleft palate and bilateral cataracts. He had a flat midface, micrognathia, and limitations in bilateral elbow flexion. Radiographs showed mild spondyloepiphyseal dysplasia. Initially, we suspected Marshall syndrome, but no mutation was identified in COL11A1. At 8 years old, his height was 116.2 cm (-1.89 standard deviation), and his orofacial characteristics appeared unremarkable. We analyzed the COL2A1 gene and found a novel heterozygous mutation (c.1142 G > A, p.Gly381Asp). CONCLUSIONS: In this case report, we identify a novel missense mutation in the COL2A1 gene in a patient with Stickler syndrome type 1, and we describe age-related changes in the clinical phenotype with regard to orofacial characteristics and height. Genetic analysis is helpful for the diagnosis of this clinically variable and genetically heterogeneous disorder.


Assuntos
Artrite/genética , Colágeno Tipo II/genética , Doenças do Tecido Conjuntivo/genética , Perda Auditiva Neurossensorial/genética , Descolamento Retiniano/genética , Artrite/complicações , Artrite/diagnóstico , Catarata/diagnóstico , Catarata/etiologia , Catarata/genética , Criança , Pré-Escolar , Fissura Palatina/etiologia , Fissura Palatina/genética , Colágeno Tipo XI/deficiência , Doenças do Tecido Conjuntivo/complicações , Doenças do Tecido Conjuntivo/diagnóstico , Anormalidades Craniofaciais/diagnóstico , Diagnóstico Diferencial , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/genética , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/diagnóstico , Humanos , Masculino , Micrognatismo/etiologia , Micrognatismo/genética , Mutação , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/etiologia , Osteocondrodisplasias/genética , Palato Mole/anormalidades , Fenótipo , Descolamento Retiniano/complicações , Descolamento Retiniano/diagnóstico
15.
PLoS One ; 12(8): e0182791, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28792542

RESUMO

Fibroproliferative diseases are common complex traits featuring scarring and overgrowth of connective tissue which vary widely in presentation because they affect many organ systems. Most fibroproliferative diseases are more prevalent in African-derived populations than in European populations, leading to pronounced health disparities. It is hypothesized that the increased prevalence of these diseases in African-derived populations is due to selection for pro-fibrotic alleles that are protective against helminth infections. We constructed a genetic risk score (GRS) of fibroproliferative disease risk-increasing alleles using 147 linkage disequilibrium-pruned variants identified through genome-wide association studies of seven fibroproliferative diseases with large African-European prevalence disparities. A comparison of the fibroproliferative disease GRS between 1000 Genomes Phase 3 populations detected a higher mean GRS in AFR (mean = 148 risk alleles) than EUR (mean = 136 risk alleles; T-test p-value = 1.75x10-123). To test whether differences in GRS burden are systematic and may be due to selection, we employed the quantitative trait loci (QTL) sign test. The QTL sign test result indicates that population differences in risk-increasing allele burdens at these fibroproliferative disease variants are systematic and support a model featuring selective pressure (p-value = 0.011). These observations were replicated in an independent sample and were more statistically significant (T-test p-value = 7.26x10-237, sign test p-value = 0.015). This evidence supports the role of selective pressure acting to increase frequency of fibroproliferative alleles in populations of African relative to European ancestry populations.


Assuntos
Doenças do Tecido Conjuntivo/etnologia , Doenças do Tecido Conjuntivo/genética , Predisposição Genética para Doença , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/etnologia , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Seleção Genética , Grupo com Ancestrais do Continente Africano/genética , Bases de Dados Genéticas , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Prevalência , Locos de Características Quantitativas , Medição de Risco
16.
J Med Genet ; 54(10): 710-720, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28735299

RESUMO

BACKGROUND: The laminin alpha 5 gene (LAMA5) plays a master role in the maintenance and function of the extracellular matrix (ECM) in mammalian tissues, which is critical in developmental patterning, stem cell niches, cancer and genetic diseases. Its mutations have never been reported in human disease so far. The aim of this study was to associate the first mutation in LAMA5 gene to a novel multisystem syndrome. METHODS: A detailed characterisation of a three-generation family, including clinical, biochemical, instrumental and morphological analysis, together with genetics and expression (WES and RNAseq) studies, was performed. RESULTS: The heterozygous LAMA5 mutation c.9418G>A (p.V3140M) was associated with skin anomalies, impaired scarring, night blindness, muscle weakness, osteoarthritis, joint and internal organs ligaments laxity, malabsorption syndrome and hypothyroidism. We demonstrated that the mutation alters the amount of LAMA5 peptides likely derived from protein cleavage and perturbs the activation of the epithelial-mesenchymal signalling, producing an unbalanced expression of Sonic hedgehog and GLI1, which are upregulated in cells from affected individuals, and of ECM proteins (COL1A1, MMP1 and MMP3), which are strongly inhibited. Studies carried out using human skin biopsies showed alteration of dermal papilla with a reduction of the germinative layer and an early arrest of hair follicle downgrowth. The knock-in mouse model, generated in our laboratory, shows similar changes in the tissues studied so far. CONCLUSIONS: This is the first report of a disease phenotype associated with LAMA5 mutation in humans.


Assuntos
Doenças do Tecido Conjuntivo/genética , Matriz Extracelular/fisiologia , Laminina/genética , Mutação , Animais , Oftalmopatias/genética , Feminino , Técnicas de Introdução de Genes , Humanos , Masculino , Camundongos , Doenças Musculares/genética , Linhagem , Fenótipo , Anormalidades da Pele/genética , Síndrome
17.
Eur J Med Genet ; 60(5): 275-278, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28315471

RESUMO

Stickler syndrome, a clinically as well as molecularly heterogeneous connective tissue disorder, is predominantly inherited in an autosomal dominant manner and is considered complete penetrant. Previously, mosaicism in Stickler syndrome has been reported in only a few cases. We describe a child with Stickler syndrome due to a novel splice site mutation in COL11A1. Initially, Sanger sequencing of both parents showed normal test results for the mutation. Due to mild phenotypic traits, the father was tested again using a more sensitive method (NGS), and was found to have low-grade mosaicism in various tissue samples (range 7-22% of the DNA). Therefore, we recommend using sensitive genetic testing when mosaicism is suspected. Furthermore, we support previous suggestions of parental testing even when the parents of an affected patient do not have obvious phenotypic signs of Stickler syndrome.


Assuntos
Colágeno Tipo XI/deficiência , Doenças do Tecido Conjuntivo/genética , Mosaicismo , Descolamento do Vítreo/genética , Criança , Colágeno Tipo XI/genética , Feminino , Humanos
18.
Am J Med Genet C Semin Med Genet ; 175(1): 8-26, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28306229

RESUMO

The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen-encoding genes, or in genes encoding collagen-modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes. © 2017 Wiley Periodicals, Inc.


Assuntos
Síndrome de Ehlers-Danlos/classificação , Guias de Prática Clínica como Assunto , Colágeno/genética , Doenças do Tecido Conjuntivo/genética , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Heterogeneidade Genética , Humanos , Mutação
19.
Ophthalmology ; 124(6): 896-902, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28283280

RESUMO

PURPOSE: To determine the microstructure of the fovea in patients with Stickler syndrome using imaging by spectral-domain optical coherence tomography (SD OCT) and swept-source OCT. DESIGN: Retrospective case series study. PARTICIPANTS: A total of 39 eyes of 25 patients with genetically confirmed Stickler syndrome were studied. METHODS: All of the patients had mutations in the COL2A1 gene and were diagnosed with Stickler syndrome. Cross-sectional OCT images, OCT angiography (OCTA), and en face OCT images were assessed. The ratio of the foveal inner retinal layer (fIRL) thickness to the parafoveal inner retinal layer (pIRL) thickness, the ratio of the foveal outer retinal layer (fORL) thickness to the parafoveal outer retinal layer (pORL) thickness, and the size of the foveal avascular zone (FAZ) were determined. MAIN OUTCOME MEASURES: The degree of foveal hypoplasia and the best-corrected visual acuity in patients with Stickler syndrome. RESULTS: A persistence of the inner retinal layers in the fovea with an fIRL/pIRL ratio >0.2 was present in 32 of the 39 eyes (82%). Optical coherence tomography angiography showed that the FAZ was smaller, 0 to 0.19 mm2, than that of normal eyes, in 25 eyes of 17 patients who underwent OCTA. There was no significant correlation between the visual acuities and the fIRL/pIRL ratios. CONCLUSIONS: A mild foveal hypoplasia with a persistence of the IRL is characteristic of eyes with Stickler syndrome. The visual acuities were not correlated with the fIRL/pIRL ratios.


Assuntos
Artrite/diagnóstico , Doenças do Tecido Conjuntivo/diagnóstico , Anormalidades do Olho/patologia , Fóvea Central/anormalidades , Perda Auditiva Neurossensorial/diagnóstico , Descolamento Retiniano/diagnóstico , Adolescente , Adulto , Artrite/genética , Artrite/fisiopatologia , Criança , Pré-Escolar , Colágeno Tipo II/genética , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/fisiopatologia , Estudos Transversais , Anormalidades do Olho/diagnóstico por imagem , Feminino , Angiofluoresceinografia , Fóvea Central/diagnóstico por imagem , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Descolamento Retiniano/genética , Descolamento Retiniano/fisiopatologia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Adulto Jovem
20.
Morphologie ; 101(332): 33-38, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28159459

RESUMO

The Stickler syndrome (SS) has been described as a "hereditary progressive arthro-ophtalmopathy" by Stickler in 1965, due to mutations on the collagen genes. Currently about 40 different genes have been identified which encode for at least 27 different collagens. The majority of mutations occur in the COL2A1 gene on chromosome 12q13 (SS type I). Mutations in COL11A1 are less frequent (SS type II). More recently, mutations in COL11A2 and in the COL9A1 gene have been reported with particular phenotypes. The main features of this autosomal inherited disease are ocular, auditory with orofacial abnormalities and early-onset osteoarthritis. We report the clinical presentation of an adult and his son, with a particular focus on the bone status of the father, radiography, bone densitometry and transiliac bone biopsy showing that he was suffering from osteoporosis. The lumbar bone mineral density was low with a Z-score at -2.9. Transiliac bone biopsy showed a dramatic decrease of trabecular bone volume (8.6%; Nl: 19.5±4.9%), thin trabeculae and a disorganized trabecular network. A slight increase of osteoid parameters was observed. Bone resorption was markedly increased with an excessive number of active (TRAcP+) osteoclasts. The cortical width was normal, but a slight increase of cortical porosity was found. Osteoporosis has been rarely described in the SS. It might be useful to systematically perform a bone densitometry in all patients with SS and to discuss the indication of a transiliac bone biopsy in severe cases.


Assuntos
Artrite/complicações , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Doenças do Tecido Conjuntivo/complicações , Perda Auditiva Neurossensorial/complicações , Osteoporose/diagnóstico por imagem , Descolamento Retiniano/complicações , Adulto , Artrite/sangue , Artrite/diagnóstico por imagem , Artrite/genética , Dor nas Costas/etiologia , Criança , Colágeno Tipo II/genética , Colágeno Tipo XI/genética , Doenças do Tecido Conjuntivo/sangue , Doenças do Tecido Conjuntivo/diagnóstico por imagem , Doenças do Tecido Conjuntivo/genética , Densitometria , Perda Auditiva Neurossensorial/sangue , Perda Auditiva Neurossensorial/diagnóstico por imagem , Perda Auditiva Neurossensorial/genética , Humanos , Masculino , Mutação , Miopia/etiologia , Osteoporose/etiologia , Fenótipo , Radiografia , Descolamento Retiniano/sangue , Descolamento Retiniano/diagnóstico por imagem , Descolamento Retiniano/genética
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