Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 150
Filtrar
1.
Am J Hum Genet ; 109(12): 2230-2252, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36351433

RESUMO

EMILIN1 (elastin-microfibril-interface-located-protein-1) is a structural component of the elastic fiber network and localizes to the interface between the fibrillin microfibril scaffold and the elastin core. How EMILIN1 contributes to connective tissue integrity is not fully understood. Here, we report bi-allelic EMILIN1 loss-of-function variants causative for an entity combining cutis laxa, arterial tortuosity, aneurysm formation, and bone fragility, resembling autosomal-recessive cutis laxa type 1B, due to EFEMP2 (FBLN4) deficiency. In both humans and mice, absence of EMILIN1 impairs EFEMP2 extracellular matrix deposition and LOX activity resulting in impaired elastogenesis, reduced collagen crosslinking, and aberrant growth factor signaling. Collagen fiber ultrastructure and histopathology in EMILIN1- or EFEMP2-deficient skin and aorta corroborate these findings and murine Emilin1-/- femora show abnormal trabecular bone formation and strength. Altogether, EMILIN1 connects elastic fiber network with collagen fibril formation, relevant for both bone and vascular tissue homeostasis.


Assuntos
Doenças Ósseas Metabólicas , Cútis Laxa , Animais , Humanos , Camundongos , Colágeno/genética , Cútis Laxa/genética , Elastina/metabolismo , Proteínas da Matriz Extracelular/metabolismo
2.
Am J Hum Genet ; 108(6): 1095-1114, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33991472

RESUMO

Latent transforming growth factor ß (TGFß)-binding proteins (LTBPs) are microfibril-associated proteins essential for anchoring TGFß in the extracellular matrix (ECM) as well as for correct assembly of ECM components. Variants in LTBP2, LTBP3, and LTBP4 have been identified in several autosomal recessive Mendelian disorders with skeletal abnormalities with or without impaired development of elastin-rich tissues. Thus far, the human phenotype associated with LTBP1 deficiency has remained enigmatic. In this study, we report homozygous premature truncating LTBP1 variants in eight affected individuals from four unrelated consanguineous families. Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly). In vitro studies on proband-derived dermal fibroblasts indicate distinct molecular mechanisms depending on the position of the variant in LTBP1. C-terminal variants lead to an altered LTBP1 loosely anchored in the microfibrillar network and cause increased ECM deposition in cultured fibroblasts associated with excessive TGFß growth factor activation and signaling. In contrast, N-terminal truncation results in a loss of LTBP1 that does not alter TGFß levels or ECM assembly. In vivo validation with two independent zebrafish lines carrying mutations in ltbp1 induce abnormal collagen fibrillogenesis in skin and intervertebral ligaments and ectopic bone formation on the vertebrae. In addition, one of the mutant zebrafish lines shows voluminous and hypo-mineralized vertebrae. Overall, our findings in humans and zebrafish show that LTBP1 function is crucial for skin and bone ECM assembly and homeostasis.


Assuntos
Colágeno/metabolismo , Cútis Laxa/etiologia , Variação Genética , Proteínas de Ligação a TGF-beta Latente/genética , Adolescente , Alelos , Animais , Células Cultivadas , Criança , Pré-Escolar , Cútis Laxa/patologia , Matriz Extracelular/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Lactente , Masculino , Linhagem , Pele/metabolismo , Pele/patologia , Peixe-Zebra
3.
Mol Genet Genomics ; 299(1): 81, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39172257

RESUMO

Autosomal-recessive cutis laxa type 2 (ARCL2) is a rare genetic disorder caused by pyrroline-5-carboxylate reductase 1 (PYCR1) mutations and characterized by loose and sagging skin, typical facial features, intrauterine growth retardation, and developmental delay. To study the effect of PYCR1 mutations on protein function and clinical features, we identified a homozygous missense mutation c.559G > A (p.Ala187Thr) in PYCR1 in a Chinese child with typical clinical features, especially severe developmental delays. The three-dimensional (3D) model showed the modification of the hydrogen bonds produce a misfolding in the mutant PYCR1 protein. Mutagenesis and enzyme assay study revealed decreased activity of the mutant protein in vitro, indicating that this mutation impairs PYCR1 function. Our findings confirmed abnormal enzymatic activity and neurodevelopmental trajectory of this PYCR1 mutation.


Assuntos
Cútis Laxa , Mutação de Sentido Incorreto , Pirrolina Carboxilato Redutases , delta-1-Pirrolina-5-Carboxilato Redutase , Humanos , Cútis Laxa/genética , Cútis Laxa/patologia , Pirrolina Carboxilato Redutases/genética , Pirrolina Carboxilato Redutases/metabolismo , Masculino , Feminino , Pré-Escolar , Modelos Moleculares , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Homozigoto , Genes Recessivos , Mutação
4.
Mol Biol Rep ; 51(1): 498, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38598037

RESUMO

BACKGROUND: Cutis laxa is a connective tissue disease caused by abnormal synthesis or secretion of skin elastic fibers, leading to skin flabby and saggy in various body parts. It can be divided into congenital cutis laxa and acquired cutis laxa, and inherited cutis laxa syndromes is more common in clinic. METHODS: In this study, we reported a case of a Han-Chinese male newborn with ATP6V0A2 gene variant leading to cutis laxa. The proband was identified by whole-exome sequencing to determine the novel variant, and their parents were verified by Sanger sequencing. Bioinformatics analysis and minigene assay were used to verify the effect of this variant on splicing function. RESULTS: The main manifestations of the proband are skin laxity, abnormal facial features, and enlargement of the anterior fontanelle. Whole-exome sequencing showed that the newborn carried a non-canonical splicing-site variant c.117 + 5G > T, p. (?) in ATP6V0A2 gene. Sanger sequencing showed that both parents of the proband carried the heterozygous variant. The results of bioinformatics analysis and minigene assay displayed that the variant site affected the splicing function of pre-mRNA of the ATP6V0A2 gene. CONCLUSIONS: In this study, it was identified that ATP6V0A2 gene c. 117 + 5G > T may be the cause of the disease. The non-canonical splicing variants of ATP6V0A2 gene were rarely reported in the past, and this variant expanded the variants spectrum of the gene. The functional study of minigene assay plays a certain role in improving the level of evidence for the pathogenicity of splicing variants, which lays a foundation for prenatal counseling and follow-up gene therapy.


Assuntos
Cútis Laxa , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Povo Asiático/genética , China , Cútis Laxa/genética , ATPases Translocadoras de Prótons , Splicing de RNA/genética , Pele
5.
BMC Pulm Med ; 24(1): 481, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39354494

RESUMO

BACKGROUND: Cutis laxa constitutes a diverse group of connective tissue diseases, both inherited and acquired, characterized by loose skin and varying systemic involvement, including pulmonary lesions. While cutis laxa has been linked to conditions like emphysema, asthma, and bronchiectasis, the specific pathological and radiological characteristics underlying pulmonary complications related to cutis laxa remain unclear. CASE PRESENTATION: A 36-year-old woman, diagnosed with cutis laxa at birth, presented to our outpatient clinic with severe obstructive ventilatory impairment, evident in pulmonary function tests (expiratory volume in one second (FEV1)/forced vital capacity (FVC): 34.85%; %residual volume [RV]: 186.5%; %total lung capacity [TLC]: 129.2%). Pulmonary function tests also indicated small airway disease (%FEF50%, 7.9%; %FEF75%, 5.7%; and %FEF25-75%, 6.8%). Computed tomography (CT) revealed the lack of normal increase in lung attenuation on expiratory CT scan, with no discernible emphysematous changes. Exome sequencing was performed to confirm the association between the pulmonary lesions and cutis laxa, revealing a frameshift variant in exon 30 of the elastin gene (ELN). Further analysis employing a parametric response map revealed a longitudinal increase in the percentage of functional small airway disease (fSAD) from 37.84% to 46.61% over the 8-year follow-up, despite the absence of overt changes in CT findings, specifically the lack of normal increase in lung attenuation on expiratory CT scan. Over the same follow-up interval, there was a modest reduction of 25.6 mL/year in FEV1 coupled with a significant increase in %RV. Pulmonary function test metrics, reflective of small airway disease, exhibited a continual decline; specifically, %FEF50%, %FEF75%, and %FEF25-75% diminished from 7.9% to 7.0%, 5.7% to 4.6%, and 6.8% to 5.4%, respectively. CONCLUSIONS: This case highlighted an instance of autosomal dominant cutis laxa arising from a frameshift variant in exon 30 of ELN, accompanied by small airway disease. Comprehensive investigation, utilizing quantitative CT analysis, revealed a longitudinal increase in fSAD percentage with a mild reduction in FEV1. These findings indicate that elastin deficiency may not only diminish elastic fibers in the skin but also be implicated in small airway disease by impacting components of the extracellular matrix in the lungs.


Assuntos
Cútis Laxa , Elastina , Mutação da Fase de Leitura , Adulto , Feminino , Humanos , Cútis Laxa/genética , População do Leste Asiático , Elastina/genética , Éxons , Seguimentos , Japão , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Testes de Função Respiratória , Tomografia Computadorizada por Raios X
6.
Int J Mol Sci ; 25(4)2024 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-38396846

RESUMO

Vacuolar ATPases (V-ATPases), proton pumps composed of 16 subunits, are necessary for a variety of cellular functions. Subunit "a" has four isoforms, a1-a4, each with a distinct cellular location. We identified a phosphoinositide (PIP) interaction motif, KXnK(R)IK(R), conserved in all four isoforms, and hypothesize that a/PIP interactions regulate V-ATPase recruitment/retention to different organelles. Among the four isoforms, a2 is enriched on Golgi with a2 mutations in the PIP motif resulting in cutis laxa. We hypothesize that the hydrophilic N-terminal (NT) domain of a2 contains a lipid-binding domain, and mutations in this domain prevent interaction with Golgi-enriched PIPs, resulting in cutis laxa. We recreated the cutis laxa-causing mutation K237_V238del, and a double mutation in the PIP-binding motif, K237A/V238A. Circular dichroism confirmed that there were no protein structure alterations. Pull-down assays with PIP-enriched liposomes revealed that wildtype a2NT preferentially binds phosphatidylinositol 4-phosphate (PI(4)P), while mutants decreased binding to PI(4)P. In HEK293 cells, wildtype a2NT was localized to Golgi and co-purified with microsomal membranes. Mutants reduced Golgi localization and membrane association. Rapamycin depletion of PI(4)P diminished a2NT-Golgi localization. We conclude that a2NT is sufficient for Golgi retention, suggesting the lipid-binding motif is involved in V-ATPase targeting and/or retention. Mutational analyses suggest a molecular mechanism underlying how a2 mutations result in cutis laxa.


Assuntos
Cútis Laxa , ATPases Vacuolares Próton-Translocadoras , Humanos , Cútis Laxa/genética , Cútis Laxa/metabolismo , Células HEK293 , Isoformas de Proteínas/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , Mutação
7.
Am J Med Genet A ; 191(12): 2898-2902, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37655511

RESUMO

We report a 10-year-old boy with a de novo pathogenic variant in ALDH18A1, a rare form of metabolic cutis laxa, which was complicated by atlantoaxial instability and spinal cord compression following a fall from standing height. The patient required emergent cervical spine fusion and decompression followed by a 2-month hospitalization and rehabilitation. In addition to the core clinical features of joint and skin laxity, hypotonia, and developmental delays, we expand the connective tissue phenotype by adding a new potential feature of cervical spine instability. Patients with pathogenic variants in ALDH18A1 may warrant cervical spine screening to minimize possible morbidity. Neurosurgeons, geneticists, primary care providers, and families should be aware of the increased risk of severe cervical injury from minor trauma.


Assuntos
Cútis Laxa , Instabilidade Articular , Doenças da Coluna Vertebral , Masculino , Humanos , Criança , Instabilidade Articular/diagnóstico , Instabilidade Articular/genética , Cútis Laxa/genética , Mutação , Vértebras Cervicais/cirurgia , Vértebras Cervicais/patologia
8.
Am J Med Genet A ; 188(11): 3343-3349, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35972031

RESUMO

Cutis laxa (CL) is a rare connective tissue disorder characterized by wrinkled, abundant and sagging skin, sometimes associated with systemic impairment. Biallelic alterations in latent transforming growth factor beta-binding protein 4 gene (LTBP4) cause autosomal recessive type 1C cutis laxa (ARCL1C, MIM #613177). The present report describes the case of a 17-months-old girl with cutis laxa together with a literature review of previous ARCL1C cases. Based on proband main clinical signs (cutis laxa and pulmonary emphysema), clinical exome sequencing (CES) was performed and showed a new nine base-pairs homozygous in-frame deletion in LTBP4 gene. RT-PCR and cDNA Sanger sequencing were performed in order to clarify its impact on RNA. This report demonstrates that a genetic alteration in the EGF-like 14 domain calcium-binding motif of LTBP4 gene is likely responsible for cutis laxa in our patient.


Assuntos
Cútis Laxa , Cálcio , Doenças das Cartilagens , Cútis Laxa/genética , DNA Complementar , Fator de Crescimento Epidérmico , Feminino , Gastroenteropatias , Humanos , Lactente , Proteínas de Ligação a TGF-beta Latente/genética , RNA , Doenças Respiratórias , Fator de Crescimento Transformador beta , Doenças Urológicas
9.
Mol Biol Rep ; 49(5): 4135-4140, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35445908

RESUMO

BACKGROUND: Autosomal recessive cutis laxa (ARCL) is a heterogeneous disorder with three primary forms (ARCL 1, ARCL 2 and ARCL 3). Latent transforming growth factor beta binding protein 4 (LTBP4) anomalies cause ARCL1C and are connected to different problems in the skin and other organs. Herein, we present a seven month old Iranian boy with a clinical manifestation of ARCL1 with literature review of previous cases with attributes of ARCL1C. METHODS: Considering the craniofacial characteristics and respiratory distress of the proband, cutis laxa (CL) was expected and whole-exome sequencing (WES) was performed. RESULTS: In the proband, signs of CL were mainly located in the face, thorax, and abdomen. The prenatal investigation revealed a diaphragmatic hernia and certain uncommon signs, such as an atrial septal defect and pyloric stenosis. The WES showed a novel homozygous mutation (c.533-1G > A) in exon six of the LTBP4 gene. CONCLUSION: This report showed a new variant with uncommon clinical features, such as a stenosis atrial septal defect and pyloric stenosis, which causes ARCL1C. Unfortunately, the proband developed several heart problems and died at the age of seven months and seven days. Thus, a more in-depth evaluation is needed to clarify the different aspects of CL related to LTBP4 disorder.


Assuntos
Cútis Laxa , Comunicação Interatrial , Estenose Pilórica , Doenças das Cartilagens , Cútis Laxa/genética , Gastroenteropatias , Humanos , Lactente , Irã (Geográfico) , Proteínas de Ligação a TGF-beta Latente/genética , Masculino , Doenças Respiratórias , Doenças Urológicas
10.
Pediatr Dermatol ; 39(2): 312-313, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34929762

RESUMO

Acquired cutis laxa type II (Marshall syndrome) is a post-inflammatory elastolysis occurring in infancy and childhood. It is challenging to treat with very few effective treatment options available. Herein, we describe the case of a 3-month-old boy with acquired cutis laxa type II secondary to a neutrophilic dermatosis. Early treatment of the initial inflammatory phase is essential to reduce the permanent sequelae.


Assuntos
Anormalidades Craniofaciais , Cútis Laxa , Perda Auditiva Neurossensorial , Linfadenopatia , Osteocondrodisplasias , Faringite , Estomatite Aftosa , Catarata , Criança , Colágeno Tipo XI/deficiência , Cútis Laxa/complicações , Cútis Laxa/diagnóstico , Humanos , Lactente , Masculino , Osteocondrodisplasias/complicações , Síndrome
11.
Mol Genet Metab ; 134(1-2): 87-95, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34304991

RESUMO

Cutaneous signs and symptoms may facilitate the diagnosis or can help in identifying complications or side effects of overtreatment of inherited metabolic diseases. The principal manifestations can be grouped into vascular lesions, ichthyosis, papular and nodular skin lesions, abnormal pigmentation, photosensitivity, skin laxity, hair shaft involvement, and nail abnormalities. We have summarized associations of these cutaneous signs and symptoms in 252 inherited metabolic diseases. This represents the sixth of a series of articles attempting to create and maintain a comprehensive list of clinical and metabolic differential diagnoses according to system involvement.


Assuntos
Doenças Metabólicas/fisiopatologia , Erros Inatos do Metabolismo/fisiopatologia , Dermatopatias/fisiopatologia , Pele/patologia , Diagnóstico Diferencial , Humanos , Ictiose/diagnóstico , Ictiose/fisiopatologia , Erros Inatos do Metabolismo/diagnóstico , Sobretratamento
12.
Clin Genet ; 100(2): 168-175, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33866545

RESUMO

We report three babies from two families with a severe lethal form of congenital cutis laxa. All three had redundant and doughy-textured skin and two siblings from one family had facial dysmorphism. Echocardiograms showed thickened and poorly contractile hearts, arterial dilatation and tortuosity. Post-mortem examination in two of the babies further revealed widespread ectasia and tortuosity of medium and large sized arteries, myocardial hypertrophy, rib and skull fractures. The presence of fractures initially suggested a diagnosis of osteogenesis imperfecta. Under light microscopy bony matrices were abnormal and arterial wall architecture was grossly abnormal showing fragmented elastic fibres. Molecular analysis of known cutis laxa genes did not yield any pathogenic defects. Whole exome sequencing of DNA following informed consent identified two separate homozygous variants in the LOX (Lysyl Oxidase) gene. LOX belongs to the 5-lysyl oxidase gene family involved in initiation of cross-linking of elastin and collagen. A mouse model of a different variant in this gene recapitulates the phenotype seen in the three babies. Our findings suggest that the LOX gene is a novel cause of severe congenital cutis laxa with arterial tortuosity, bone fragility and respiratory failure.


Assuntos
Anormalidades Múltiplas/etiologia , Cútis Laxa/genética , Proteína-Lisina 6-Oxidase/genética , Anormalidades Múltiplas/genética , Adulto , Cútis Laxa/etiologia , Face/anormalidades , Feminino , Homozigoto , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Gravidez
13.
Clin Genet ; 99(1): 53-66, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33058140

RESUMO

Cutis laxa (CL) syndromes comprise a rare group of multisystem disorders that share loose redundant skin folds as hallmark clinical feature. CL results from impaired elastic fiber assembly and homeostasis, and the known underlying gene defects affect different extracellular matrix proteins, intracellular trafficking, or cellular metabolism. Due to the underlying clinical and molecular heterogeneity, the diagnostic work-up of CL patients is often challenging. In this review, we provide a practical approach to the broad differential diagnosis of CL syndromes, provide an overview of the molecular pathogenesis of the different subtypes, and suggest general management guidelines.


Assuntos
Cútis Laxa/fisiopatologia , Proteínas da Matriz Extracelular/genética , Pele/fisiopatologia , Cútis Laxa/genética , Matriz Extracelular/genética , Humanos , Mutação/genética
14.
Exp Dermatol ; 30(1): 25-37, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32920888

RESUMO

Supramolecular networks composed of fibrillins (fibrillin-1 and fibrillin-2) and associated ligands form intricate cellular microenvironments which balance skin homoeostasis and direct remodelling. Fibrillins assemble into microfibrils which are not only indispensable for conferring elasticity to the skin, but also control the bioavailability of growth factors targeted to the extracellular matrix architecture. Fibrillin microfibrils (FMF) represent the core scaffolds for elastic fibre formation, and they also decorate the surface of elastic fibres and form independent networks. In normal dermis, elastic fibres are suspended in a three-dimensional basket-like lattice of FMF intersecting basement membranes at the dermal-epidermal junction and thus conferring pliability to the skin. The importance of FMF for skin homoeostasis is illustrated by the clinical features caused by mutations in the human fibrillin genes (FBN1, FBN2), summarized as "fibrillinopathies." In skin, fibrillin mutations result in phenotypes ranging from thick, stiff and fibrotic skin to thin, lax and hyperextensible skin. The most plausible explanation for this spectrum of phenotypic outcomes is that FMF regulate growth factor signalling essential for proper growth and homoeostasis of the skin. Here, we will give an overview about the current understanding of the underlying pathomechanisms leading to fibrillin-dependent fibrosis as well as forms of cutis laxa caused by mutational inactivation of FMF-associated ligands.


Assuntos
Doenças do Tecido Conjuntivo/genética , Tecido Elástico/metabolismo , Fibrilinas/genética , Fibrilinas/metabolismo , Homeostase , Pele/metabolismo , Animais , Doenças do Desenvolvimento Ósseo/genética , Tecido Elástico/ultraestrutura , Elasticidade , Fibrilinas/ultraestrutura , Fibrose , Humanos , Deformidades Congênitas dos Membros/genética , Microfibrilas/metabolismo , Microfibrilas/ultraestrutura , Conformação Molecular , Transdução de Sinais , Pele/patologia , Pele/ultraestrutura , Fenômenos Fisiológicos da Pele , Fator de Crescimento Transformador beta/metabolismo
15.
Am J Med Genet A ; 185(3): 955-965, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33369135

RESUMO

ATP6V0A2-related cutis laxa, also known as autosomal recessive cutis laxa type 2A (ARCL2A), is a subtype of hereditary cutis laxa originally characterized by skin, skeletal, and neurological involvement, and a combined defect of N-glycosylation and O-glycosylation. The associated clinical spectrum subsequently expanded to a less severe phenotype dominated by cutaneous involvement. At the moment, ARCL2A was described in a few case reports and series only. An Italian adult woman ARCL2A with a phenotype restricted to skin and the two novel c.3G>C and c.1101dup ATP6V0A2 variants has been reported. A systematic literature review allowed us to identify 69 additional individuals from 64 families. Available data were scrutinized in order to describe the clinical and molecular variability of ARCL2A. About 78.3% of known variants were predicted null alleles, while 11 were missense and 2 affected noncanonical splice sites. Age at ascertainment appeared as the unique phenotypic discriminator with earlier age more commonly associated with facial dysmorphism (p .02), high/cleft palate (p .005), intellectual disability/global developmental delay (p .013), and seizures (p .024). No specific genotype-phenotype correlations were identified. This work confirmed the existence of an attenuated phenotype associated with ATP6V0A2 biallelic variants and offers an updated critique to the clinical and molecular variability of ARCL2A.


Assuntos
Cútis Laxa/genética , ATPases Translocadoras de Prótons/genética , Adulto , Fatores Etários , Alelos , Sequência de Bases , Códon sem Sentido , Cútis Laxa/diagnóstico , Éxons/genética , Feminino , Mutação da Fase de Leitura , Genes Recessivos , Estudos de Associação Genética , Heterogeneidade Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Expectativa de Vida , Mutação com Perda de Função , Mutação de Sentido Incorreto , Linhagem , Fenótipo , ATPases Translocadoras de Prótons/deficiência , Sítios de Splice de RNA/genética , Pele/patologia
16.
J Inherit Metab Dis ; 44(4): 972-986, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33320377

RESUMO

Several inborn errors of metabolism show cutis laxa as a highly recognizable feature. One group of these metabolic cutis laxa conditions is autosomal recessive cutis laxa type 2 caused by defects in v-ATPase components or the mitochondrial proline cycle. Besides cutis laxa, muscular hypotonia and cardiac abnormalities are hallmarks of autosomal recessive cutis laxa type 2D (ARCL2D) due to pathogenic variants in ATP6V1A encoding subunit A of the v-ATPase. Here, we report on three affected individuals from two families with ARCL2D in whom we performed whole exome and Sanger sequencing. We performed functional studies in fibroblasts from one individual, summarized all known probands' clinical, molecular, and biochemical features and compared them, also to other metabolic forms of cutis laxa. We identified novel missense and the first nonsense variant strongly affecting ATP6V1A expression. All six ARCL2D affected individuals show equally severe cutis laxa and dysmorphism at birth. While for one no information was available, two died in infancy and three are now adolescents with mild or absent intellectual disability. Muscular weakness, ptosis, contractures, and elevated muscle enzymes indicated a persistent myopathy. In cellular studies, a fragmented Golgi compartment, a delayed Brefeldin A-induced retrograde transport and glycosylation abnormalities were present in fibroblasts from two individuals. This is the second and confirmatory report on pathogenic variants in ATP6V1A as the cause of this extremely rare condition and the first to describe a nonsense allele. Our data highlight the tremendous clinical variability of ATP6V1A related phenotypes even within the same family.


Assuntos
Cútis Laxa/genética , Mutação de Sentido Incorreto , ATPases Vacuolares Próton-Translocadoras/genética , Adolescente , Alelos , Estudos de Casos e Controles , Fibroblastos/metabolismo , Complexo de Golgi/metabolismo , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Linhagem , Fenótipo
17.
BMC Pregnancy Childbirth ; 21(1): 548, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34384376

RESUMO

BACKGROUND: Arterial tortuosity syndrome (ATS) is a rare autosomal recessive connective tissue disorder chiefly characterized by elongated and tortuosity of the large and medium sized arteries and anomalies of the vascular elastic fibers. Here we reported cases of brother about ATS from the same family on the prenatal ultrasound diagnosis. Reports of this case are rare in antenatally and we draw the vessel simulated diagram to display visually. CASE PRESENTATION: Prenatal ultrasound scanning at 29 weeks of gestation of the first fetus showed obvious tortuous and elongated of the aortic arch, ductus arteriosus, left and right pulmonary arteries, carotid and subclavian arteries. Three months after delivery, Contrast-enhanced computed tomography images (CTA) were performed to clearly display vascular abnormalities consistent with prenatal diagnosis of ultrasound. Whole exome sequencing (WES) was performed eight months after birth, two heterozygous variants of SLC2A10 gene was detected in newborn and their father and mother, respectively. Prenatal ultrasound scan at 22 weeks of gestation of the second fetus showed similar cardiovascular imaging. After birth the siblings have facial characteristic features gradually as aging. No surgical intervention was performed in the siblings follow up 19 months. CONCLUSIONS: The key points of prenatal ultrasound diagnosis of ATS are the elongation and tortuosity of the large and medium sized arteries. Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions.


Assuntos
Artérias/anormalidades , Sequenciamento do Exoma , Doenças Fetais/diagnóstico , Doenças Fetais/genética , Proteínas Facilitadoras de Transporte de Glucose/genética , Instabilidade Articular/diagnóstico , Instabilidade Articular/genética , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/genética , Malformações Vasculares/diagnóstico , Malformações Vasculares/genética , Artérias/diagnóstico por imagem , Feminino , Doenças Fetais/diagnóstico por imagem , Humanos , Lactente , Recém-Nascido , Instabilidade Articular/diagnóstico por imagem , Masculino , Mutação , Pais , Gravidez , Diagnóstico Pré-Natal , Irmãos , Dermatopatias Genéticas/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Ultrassonografia Pré-Natal , Malformações Vasculares/diagnóstico por imagem
18.
Echocardiography ; 38(12): 2095-2099, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34845761

RESUMO

Aortic aneurysms are rare in the pediatric age group and are commonly caused by genetic disorders associated with vasculopathy, weakness and fragility of arterial walls with progressive dilatation or even rupture. We reported a giant aortic aneurysm involving the ascending aorta and aortic arch in a 20-month-old girl with autosomal recessive cutis laxa type 1B (ARCL1B) who presented with hemorrhagic pericardial effusion and tamponade (impending rupture). Successful surgical repair has been done through excision of the aneurysmal part and replacement by Hemashield graft with preservation of the aortic valve.


Assuntos
Aneurisma da Aorta Torácica , Aneurisma Aórtico , Tamponamento Cardíaco , Cútis Laxa , Derrame Pericárdico , Tamponamento Cardíaco/diagnóstico , Tamponamento Cardíaco/diagnóstico por imagem , Criança , Cútis Laxa/diagnóstico , Cútis Laxa/diagnóstico por imagem , Feminino , Humanos , Lactente
19.
Adv Exp Med Biol ; 1348: 1-3, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34807413

RESUMO

Just like the first edition of this widely successful book the second edition provides latest updates of our understanding of pathophysiology, pathology, clinical presentation and treatment of heritable soft connective tissue diseases. In addition, new knowledge of not only structures but also of functions of basic components of connective tissues (e.g., collagen), and of organs such as tendons has been added as well. Moreover, readers will learn more about new syndromes and new subgroups of previously described syndromes and disorders as well. The authors are not only prominent investigators in their field, but they are also good writers and that should provide an additional incentive for interested readers.


Assuntos
Síndrome de Ehlers-Danlos , Colágeno , Tecido Conjuntivo , Humanos
20.
Adv Exp Med Biol ; 1348: 273-309, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34807425

RESUMO

Cutis laxa (CL) syndromes are a large and heterogeneous group of rare connective tissue disorders that share loose redundant skin as a hallmark clinical feature, which reflects dermal elastic fiber fragmentation. Both acquired and congenital-Mendelian- forms exist. Acquired forms are progressive and often preceded by inflammatory triggers in the skin, but may show systemic elastolysis. Mendelian forms are often pleiotropic in nature and classified upon systemic manifestations and mode of inheritance. Though impaired elastogenesis is a common denominator in all Mendelian forms of CL, the underlying gene defects are diverse and affect structural components of the elastic fiber or impair metabolic pathways interfering with cellular trafficking, proline synthesis, or mitochondrial functioning. In this chapter we provide a detailed overview of the clinical and molecular characteristics of the different cutis laxa types and review the latest insights on elastic fiber assembly and homeostasis from both human and animal studies.


Assuntos
Cútis Laxa , Animais , Cútis Laxa/genética , Tecido Elástico , Homeostase , Humanos , Redes e Vias Metabólicas , Síndrome
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA