RESUMEN
BACKGROUND: Marfan syndrome (MFS) is a multisystem disease with a unique combination of skeletal, cardiovascular and ocular features. Geleophysic/acromicric dysplasias (GPHYSD/ACMICD), characterised by short stature and extremities, are described as 'the mirror image' of MFS. The numerous FBN1 pathogenic variants identified in MFS are located all along the gene and lead to the same final pathogenic sequence. Conversely, in GPHYSD/ACMICD, the 28 known heterozygous FBN1 pathogenic variants all affect exons 41-42 encoding TGFß-binding protein-like domain 5 (TB5). METHODS: Since 1996, more than 5000 consecutive probands have been referred nationwide to our laboratory for molecular diagnosis of suspected MFS. RESULTS: We identified five MFS probands carrying distinct heterozygous pathogenic in-frame variants affecting the TB5 domain of FBN1. The clinical data showed that the probands displayed a classical form of MFS. Strikingly, one missense variant affects an amino acid that was previously involved in GPHYSD. CONCLUSION: Surprisingly, pathogenic variants in the TB5 domain of FBN1 can lead to two opposite phenotypes: GPHYSD/ACMICD and MFS, suggesting the existence of different pathogenic sequences with the involvement of tissue specificity. Further functional studies are ongoing to determine the precise role of this domain in the physiopathology of each disease.
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Enfermedades del Desarrollo Óseo , Deformidades Congénitas de las Extremidades , Síndrome de Marfan , Humanos , Enfermedades del Desarrollo Óseo/genética , Fibrilina-1/genética , Síndrome de Marfan/genética , Síndrome de Marfan/patología , MutaciónRESUMEN
BACKGROUND: Weill-Marchesani syndrome (WMS) belongs to the group of acromelic dysplasias, defined by short stature, brachydactyly and joint limitations. WMS is characterised by specific ophthalmological abnormalities, although cardiovascular defects have also been reported. Monoallelic variations in FBN1 are associated with a dominant form of WMS, while biallelic variations in ADAMTS10, ADAMTS17 and LTBP2 are responsible for a recessive form of WMS. OBJECTIVE: Natural history description of WMS and genotype-phenotype correlation establishment. MATERIALS AND METHODS: Retrospective multicentre study and literature review. INCLUSION CRITERIA: clinical diagnosis of WMS with identified pathogenic variants. RESULTS: 61 patients were included: 18 individuals from our cohort and 43 patients from literature. 21 had variants in ADAMTS17, 19 in FBN1, 19 in ADAMTS10 and 2 in LTBP2. All individuals presented with eye anomalies, mainly spherophakia (42/61) and ectopia lentis (39/61). Short stature was present in 73% (from -2.2 to -5.5 SD), 10/61 individuals had valvulopathy. Regarding FBN1 variants, patients with a variant located in transforming growth factor (TGF)-ß-binding protein-like domain 5 (TB5) domain were significantly smaller than patients with FBN1 variant outside TB5 domain (p=0.0040). CONCLUSION: Apart from the ophthalmological findings, which are mandatory for the diagnosis, the phenotype of WMS seems to be more variable than initially described, partially explained by genotype-phenotype correlation.
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Enanismo , Anomalías del Ojo , Síndrome de Weill-Marchesani , Humanos , Síndrome de Weill-Marchesani/genética , Síndrome de Weill-Marchesani/diagnóstico , Síndrome de Weill-Marchesani/patología , Enanismo/genética , Fenotipo , Estudios de Asociación Genética , Fibrilina-1/genética , Proteínas de Unión a TGF-beta Latente/genética , Estudios Multicéntricos como AsuntoRESUMEN
Mutations in the fibrillin-1 (FBN1) gene are responsible for the autosomal dominant form of geleophysic dysplasia (GD), which is characterized by short stature and extremities, thick skin and cardiovascular disease. All known FBN1 mutations in patients with GD are localized within the region encoding the transforming growth factor-ß binding protein-like 5 (TB5) domain of this protein. Herein, we generated a knock-in mouse model, Fbn1Y1698C by introducing the p.Tyr1696Cys mutation from a patient with GD into the TB5 domain of murine Fbn1 to elucidate the specific role of this domain in endochondral ossification. We found that both Fbn1Y1698C/+ and Fbn1Y1698C/Y1698C mice exhibited a reduced stature reminiscent of the human GD phenotype. The Fbn1 point mutation introduced in these mice affected the growth plate formation owing to abnormal chondrocyte differentiation such that mutant chondrocytes failed to establish a dense microfibrillar network composed of FBN1. This original Fbn1 mutant mouse model offers new insight into the pathogenic events underlying GD. Our findings suggest that the etiology of GD involves the dysregulation of the extracellular matrix composed of an abnormal FBN1 microfibril network impacting the differentiation of the chondrocytes.
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Enfermedades del Desarrollo Óseo , Fibrilina-1 , Deformidades Congénitas de las Extremidades , Síndrome de Marfan , Animales , Humanos , Ratones , Enfermedades del Desarrollo Óseo/metabolismo , Fibrilina-1/genética , Deformidades Congénitas de las Extremidades/genética , Síndrome de Marfan/genética , Mutación , Osteogénesis/genéticaRESUMEN
The term "fibrillinopathies" gathers various diseases with a wide spectrum of clinical features and severity but all share mutations in the fibrillin genes. The first described fibrillinopathy, Marfan syndrome (MFS), is a multisystem disease with a unique combination of skeletal, thoracic aortic aneurysm (TAA) and ocular features. The numerous FBN1 mutations identified in MFS are located all along the gene, leading to the same pathogenic mechanism. The geleophysic/acromicric dysplasias (GD/AD), characterized by short stature, short extremities, and joint limitation are described as "the mirror image" of MFS. Previously, in GD/AD patients, we identified heterozygous FBN1 mutations all affecting TGFß-binding protein-like domain 5 (TB5). ADAMTS10, ADAMTS17 and, ADAMTSL2 are also involved in the pathogenic mechanism of acromelic dysplasia. More recently, in TAA patients, we identified mutations in THSD4, encoding ADAMTSL6, a protein belonging to the ADAMTSL family suggesting that ADAMTSL proteins are also involved in the Marfanoid spectrum. Together with human genetic data and generated knockout mouse models targeting the involved genes, we provide herein an overview of the role of fibrillin-1 in opposite phenotypes. Finally, we will decipher the potential biological cooperation of ADAMTS-fibrillin-1 involved in these opposite phenotypes.
RESUMEN
PURPOSE: Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. METHODS: Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. RESULTS: These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. CONCLUSION: This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.
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Síndrome de Marfan , Exones , Fibrilina-1/genética , Fibrilinas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Mosaicismo , MutaciónRESUMEN
PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. METHODS: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. RESULTS: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. CONCLUSION: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.
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Aneurisma de la Aorta Torácica , Disección Aórtica , Proteínas ADAM , Disección Aórtica/genética , Animales , Aneurisma de la Aorta Torácica/genética , Exoma/genética , Fibrilina-1/genética , Humanos , RatonesRESUMEN
Extracellular matrix (ECM) in the vascular wall is a highly dynamic structure composed of a set of different molecules such as elastins, collagens, fibronectin (Fn), laminins, proteoglycans, and polysaccharides. ECM undergoes remodeling processes to regulate vascular smooth muscle and endothelial cells' proliferation, differentiation, and adhesion. Abnormalities affecting the ECM can lead to alteration in cellular behavior and from this, this can conduce to the development of pathologies. Metalloproteases play a key role in maintaining the homeostasis of ECM by mediating the cleavage of different ECM components. There are different types of metalloproteases: matrix metalloproteinases (MMPs), disintegrin and metalloproteinases (ADAMs), and ADAMs with thrombospondin motifs (ADAMTSs). ADAMTSs have been found to participate in cardiovascular physiology and diseases and specifically in aortic aneurysms. This review aims to decipher the potential role of ADAMTS proteins in the physiopathologic development of Thoracic Aortic Aneurysms (TAA) and Abdominal Aortic Aneurysms (AAA). This review will focus on what is known on the ADAMTS family involved in human aneurysms from human tissues to mouse models. The recent findings on THSD4 (encoding ADAMTSL6) mutations in TAA give a new insight on the involvement of the ADAMTS family in TAA.
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Proteínas ADAMTS/metabolismo , Aneurisma de la Aorta Abdominal/enzimología , Aneurisma de la Aorta Torácica/enzimología , Células Endoteliales/enzimología , Músculo Liso Vascular/enzimología , Remodelación Vascular , Animales , Humanos , RatonesRESUMEN
SKI pathogenic variations are associated with Shprintzen-Goldberg Syndrome (SGS), a rare systemic connective tissue disorder characterized by craniofacial, skeletal and cardiovascular features. So far, the clinical description, including intellectual disability, has been relatively homogeneous, and the known pathogenic variations were located in two different hotspots of the SKI gene. In the course of diagnosing Marfan syndrome and related disorders, we identified nine sporadic probands (aged 2-47 years) carrying three different likely pathogenic or pathogenic variants in the SKI gene affecting the same amino acid (Thr180). Seven of these molecular events were confirmed de novo. All probands displayed a milder morphological phenotype with a marfanoid habitus that did not initially lead to a clinical diagnosis of SGS. Only three of them had learning disorders, and none had intellectual disability. Six out of nine presented thoracic aortic aneurysm, which led to preventive surgery in the oldest case. This report extends the phenotypic spectrum of variants identified in the SKI gene. We describe a new mutational hotspot associated with a marfanoid syndrome with no intellectual disability. Cardiovascular involvement was confirmed in a significant number of cases, highlighting the importance of accurately diagnosing SGS and ensuring appropriate medical treatment and follow-up.
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Aracnodactilia , Craneosinostosis , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Síndrome de Marfan , Mutación , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Adolescente , Adulto , Aracnodactilia/diagnóstico , Aracnodactilia/genética , Aracnodactilia/metabolismo , Niño , Preescolar , Craneosinostosis/diagnóstico , Craneosinostosis/genética , Craneosinostosis/metabolismo , Femenino , Humanos , Masculino , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Síndrome de Marfan/metabolismo , Persona de Mediana Edad , Patología MolecularRESUMEN
Mutations in the a disintegrin and metalloproteinase with thrombospondin motif-like 2 ( ADAMTSL2) gene are responsible for the autosomal recessive form of geleophysic dysplasia, which is characterized by short stature, short extremities, and skeletal abnormalities. However, the exact function of ADAMTSL2 is unknown. To elucidate the role of this protein in skeletal development, we generated complementary knockout (KO) mouse models with either total or chondrocyte Adamtsl2 deficiency. We observed that the Adamtsl2 KO mice displayed skeletal abnormalities reminiscent of the human phenotype. Adamtsl2 deletion affected the growth plate formation with abnormal differentiation and proliferation of chondrocytes. In addition, a TGF-ß signaling impairment in limbs lacking Adamtsl2 was demonstrated. Further investigations revealed that Adamtsl2 KO chondrocytes failed to establish a microfibrillar network composed by fibrillin1 and latent TGF-ß binding protein 1 fibrils. Chondrocyte Adamtsl2 KO mice also exhibited dwarfism. These studies uncover the function of Adamtsl2 in the maintenance of the growth plate ECM by modulating the microfibrillar network.-Delhon, L., Mahaut, C., Goudin, N., Gaudas, E., Piquand, K., Le Goff, W., Cormier-Daire, V., Le Goff, C. Impairment of chondrogenesis and microfibrillar network in Adamtsl2 deficiency.
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Proteínas ADAMTS/fisiología , Enfermedades del Desarrollo Óseo/etiología , Condrogénesis , Enanismo/etiología , Proteínas de la Matriz Extracelular/fisiología , Microfibrillas/patología , Animales , Enfermedades del Desarrollo Óseo/metabolismo , Enfermedades del Desarrollo Óseo/patología , Enanismo/metabolismo , Enanismo/patología , Heterocigoto , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microfibrillas/metabolismo , Mutación , Fenotipo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Acrodysostosis (MIM 101800) is a dominantly inherited condition associating (1) skeletal features (short stature, facial dysostosis, and brachydactyly with cone-shaped epiphyses), (2) resistance to hormones and (3) possible intellectual disability. Acroscyphodysplasia (MIM 250215) is characterized by growth retardation, brachydactyly, and knee epiphyses embedded in cup-shaped metaphyses. We and others have identified PDE4D or PRKAR1A variants in acrodysostosis; PDE4D variants have been reported in three cases of acroscyphodysplasia. Our study aimed at reviewing the clinical and molecular findings in a cohort of 27 acrodysostosis and 5 acroscyphodysplasia cases. Among the acrodysostosis cases, we identified 9 heterozygous de novo PRKAR1A variants and 11 heterozygous PDE4D variants. The 7 patients without variants presented with symptoms of acrodysostosis (brachydactyly and cone-shaped epiphyses), but none had the characteristic facial dysostosis. In the acroscyphodysplasia cases, we identified 2 PDE4D variants. For 2 of the 3 negative cases, medical records revealed early severe infection, which has been described in some reports of acroscyphodysplasia. Subdividing our series of acrodysostosis based on the disease-causing gene, we confirmed genotype-phenotype correlations. Hormone resistance was consistently observed in patients carrying PRKAR1A variants, whereas no hormone resistance was observed in 9 patients with PDE4D variants. All patients with PDE4D variants shared characteristic facial features (midface hypoplasia with nasal hypoplasia) and some degree of intellectual disability. Our findings of PDE4D variants in two cases of acroscyphodysplasia support that PDE4D may be responsible for this severe skeletal dysplasia. We eventually emphasize the importance of some specific assessments in the long-term follow up, including cardiovascular and thromboembolic risk factors.
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Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Disostosis/genética , Epífisis/anomalías , Exostosis Múltiple Hereditaria/genética , Deformidades Congénitas de la Mano/genética , Discapacidad Intelectual/genética , Rodilla/anomalías , Osteocondrodisplasias/genética , Fenotipo , Adolescente , Adulto , Niño , Disostosis/patología , Epífisis/patología , Exostosis Múltiple Hereditaria/patología , Femenino , Deformidades Congénitas de la Mano/patología , Heterocigoto , Humanos , Discapacidad Intelectual/patología , Rodilla/patología , Masculino , Mutación , Osteocondrodisplasias/patología , SíndromeRESUMEN
Objective- Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by the infiltration of multiple tissues with lipid-laden histiocytes. Cardiovascular involvement is frequent in ECD and leads to a severe prognosis. The objective of this study was to determine whether an alteration of lipid metabolism participates in the lipid accumulation in histiocytes and the cardiovascular involvement in ECD. Approach and Results- An analysis of plasma lipid levels indicated that male ECD patients carrying the BRAFV600E (B-Raf proto-oncogene, serine/threonine kinase) mutation exhibited hypoalphalipoproteinemia, as demonstrated by low plasma HDL-C (high-density lipoprotein cholesterol) levels. Capacity of sera from male BRAFV600E ECD patients to mediate free cholesterol efflux from human macrophages was reduced compared with control individuals. Cardiovascular involvement was detected in 84% of the ECD patients, and we reported that the presence of the BRAFV600E mutation and hypoalphalipoproteinemia is an independent determinant of aortic infiltration in ECD. Phenotyping of blood CD14+ cells, the precursors of histiocytes, enabled the identification of a specific inflammatory signature associated with aortic infiltration which was partially affected by the HDL phenotype. Finally, the treatment with vemurafenib, an inhibitor of the BRAFV600E mutation, restored the defective sera cholesterol efflux capacity and reduced the aortic infiltration. Conclusions- Our findings indicate that hypoalphalipoproteinemia in male ECD patients carrying the BRAFV600E mutation favors the formation of lipid-laden histiocytes. In addition, we identified the BRAF status and the HDL phenotype as independent determinants of the aortic involvement in ECD with a potential role of HDL in modulating the infiltration of blood CD14+ cells into the aorta.
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Aorta/metabolismo , Enfermedades de la Aorta/genética , HDL-Colesterol/sangre , Enfermedad de Erdheim-Chester/genética , Histiocitos/metabolismo , Hipoalfalipoproteinemias/genética , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Aorta/efectos de los fármacos , Aorta/patología , Enfermedades de la Aorta/tratamiento farmacológico , Enfermedades de la Aorta/enzimología , Biomarcadores/sangre , Estudios de Casos y Controles , Enfermedad de Erdheim-Chester/sangre , Enfermedad de Erdheim-Chester/diagnóstico , Enfermedad de Erdheim-Chester/tratamiento farmacológico , Femenino , Predisposición Genética a la Enfermedad , Histiocitos/efectos de los fármacos , Histiocitos/patología , Humanos , Hipoalfalipoproteinemias/sangre , Hipoalfalipoproteinemias/diagnóstico , Hipoalfalipoproteinemias/tratamiento farmacológico , Receptores de Lipopolisacáridos/sangre , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Fenotipo , Inhibidores de Proteínas Quinasas/uso terapéutico , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Factores de Riesgo , Factores Sexuales , Células THP-1 , Vemurafenib/uso terapéutico , Adulto JovenRESUMEN
Although the ability to elaborate calcium carbonate biominerals was apparently gained independently during animal evolution, members of the alpha carbonic anhydrases (α-CAs) family, which catalyze the interconversion of CO2 into HCO3-, are involved in the biomineralization process across metazoans. In the Mediterranean red coral Corallium rubrum, inhibition studies suggest an essential role of CAs in the synthesis of two biominerals produced in this octocoral, the axial skeleton and the sclerites. Hitherto no molecular characterization of these enzymes was available. In the present study we determined the complete set of α-CAs in C. rubrum by data mining the genome and transcriptome, and measured their differential gene expression between calcifying and non-calcifying tissues. We identified six isozymes (CruCA1-6), one cytosolic and five secreted/membrane-bound among which one lacked two of the three zinc-binding histidines and was so referred to as a carbonic anhydrase related protein (CARP). One secreted isozyme (CruCA4) showed specific expression both by qPCR and western-blot in the calcifying tissues, suggesting its involvement in biomineralization. Moreover, phylogenetic analyses of α-CAs, identified in six representative cnidarians with complete genome, support an independent recruitment of α-CAs for biomineralization within anthozoans. Finally, characterization of cnidarian CARPs highlighted two families: the monophyletic cytosolic CARPs, and the polyphyletic secreted CARPs harboring a cnidarian specific cysteine disulfide bridge. Alignment of the cytosolic CARPs revealed an evolutionary conserved R-H-Q motif in place of the characteristic zinc-binding H-H-H necessary for the catalytic function of α-CAs.
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Evolución Biológica , Anhidrasas Carbónicas/genética , Cnidarios/enzimología , Cnidarios/genética , Filogenia , Secuencia de Aminoácidos , Animales , Calcificación Fisiológica , Cnidarios/clasificación , Perfilación de la Expresión Génica , Genoma , Isoenzimas , Modelos Moleculares , Conformación Proteica , Homología de Secuencia de AminoácidoRESUMEN
Cardiospondylocarpofacial (CSCF) syndrome is characterized by growth retardation, dysmorphic facial features, brachydactyly with carpal-tarsal fusion and extensive posterior cervical vertebral synostosis, cardiac septal defects with valve dysplasia, and deafness with inner ear malformations. Whole-exome sequencing identified heterozygous MAP3K7 mutations in six distinct CSCF-affected individuals from four families and ranging in age from 5 to 37 years. MAP3K7 encodes transforming growth factor ß (TGF-ß)-activated kinase 1 (TAK1), which is involved in the mitogen-activated protein kinase (MAPK)-p38 signaling pathway. MAPK-p38 signaling was markedly altered when expression of non-canonical TGF-ß-driven target genes was impaired. These findings support the loss of transcriptional control of the TGF-ß-MAPK-p38 pathway in fibroblasts obtained from affected individuals. Surprisingly, although TAK1 is located at the crossroad of inflammation, immunity, and cancer, this study reports MAP3K7 mutations in a developmental disorder affecting mainly cartilage, bone, and heart.
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Huesos del Carpo/anomalías , Vértebras Cervicales/anomalías , Pérdida Auditiva Conductiva/genética , Heterocigoto , Quinasas Quinasa Quinasa PAM/genética , Insuficiencia de la Válvula Mitral/genética , Mutación/genética , Huesos Tarsianos/anomalías , Anomalías Múltiples , Adolescente , Adulto , Niño , Preescolar , Femenino , Fibroblastos , Regulación de la Expresión Génica , Pérdida Auditiva Bilateral , Humanos , Interleucina-1beta/metabolismo , Sistema de Señalización de MAP Quinasas , Masculino , Osteosclerosis , Síndrome , Factor de Crecimiento Transformador beta/metabolismo , Adulto Joven , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: Acromelic dysplasias are a group of disorders characterised by short stature, brachydactyly, limited joint extension and thickened skin and comprises acromicric dysplasia (AD), geleophysic dysplasia (GD), Myhre syndrome and Weill-Marchesani syndrome. Mutations in several genes have been identified for these disorders (including latent transforming growth factor ß (TGF-ß)-binding protein-2 (LTBP2), ADAMTS10, ADAMSTS17 and fibrillin-1 (FBN1) for Weill-Marchesani syndrome, ADAMTSL2 for recessive GD and FBN1 for AD and dominant GD), encoding proteins involved in the microfibrillar network. However, not all cases have mutations in these genes. METHODS: Individuals negative for mutations in known acromelic dysplasia genes underwent whole exome sequencing. RESULTS: A heterozygous missense mutation (exon 14: c.2087C>G: p.Ser696Cys) in latent transforming growth factor ß (TGF-ß)-binding protein-3 (LTBP3) was identified in a dominant AD family. Two distinct de novo heterozygous LTPB3 mutations were also identified in two unrelated GD individuals who had died in early childhood from respiratory failure-a donor splice site mutation (exon 12 c.1846+5G>A) and a stop-loss mutation (exon 28: c.3912A>T: p.1304*Cysext*12). CONCLUSIONS: The constellation of features in these AD and GD cases, including postnatal growth retardation of long bones and lung involvement, is reminiscent of the null ltbp3 mice phenotype. We conclude that LTBP3 is a novel component of the microfibrillar network involved in the acromelic dysplasia spectrum.
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Enfermedades del Desarrollo Óseo/genética , Proteínas de Unión a TGF-beta Latente/genética , Deformidades Congénitas de las Extremidades/genética , Mutación Missense/genética , Exoma/genética , Exones/genética , Fibrilina-1/genética , Heterocigoto , Humanos , Proteínas de Microfilamentos/genética , Mutación , Fenotipo , Factor de Crecimiento Transformador beta/genética , Síndrome de Weill-Marchesani/genéticaRESUMEN
Human chondrodysplasias are a group of conditions that affect the cartilage. This review is focused on the involvement of transforming growth factor-ß signaling in a group of chondrodysplasias, entitled acromelic dysplasia, characterized by short stature, short hands and restricted joint mobility.
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Myhre syndrome is characterized by short stature, brachydactyly, facial features, pseudomuscular hypertrophy, joint limitation and hearing loss. We identified SMAD4 mutations as the cause of Myhre syndrome. SMAD4 mutations have also been identified in laryngotracheal stenosis, arthropathy, prognathism and short stature syndrome (LAPS). This study aimed to review the features of Myhre and LAPS patients to define the clinical spectrum of SMAD4 mutations. We included 17 females and 15 males ranging in age from 8 to 48 years. Thirty were diagnosed with Myhre syndrome and two with LAPS. SMAD4 coding sequence was analyzed by Sanger sequencing. Clinical and radiological features were collected from a questionnaire completed by the referring physicians. All patients displayed a typical facial gestalt, thickened skin, joint limitation and muscular pseudohypertrophy. Growth retardation was common (68.7%) and was variable in severity (from -5.5 to -2 SD), as was mild-to-moderate intellectual deficiency (87.5%) with additional behavioral problems in 56.2% of the patients. Significant health concerns like obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis, pericarditis and early death occurred in four. Twenty-nine patients had a de novo heterozygous SMAD4 mutation, including both patients with LAPS. In 27 cases mutation affected Ile500 and in two cases Arg496. The three patients without SMAD4 mutations had typical findings of Myhre syndrome. Myhre-LAPS syndrome is a clinically homogenous condition with life threatening complications in the course of the disease. Our identification of SMAD4 mutations in 29/32 cases confirms that SMAD4 is the major gene responsible for Myhre syndrome.
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Criptorquidismo/genética , Trastornos del Crecimiento/genética , Deformidades Congénitas de la Mano/genética , Hipertrofia/genética , Discapacidad Intelectual/genética , Artropatías/genética , Proteína Smad4/genética , Adolescente , Adulto , Niño , Facies , Femenino , Estudios de Seguimiento , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
UNLABELLED: Acromicric dysplasia (AD) is an autosomal dominant disorder characterized by short stature, short extremities, stiff joint and skeleton features including brachymetacarpia, cone-shaped epiphyses, internal notch of the femoral head, and delayed bone age. Recently, we identified fibrillin 1 (FBN1) as the disease gene of AD. The aim of our study was to further describe the long-term follow up of AD patients with an emphasis on orthopedic management. Nine patients with FBN1 mutations were included in the study ranging in age from 5.5 to 64 years. For all, detailed clinical and radiological data were available. RESULTS: Birth parameters were always normal and patients progressively developed short stature <-3 SD. Carpal tunnel syndrome was observed in four patients. We found discrepancy between the carpal bone age and the radius and ulna epiphysis bone ages, a variable severity of hip dysplasia with acetabular dysplasia, epiphyseal and metaphyseal femoral dysplasia resembling Legg-Perthes-Calvé disease and variable pelvic anteversion and hyperlordosis. Orthopedic surgery was required in two patients for hip dysplasia, in one for limb lengthening and in three for carpal tunnel syndrome. Our observations expand the AD phenotype and emphasize the importance of regular orthopedic survey.
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Enfermedades del Desarrollo Óseo/cirugía , Deformidades Congénitas de las Extremidades/cirugía , Procedimientos Ortopédicos , Adolescente , Adulto , Enfermedades del Desarrollo Óseo/diagnóstico , Enfermedades del Desarrollo Óseo/genética , Huesos/diagnóstico por imagen , Huesos/patología , Niño , Preescolar , Femenino , Fibrilina-1 , Fibrilinas , Estudios de Seguimiento , Heterocigoto , Humanos , Deformidades Congénitas de las Extremidades/diagnóstico , Deformidades Congénitas de las Extremidades/genética , Masculino , Proteínas de Microfilamentos/genética , Persona de Mediana Edad , Mutación , Ortopedia , Radiografía , Adulto JovenRESUMEN
Geleophysic dysplasia (GD) is a rare genetic disorder characterized by acromelic dysplasia. Geleophysic dysplasia type 1 (MIM 231050) is autosomal recessive and is caused by homozygous or compound heterozygous mutation in the ADAMTSL2 (a disintegrin and metalloproteinase with thrombosponding repeats-like 2) gene. Geleophysic dysplasia type 2 (MIM 614185) is autosomal dominant and is caused by heterozygous mutation in the fibrillin 1 (FBN1) gene. Here, we present the clinical and histopathologic findings in a child with GD with newly identified ADAMTSL2 mutations. The 1st mutation was probably a pathogenic one, c.[1934G>A] p.[Arg645His], located in exon 13; the 2nd, in intron 8, was probably changing a splice site. While the light and electron microscopic findings were similar to those previously described, hydrocephalus due to aqueductal stenosis might be a new associated finding in these patients. This child with these 2 novel mutations also had an aggressive clinical course with early-onset progressive cardiac valvular disease.
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Proteínas ADAM/genética , Enfermedades del Desarrollo Óseo/genética , Enfermedades del Desarrollo Óseo/patología , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades/patología , Proteínas ADAMTS , Anomalías Múltiples/genética , Humanos , Lactante , Masculino , MutaciónRESUMEN
Floating-Harbor syndrome (FHS) is a rare disorder characterized by short stature, delayed bone age, speech delay, and dysmorphic facial features. We report here the molecular analysis of nine cases, fulfilling the diagnostic criteria for FHS. Using exome sequencing, we identified SRCAP as the disease gene in two cases and subsequently found SRCAP truncating mutations in 6/9 cases. All mutations occurred de novo and were located in exon 34, in accordance with the recent report of Hood et al. However, the absence of SRCAP mutations in 3/9 cases supported genetic heterogeneity of FH syndrome. Importantly, no major clinical differences were observed supporting clinical homogeneity in this series of FHS patients.