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[PMID]:29390344
[Au] Autor:Hsu SF; Lin CC
[Ad] Endereço:Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital.
[Ti] Título:Van Buchem disease: First case report in Taiwan.
[So] Source:Medicine (Baltimore);96(50):e9209, 2017 Dec.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Van Buchem disease (VBD) is a very rare autosomal recessive disease. According to our review of the relevant literature, this article is the first case report of VBD in Taiwan. PATIENT CONCERNS: A 54-year-old woman developed a protruding chin, frontal bossing, and macrocephaly at the age of 40 years. She noted the onset of progressive bilateral visual and hearing impairment at the age of 40 and 45 years, respectively. Intermittent headaches, peripheral facial palsy, recurrent bilateral trigeminal neuralgia, and back pain were also observed since age 40. DIAGNOSES: She received a diagnosis of VBD based on the phenotypic abnormalities of the skull and mandible, facial nerve involvement, radiological images of the skeleton, and her family history. INTERVENTIONS: She received symptomatic treatment and surgical decompression for spinal stenosis. OUTCOMES: Her clinical condition did not improve satisfactorily. LESSONS: We hope to promote clinician awareness of this very rare disease and its symptoms and signs. A comprehensive understanding of VBD might lead to the development of a curative therapy in the future.
[Mh] Termos MeSH primário: Osteocondrodisplasias/diagnóstico
Osteocondrodisplasias/terapia
[Mh] Termos MeSH secundário: Descompressão Cirúrgica
Diagnóstico Diferencial
Feminino
Seres Humanos
Meia-Idade
Fenótipo
Doenças Raras
Taiwan
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180203
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009209


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[PMID]:29287114
[Au] Autor:Shimbo M; Suzuki R; Fuseya S; Sato T; Kiyohara K; Hagiwara K; Okada R; Wakui H; Tsunakawa Y; Watanabe H; Kimata K; Narimatsu H; Kudo T; Takahashi S
[Ad] Endereço:Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
[Ti] Título:Postnatal lethality and chondrodysplasia in mice lacking both chondroitin sulfate N-acetylgalactosaminyltransferase-1 and -2.
[So] Source:PLoS One;12(12):e0190333, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chondroitin sulfate (CS) is a sulfated glycosaminoglycan (GAG) chain. In cartilage, CS plays important roles as the main component of the extracellular matrix (ECM), existing as side chains of the major cartilage proteoglycan, aggrecan. Six glycosyltransferases are known to coordinately synthesize the backbone structure of CS; however, their in vivo synthetic mechanism remains unknown. Previous studies have suggested that two glycosyltransferases, Csgalnact1 (t1) and Csgalnact2 (t2), are critical for initiation of CS synthesis in vitro. Indeed, t1 single knockout mice (t1 KO) exhibit slight dwarfism and a reduction in CS content in cartilage compared with wild-type (WT) mice. To reveal the synergetic roles of t1 and t2 in CS synthesis in vivo, we generated systemic single and double knockout (DKO) mice and cartilage-specific t1 and t2 double knockout (Col2-DKO) mice. DKO mice exhibited postnatal lethality, whereas t2 KO mice showed normal size and skeletal development. Col2-DKO mice survived to adulthood and showed severe dwarfism compared with t1 KO mice. Histological analysis of epiphyseal cartilage from Col2-DKO mice revealed disrupted endochondral ossification, characterized by drastic GAG reduction in the ECM. Moreover, DKO cartilage had reduced chondrocyte proliferation and an increased number of apoptotic chondrocytes compared with WT cartilage. Conversely, primary chondrocyte cultures from Col2-DKO knee cartilage had the same proliferation rate as WT chondrocytes and low GAG expression levels, indicating that the chondrocytes themselves had an intact proliferative ability. Quantitative RT-PCR analysis of E18.5 cartilage showed that the expression levels of Col2a1 and Ptch1 transcripts tended to decrease in DKO compared with those in WT mice. The CS content in DKO cartilage was decreased compared with that in t1 KO cartilage but was not completely absent. These results suggest that aberrant ECM caused by CS reduction disrupted endochondral ossification. Overall, we propose that both t1 and t2 are necessary for CS synthesis and normal chondrocyte differentiation but are not sufficient for all CS synthesis in cartilage.
[Mh] Termos MeSH primário: Genes Letais
N-Acetilgalactosaminiltransferases/genética
Osteocondrodisplasias/genética
[Mh] Termos MeSH secundário: Animais
Apoptose/genética
Proliferação Celular/genética
Células Cultivadas
Condrócitos/patologia
Camundongos
Camundongos Knockout
RNA Mensageiro/genética
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (RNA, Messenger); EC 2.4.1.- (N-Acetylgalactosaminyltransferases); EC 2.4.1.- (chondroitin sulfate N-acetylgalactosaminyltransferase-1); EC 2.4.1.- (chondroitin sulfate N-acetylgalactosaminyltransferase-2)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171230
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190333


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[PMID]:28868793
[Au] Autor:Sharma R; Sierra Potchanant E; Schwartz JE; Nalepa G
[Ad] Endereço:Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana.
[Ti] Título:Chronic steroid-response pancytopenia and increased bone density due to thromboxane synthase deficiency.
[So] Source:Pediatr Blood Cancer;65(1), 2018 Jan.
[Is] ISSN:1545-5017
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Diagnosis of bone marrow failure (BMF) disorders is challenging but essential for optimal patient management. Here, we report a young adult from nonconsanguineous parents with progressive pancytopenia since childhood, bone pain, increased bone density, and haphazard ossification replacing hematopoiesis within the bone marrow. Sequencing revealed two novel biallelic variants of unknown significance within the thromboxane A synthase gene, TBXAS1 (c.266T > C; c.989T > C), bioinformatically predicted to disrupt the protein. TBXAS1 mutations result in Ghosal hematodiaphyseal dysplasia (OMIM 231095), the autosomal recessive syndrome associated with abnormal bone structure and BMF. Identification of the genetic defect prompted steroid therapy leading to resolution of symptoms.
[Mh] Termos MeSH primário: Anemia Refratária
Densidade Óssea/genética
Osteocondrodisplasias
Pancitopenia
Mutação Puntual
Tromboxano-A Sintase/deficiência
[Mh] Termos MeSH secundário: Anemia Refratária/enzimologia
Anemia Refratária/genética
Anemia Refratária/patologia
Doença Crônica
Feminino
Seres Humanos
Lactente
Osteocondrodisplasias/enzimologia
Osteocondrodisplasias/genética
Osteocondrodisplasias/patologia
Pancitopenia/enzimologia
Pancitopenia/genética
Pancitopenia/patologia
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
EC 5.3.99.5 (Thromboxane-A Synthase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171129
[Lr] Data última revisão:
171129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170905
[St] Status:MEDLINE
[do] DOI:10.1002/pbc.26777


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[PMID]:28742282
[Au] Autor:Balasubramanian K; Li B; Krakow D; Nevarez L; Ho PJ; Ainsworth JA; Nickerson DA; Bamshad MJ; Immken L; Lachman RS; Cohn DH
[Ad] Endereço:Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, California.
[Ti] Título:MED resulting from recessively inherited mutations in the gene encoding calcium-activated nucleotidase CANT1.
[So] Source:Am J Med Genet A;173(9):2415-2421, 2017 Sep.
[Is] ISSN:1552-4833
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Multiple Epiphyseal Dysplasia (MED) is a relatively mild skeletal dysplasia characterized by mild short stature, joint pain, and early-onset osteoarthropathy. Dominantly inherited mutations in COMP, MATN3, COL9A1, COL9A2, and COL9A3, and recessively inherited mutations in SLC26A2, account for the molecular basis of disease in about 80-85% of the cases. In two families with recurrent MED of an unknown molecular basis, we used exome sequencing and candidate gene analysis to identify homozygosity for recessively inherited missense mutations in CANT1, which encodes calcium-activated nucleotidase 1. The MED phenotype is thus allelic to the more severe Desbuquois dysplasia phenotype and the results identify CANT1 as a second locus for recessively inherited MED.
[Mh] Termos MeSH primário: Genes Recessivos
Nucleotidases/genética
Osteocondrodisplasias/genética
[Mh] Termos MeSH secundário: Adulto
Sequência de Bases
Criança
Pré-Escolar
Exoma/genética
Feminino
Seres Humanos
Masculino
Mutação de Sentido Incorreto/genética
Osteocondrodisplasias/diagnóstico por imagem
Osteocondrodisplasias/fisiopatologia
Linhagem
Radiografia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.1.3.- (CANT1 protein, human); EC 3.1.3.- (Nucleotidases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171130
[Lr] Data última revisão:
171130
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1002/ajmg.a.38349


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[PMID]:29100092
[Au] Autor:Lee CS; Fu H; Baratang N; Rousseau J; Kumra H; Sutton VR; Niceta M; Ciolfi A; Yamamoto G; Bertola D; Marcelis CL; Lugtenberg D; Bartuli A; Kim C; Hoover-Fong J; Sobreira N; Pauli R; Bacino C; Krakow D; Parboosingh J; Yap P; Kariminejad A; McDonald MT; Aracena MI; Lausch E; Unger S; Superti-Furga A; Lu JT; Cohn DH; Tartaglia M; Lee BH; Reinhardt DP; Campeau PM; Baylor-Hopkins Center for Mendelian Genomics
[Ad] Endereço:Department of Anatomy and Cell Biology and Faculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada.
[Ti] Título:Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures".
[So] Source:Am J Hum Genet;101(5):815-823, 2017 Nov 02.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylometaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of "corner fractures" at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70 kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.
[Mh] Termos MeSH primário: Fibronectinas/genética
Fraturas Ósseas/genética
Mutação/genética
Osteocondrodisplasias/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Doenças do Desenvolvimento Ósseo/genética
Osso e Ossos/patologia
Cartilagem/patologia
Criança
Pré-Escolar
Exoma/genética
Feminino
Seres Humanos
Masculino
Fenótipo
Escoliose/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (FN1 protein, human); 0 (Fibronectins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171118
[Lr] Data última revisão:
171118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171104
[St] Status:MEDLINE


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[PMID]:28964299
[Au] Autor:Marques LHS; Martins DV; Juares GL; Lorenzetti FTM; Monsanto RDC
[Ad] Endereço:Department of Otolaryngology, Head and Neck Surgery, Banco de Olhos de Sorocaba Hospital, Sorocaba, Brazil.
[Ti] Título:Otologic manifestations of Larsen syndrome.
[So] Source:Int J Pediatr Otorhinolaryngol;101:223-229, 2017 Oct.
[Is] ISSN:1872-8464
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To describe and discuss otologic manifestations of Larsen syndrome, based on a case report and a systematic review of the literature. MATERIALS AND METHODS: We performed a PubMED database search, and we selected studies reporting otolaryngologic manifestations secondary to Larsen syndrome. The selected articles were read in full, and three researchers independently extracted data from the studies. In parallel, we report the case of a 14-year-old patient who had hearing loss secondary to Larsen syndrome. RESULTS: Fifteen studies met our selection criteria. Seven studies reported hearing loss in patients with Larsen syndrome (4 had conductive hearing loss and 3 had mixed hearing loss). The conductive hearing loss may be secondary to ossicular malformations and/or middle ear effusions. Other causes for conductive hearing loss are mesenchymal remnants in the middle ear, Eustachian tube dysfunction, and cleft palate. Surgical management of the hearing loss is possible in selected cases, although the surgical and anesthetic risks should be considered. Hearing aids seem to be safe and effective treatment options for the hearing loss secondary to Larsen syndrome. CONCLUSION: Although rare, patients with Larsen syndrome may have hearing loss. The most frequent type of deficit is conductive, either secondary to malformation of the ossicles or middle ear effusion. Possible surgical correction of these abnormalities should be weighed against the anesthetic risks of these patients.
[Mh] Termos MeSH primário: Perda Auditiva/etiologia
Osteocondrodisplasias/complicações
[Mh] Termos MeSH secundário: Adolescente
Pré-Escolar
Orelha Média/anormalidades
Auxiliares de Audição/efeitos adversos
Perda Auditiva/terapia
Seres Humanos
Masculino
Tomografia Computadorizada por Raios X
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; REVIEW
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171002
[St] Status:MEDLINE


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[PMID]:28869591
[Au] Autor:Kemp JP; Morris JA; Medina-Gomez C; Forgetta V; Warrington NM; Youlten SE; Zheng J; Gregson CL; Grundberg E; Trajanoska K; Logan JG; Pollard AS; Sparkes PC; Ghirardello EJ; Allen R; Leitch VD; Butterfield NC; Komla-Ebri D; Adoum AT; Curry KF; White JK; Kussy F; Greenlaw KM; Xu C; Harvey NC; Cooper C; Adams DJ; Greenwood CMT; Maurano MT; Kaptoge S; Rivadeneira F; Tobias JH; Croucher PI; Ackert-Bicknell CL; Bassett JHD; Williams GR; Richards JB; Evans DM
[Ad] Endereço:University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
[Ti] Título:Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis.
[So] Source:Nat Genet;49(10):1468-1475, 2017 Oct.
[Is] ISSN:1546-1718
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study (GWAS) in 142,487 individuals from the UK Biobank to identify loci associated with BMD as estimated by quantitative ultrasound of the heel. We identified 307 conditionally independent single-nucleotide polymorphisms (SNPs) that attained genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance. These included 153 previously unreported loci, and several rare variants with large effect sizes. To investigate the underlying mechanisms, we undertook (1) bioinformatic, functional genomic annotation and human osteoblast expression studies; (2) gene-function prediction; (3) skeletal phenotyping of 120 knockout mice with deletions of genes adjacent to lead independent SNPs; and (4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts. The results implicate GPC6 as a novel determinant of BMD, and also identify abnormal skeletal phenotypes in knockout mice associated with a further 100 prioritized genes.
[Mh] Termos MeSH primário: Densidade Óssea/genética
Calcâneo/patologia
Estudo de Associação Genômica Ampla
Osteoporose/genética
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Feminino
Fêmur/química
Perfilação da Expressão Gênica
Glipicanas/deficiência
Glipicanas/genética
Glipicanas/fisiologia
Transtornos do Crescimento/genética
Seres Humanos
Masculino
Camundongos
Camundongos Knockout
Anotação de Sequência Molecular
Osteoblastos/metabolismo
Osteocondrodisplasias/congênito
Osteocondrodisplasias/genética
Osteoclastos/metabolismo
Osteócitos/metabolismo
Osteoporose/patologia
Fenótipo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glypicans); 0 (glypican 6 protein, mouse)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171028
[Lr] Data última revisão:
171028
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170905
[St] Status:MEDLINE
[do] DOI:10.1038/ng.3949


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[PMID]:28842488
[Au] Autor:Cooper PE; McClenaghan C; Chen X; Stary-Weinzinger A; Nichols CG
[Ad] Endereço:From the Department of Cell Biology and Physiology and Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri 63110 and.
[Ti] Título:Conserved functional consequences of disease-associated mutations in the slide helix of Kir6.1 and Kir6.2 subunits of the ATP-sensitive potassium channel.
[So] Source:J Biol Chem;292(42):17387-17398, 2017 Oct 20.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cantu syndrome (CS) is a condition characterized by a range of anatomical defects, including cardiomegaly, hyperflexibility of the joints, hypertrichosis, and craniofacial dysmorphology. CS is associated with multiple missense mutations in the genes encoding the regulatory sulfonylurea receptor 2 (SUR2) subunits of the ATP-sensitive K (K ) channel as well as two mutations (V65M and C176S) in the Kir6.1 ( ) subunit. Previous analysis of leucine and alanine substitutions at the Val-65-equivalent site (Val-64) in Kir6.2 indicated no major effects on channel function. In this study, we characterized the effects of both valine-to-methionine and valine-to-leucine substitutions at this position in both Kir6.1 and Kir6.2 using ion flux and patch clamp techniques. We report that methionine substitution, but not leucine substitution, results in increased open state stability and hence significantly reduced ATP sensitivity and a marked increase of channel activity in the intact cell irrespective of the identity of the coassembled SUR subunit. Sulfonylurea inhibitors, such as glibenclamide, are potential therapies for CS. However, as a consequence of the increased open state stability, both Kir6.1(V65M) and Kir6.2(V64M) mutations essentially abolish high-affinity sensitivity to the K blocker glibenclamide in both intact cells and excised patches. This raises the possibility that, at least for some CS mutations, sulfonylurea therapy may not prove to be successful and highlights the need for detailed pharmacogenomic analyses of CS mutations.
[Mh] Termos MeSH primário: Cardiomegalia/metabolismo
Hipertricose/metabolismo
Canais KATP/metabolismo
Mutação de Sentido Incorreto
Osteocondrodisplasias/metabolismo
Canais de Potássio Corretores do Fluxo de Internalização/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Células COS
Cardiomegalia/genética
Cercopithecus aethiops
Glibureto/farmacologia
Seres Humanos
Hipertricose/genética
Canais KATP/química
Canais KATP/genética
Camundongos
Osteocondrodisplasias/genética
Técnicas de Patch-Clamp
Canais de Potássio Corretores do Fluxo de Internalização/química
Canais de Potássio Corretores do Fluxo de Internalização/genética
Estabilidade Proteica/efeitos dos fármacos
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KATP Channels); 0 (Kir6.2 channel); 0 (Potassium Channels, Inwardly Rectifying); 0 (uK-ATP-1 potassium channel); SX6K58TVWC (Glyburide)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171028
[Lr] Data última revisão:
171028
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170827
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.804971


  9 / 4052 MEDLINE  
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[PMID]:28796785
[Au] Autor:Lipska-Zietkiewicz BS; Gellermann J; Boyer O; Gribouval O; Zietkiewicz S; Kari JA; Shalaby MA; Ozaltin F; Dusek J; Melk A; Bayazit AK; Massella L; Hyla-Klekot L; Habbig S; Godron A; Szczepanska M; Bienias B; Drozdz D; Odeh R; Jarmuzek W; Zachwieja K; Trautmann A; Antignac C; Schaefer F; PodoNet Consortium
[Ad] Endereço:Department of Biology and Medical Genetics, Clinical Genetics Unit, Medical University of Gdansk, Gdansk, Poland.
[Ti] Título:Low renal but high extrarenal phenotype variability in Schimke immuno-osseous dysplasia.
[So] Source:PLoS One;12(8):e0180926, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Schimke immuno-osseous dysplasia (SIOD) is a rare multisystem disorder with early mortality and steroid-resistant nephrotic syndrome (SRNS) progressing to end-stage kidney disease. We hypothesized that next-generation gene panel sequencing may unsurface oligosymptomatic cases of SIOD with potentially milder disease courses. We analyzed the renal and extrarenal phenotypic spectrum and genotype-phenotype associations in 34 patients from 28 families, the largest SMARCAL1-associated nephropathy cohort to date. In 11 patients the diagnosis was made unsuspectedly through SRNS gene panel testing. Renal disease first manifested at median age 4.5 yrs, with focal segmental glmerulosclerosis or minimal change nephropathy on biopsy and rapid progression to end-stage kidney disease (ESKD) at median age 8.7 yrs. Whereas patients diagnosed by phenotype more frequently developed severe extrarenal complications (cerebral ischemic events, septicemia) and were more likely to die before age 10 years than patients identified by SRNS-gene panel screening (88 vs. 40%), the subgroups did not differ with respect to age at proteinuria onset and progression to ESKD. Also, 10 of 11 children diagnosed unsuspectedly by Next Generation Sequencing were small at diagnosis and all showed progressive growth failure. Severe phenotypes were usually associated with biallelic truncating mutations and milder phenotypes with biallelic missense mutations. However, no genotype-phenotype correlation was observed for the renal disease course. In conclusion, while short stature is a reliable clue to SIOD in children with SRNS, other systemic features are highly variable. Our findings support routine SMARCAL1 testing also in non-syndromic SRNS.
[Mh] Termos MeSH primário: Arteriosclerose/genética
Arteriosclerose/patologia
Síndromes de Imunodeficiência/genética
Síndromes de Imunodeficiência/patologia
Rim/patologia
Síndrome Nefrótica/genética
Síndrome Nefrótica/patologia
Osteocondrodisplasias/genética
Osteocondrodisplasias/patologia
Embolia Pulmonar/genética
Embolia Pulmonar/patologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Arteriosclerose/diagnóstico
Criança
Pré-Escolar
Estudos de Coortes
DNA Helicases/genética
Testes Genéticos
Genótipo
Seres Humanos
Síndromes de Imunodeficiência/diagnóstico
Lactente
Mutação
Síndrome Nefrótica/diagnóstico
Osteocondrodisplasias/diagnóstico
Fenótipo
Embolia Pulmonar/diagnóstico
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.7.- (SMARCAL1 protein, human); EC 3.6.4.- (DNA Helicases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170811
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180926


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[PMID]:28696225
[Au] Autor:Capurro M; Izumikawa T; Suarez P; Shi W; Cydzik M; Kaneiwa T; Gariepy J; Bonafe L; Filmus J
[Ad] Endereço:Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
[Ti] Título:Glypican-6 promotes the growth of developing long bones by stimulating Hedgehog signaling.
[So] Source:J Cell Biol;216(9):2911-2926, 2017 Sep 04.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Autosomal-recessive omodysplasia (OMOD1) is a genetic condition characterized by short stature, shortened limbs, and facial dysmorphism. OMOD1 is caused by loss-of-function mutations of glypican 6 ( ). In this study, we show that -null embryos display most of the abnormalities found in OMOD1 patients and that Hedgehog (Hh) signaling is significantly reduced in the long bones of these embryos. The Hh-stimulatory activity of GPC6 was also observed in cultured cells, where this GPC increased the binding of Hh to Patched 1 (Ptc1). Consistent with this, GPC6 interacts with Hh through its core protein and with Ptc1 through its glycosaminoglycan chains. Hh signaling is triggered at the primary cilium. In the absence of Hh, we observed that GPC6 is localized outside of the cilium but moves into the cilium upon the addition of Hh. We conclude that GPC6 stimulates Hh signaling by binding to Hh and Ptc1 at the cilium and increasing the interaction of the receptor and ligand.
[Mh] Termos MeSH primário: Fêmur/metabolismo
Glipicanas/metabolismo
Transtornos do Crescimento/metabolismo
Proteínas Hedgehog/metabolismo
Osteocondrodisplasias/congênito
Osteogênese
Tíbia/metabolismo
[Mh] Termos MeSH secundário: Animais
Proliferação Celular
Cílios/metabolismo
Modelos Animais de Doenças
Fêmur/embriologia
Predisposição Genética para Doença
Glicosaminoglicanos/metabolismo
Glipicanas/deficiência
Glipicanas/genética
Transtornos do Crescimento/embriologia
Transtornos do Crescimento/genética
Células HEK293
Proteínas Hedgehog/genética
Seres Humanos
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Células NIH 3T3
Osteocondrodisplasias/embriologia
Osteocondrodisplasias/genética
Osteocondrodisplasias/metabolismo
Receptor Patched-1/metabolismo
Fenótipo
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Transdução de Sinais
Tíbia/embriologia
Fatores de Tempo
Transfecção
Proteína GLI1 em Dedos de Zinco/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gli protein, mouse); 0 (Glycosaminoglycans); 0 (Glypicans); 0 (Hedgehog Proteins); 0 (Patched-1 Receptor); 0 (Ptch1 protein, mouse); 0 (Shh protein, mouse); 0 (Zinc Finger Protein GLI1); 0 (glypican 6 protein, mouse); 0 (ihh protein, mouse)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201605119



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