Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.098
Filtrar
1.
BMC Med Genet ; 20(1): 200, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31856751

RESUMO

BACKGROUND: Schmid-type metaphyseal chondrodysplasia (MCDS) is an autosomal dominant disorder caused by COL10A1 mutations, which is characterized by short stature, waddling gait, coxa vara and bowing of the long bones. However, descriptions of the expressivity of MCDS are rare. METHODS: Two probands and available family members affected with MCDS were subjected to clinical and radiological examination. Genomic DNA of all affected individuals was subjected to whole-exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and in 250 healthy donors. A spatial model of the type X collagen (α1) C-terminal noncollagenous (NC1) domain was further constructed. RESULTS: We found that the phenotype of affected family members exhibited incomplete dominance. Mutation analysis indicated that there were two novel heterozygous missense mutations, [c.1765 T > A (p.Phe589Ile)] and [c.1846A > G (p.Lys616Glu)] in the COL10A1 gene in family 1 and 2, respectively. The two novel substitution sites were highly conserved and the mutations were predicted to be deleterious by in silico analysis. Furthermore, protein modeling revealed that the two substitutions were located in the NC1 domain of collagen X (α1), which potentially impacted the trimerization of collagen X (α1) and combination with molecules in the pericellular matrix. CONCLUSION: Two novel mutations were identified in the present study, which will facilitate diagnosis of MCDS and further expand the spectrum of the COL10A1 mutations associated with MCDS patients. In addition, our research revealed the phenomenon of incomplete dominance in MCDS.


Assuntos
Colágeno Tipo X/genética , Heterozigoto , Mutação , Osteocondrodisplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem
2.
Yi Chuan ; 41(12): 1084-1098, 2019 Dec 20.
Artigo em Chinês | MEDLINE | ID: mdl-31857280

RESUMO

SMARCAL1 is an ATP-driven DNA annealing helicase that is similar in structure to the chromatin regulators in the subfamily A group of the SWI/SNF-related matrix-associated actin-dependent chromatin regulators. SMARCAL1 catalyzes the formation of dsDNA by annealing the single-stranded binding protein RPA coated ssDNA with its complementary strand both in vitro and in vivo. In humans, different mutations of Smarcal1 gene are found to be closely related to different symptoms shown in individuals with Schimke immuno-osseous dysplasia (SIOD). This paper reviews the recent research progress of SMARCAL1 functions in remodeling DNA replication forks at damaged DNA sites, working in classical non-homologous end joining (NHEJ) repair of DNA double-stranded breaks, and in maintaining chromosomal telomere integrity. The relationships between the mutations of Smarcal1 gene in different SIOD symptoms, and the possible involvements of SMARCAL1 in neuromuscular degenerative diseases associated with trinucleotide repeats expansions are also updated and discussed to better understand the roles and mechanisms of the annealing helicase in genome stability maintenance.


Assuntos
DNA Helicases , Instabilidade Genômica , Quebras de DNA de Cadeia Dupla , Dano ao DNA , DNA Helicases/metabolismo , Instabilidade Genômica/genética , Humanos , Osteocondrodisplasias/enzimologia , Osteocondrodisplasias/genética
4.
Nat Commun ; 10(1): 4457, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575858

RESUMO

Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.


Assuntos
Trifosfato de Adenosina/metabolismo , Canalopatias/metabolismo , Predisposição Genética para Doença/genética , Deficiência Intelectual/metabolismo , Doenças Musculares/metabolismo , Mutação , Receptores Sulfonilureia/genética , Receptores Sulfonilureia/metabolismo , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Cardiomegalia/genética , Cardiomegalia/metabolismo , Linhagem Celular , Criança , Modelos Animais de Doenças , Facies , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Coração , Cardiopatias/genética , Cardiopatias/metabolismo , Homozigoto , Humanos , Hipertricose/genética , Hipertricose/metabolismo , Deficiência Intelectual/parasitologia , Masculino , Complexo Mediador/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Doenças Musculares/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/fisiopatologia , Osteocondrodisplasias/genética , Osteocondrodisplasias/metabolismo , Linhagem , Fenótipo , Rubídio , Sequenciamento Completo do Genoma , Adulto Jovem , Peixe-Zebra
5.
BMJ Case Rep ; 12(8)2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31413057

RESUMO

Metaphyseal dysplasias are a heterogeneous group of skeletal dysplasias characterised by metaphyseal irregularities. Due to the presence of metaphyseal changes accompanied with bowing deformity of lower limb, they are likely to be mistaken for rickets. We present a case of a 7-year-old boy, finally diagnosed with metaphyseal dysplasia, Spahr type (MDST) (OMIM # 250400) after his exome sequencing revealed novel variations in the MMP13 gene (OMIM * 600108). This is a rare skeletal dysplasia with only a few cases reported in literature. A compilation of the presentation of the reported cases is given to help the reader understand this rare disorder. To the best of our knowledge, this case of MDST is the first to be reported from India.


Assuntos
Osteocondrodisplasias/diagnóstico , Criança , Diagnóstico Diferencial , Humanos , Masculino , Metaloproteinase 13 da Matriz/genética , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/genética , Raquitismo/diagnóstico
6.
Transfus Apher Sci ; 58(4): 449-452, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31395426

RESUMO

Ghosal hematodiaphyseal dysplasia (GHDD) is an autosomal recessive inherited disorder associated with biallelic mutations in the TBXAS1 gene located on the chromosome 7q33-34, which encodes thromboxane-A-synthase. GHDD is characterized by defective hematopoiesis due to bone marrow fibrosis and metadiaphyseal dysplasia of long bones. The accurate diagnosis of this rare syndrome is critical since it reduces the need of blood transfusions by corticosteroid therapy, leading to a significant improvement in anemia and bone changes. The aim of this study is to report two adult siblings diagnosed as GHDD, who admitted with pancytopenia and treated with steroids treatment in adult hematology clinic.


Assuntos
Anemia Refratária , Anemia , Doenças Autoimunes , Cromossomos Humanos Par 7/genética , Mutação , Osteocondrodisplasias , Irmãos , Adulto , Anemia/diagnóstico por imagem , Anemia/tratamento farmacológico , Anemia/genética , Anemia Refratária/diagnóstico por imagem , Anemia Refratária/tratamento farmacológico , Anemia Refratária/genética , Doenças Autoimunes/diagnóstico por imagem , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/genética , Humanos , Masculino , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/tratamento farmacológico , Osteocondrodisplasias/genética
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 694-696, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302913

RESUMO

OBJECTIVE: To explore the molecular basis for a pedigree affected with spondyloepiphyseal dysplasia congenita (SEDC). METHODS: The proband was subjected to whole exome sequencing. Suspected variant was verified by Sanger sequencing. RESULTS: All patients from the pedigree were found to carry a novel missense variant c.1394G>C (p.Gly465Ala) of the COL2A1 gene. The variant was not reported previously. Provean, Polyphen-2 and Mutation Taster software predicted that the variant is highly likely to be pathogenic. CONCLUSION: The c.1394G>C (p.Gly465Ala) variant of the COL2A1 gene probably underlies the SEDC in this pedigree.


Assuntos
Colágeno Tipo II/genética , Osteocondrodisplasias/congênito , Grupo com Ancestrais do Continente Asiático , Humanos , Osteocondrodisplasias/genética , Linhagem
8.
BMC Med Genet ; 20(1): 126, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311520

RESUMO

BACKGROUND: Osteodysplasia of the oral and maxillofacial bone is generally accompanied by systemic bone abnormalities (such as short stature, joint contracture) or other systemic abnormalities (such as renal, dermatological, cardiovascular, optic, or hearing disorders). However, it does not always present this way. Recent reports have suggested that genome-wide sequencing is an effective method for identifying rare or new disorders. Here, we performed whole-exome sequencing (WES) in a patient with a unique form of acquired, local osteodysplasia of the oral and maxillofacial region. CASE PRESENTATION: A 46-year-old woman presented to our hospital with the complaint of gradually moving mandibular teeth (for 6 months), changing facial appearance, and acquired osteolysis of the oral and maxillofacial bones, showing mandibular hypoplasia without family history. Upon skeletal examination, there were no abnormal findings outside of the oral and maxillofacial area; the patient had a height of 157 cm and bone mineral density (according to dual energy x-ray absorptiometry) of 90%. Results of blood and urine tests, including evaluation of bone metabolism markers and neurological and cardiovascular examinations, were normal. We performed WES of genomic DNA extracted from the blood of this patient and her mother, who did not have the disease, as a negative control. We identified 83 new missense variants in the patient, not detected in her mother, including a candidate single nucleotide variant in exon 14 of PCNT (pericentrin). Critical homozygous or compound heterozygous variants in PCNT are a known cause of microcephalic osteodysplastic primordial dwarfism type II accompanied by mandibular hypoplasia, which is similar to the maxillofacial phenotype in this patient. CONCLUSIONS: Protein simulations performed using Polymorphism Phenotyping v2 and Combined Annotation Dependent Depletion software indicated that this missense variant is likely to disrupt the PCNT protein structure. These results suggest that this is a new form of osteolysis related to this PCNT variant.


Assuntos
Antígenos/genética , Nanismo/genética , Retardo do Crescimento Fetal/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Microcefalia/genética , Osteocondrodisplasias/genética , Antígenos/química , Sequência de Bases , Densidade Óssea , Nanismo/diagnóstico por imagem , Nanismo/fisiopatologia , Éxons , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Retardo do Crescimento Fetal/fisiopatologia , Heterozigoto , Homozigoto , Humanos , Mandíbula/patologia , Microcefalia/diagnóstico por imagem , Microcefalia/fisiopatologia , Pessoa de Meia-Idade , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/fisiopatologia , Osteólise , Fenótipo , Tomógrafos Computadorizados , Odontopatias/congênito , Odontopatias/diagnóstico por imagem , Odontopatias/genética , Raiz Dentária/anormalidades , Raiz Dentária/diagnóstico por imagem , Sequenciamento Completo do Exoma
9.
PLoS Genet ; 15(7): e1008215, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31260448

RESUMO

The unfolded protein response (UPR) is a conserved cellular response to the accumulation of proteinaceous material in endoplasmic reticulum (ER), active both in health and disease to alleviate cellular stress and improve protein folding. Multiple epiphyseal dysplasia (EDM5) is a genetic skeletal condition and a classic example of an intracellular protein aggregation disease, whereby mutant matrilin-3 forms large insoluble aggregates in the ER lumen, resulting in a specific 'disease signature' of increased expression of chaperones and foldases, and alternative splicing of the UPR effector XBP1. Matrilin-3 is expressed exclusively by chondrocytes thereby making EDM5 a perfect model system to study the role of protein aggregation in disease. In order to dissect the role of XBP1 signalling in aggregation-related conditions we crossed a p.V194D Matn3 knock-in mouse model of EDM5 with a mouse line carrying a cartilage specific deletion of XBP1 and analysed the resulting phenotype. Interestingly, the growth of mice carrying the Matn3 p.V194D mutation compounded with the cartilage specific deletion of XBP1 was severely retarded. Further phenotyping revealed increased intracellular retention of amyloid-like aggregates of mutant matrilin-3 coupled with dramatically decreased cell proliferation and increased apoptosis, suggesting a role of XBP1 signalling in protein accumulation and/or degradation. Transcriptomic analysis of chondrocytes extracted from wild type, EDM5, Xbp1-null and compound mutant lines revealed that the alternative splicing of Xbp1 is crucial in modulating levels of protein aggregation. Moreover, through detailed transcriptomic comparison with a model of metaphyseal chondrodysplasia type Schmid (MCDS), an UPR-related skeletal condition in which XBP1 was removed without overt consequences, we show for the first time that the differentiation-state of cells within the cartilage growth plate influences the UPR resulting from retention of a misfolded mutant protein and postulate that modulation of XBP1 signalling pathway presents a therapeutic target for aggregation related conditions in cells undergoing proliferation.


Assuntos
Mutação , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Proteína 1 de Ligação a X-Box/genética , Processamento Alternativo , Animais , Apoptose , Proliferação de Células , Células Cultivadas , Condrócitos/citologia , Condrócitos/metabolismo , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Perfilação da Expressão Gênica , Humanos , Proteínas Matrilinas/química , Proteínas Matrilinas/genética , Camundongos , Osteocondrodisplasias/metabolismo , Agregados Proteicos , Transdução de Sinais , Resposta a Proteínas não Dobradas , Proteína 1 de Ligação a X-Box/metabolismo
10.
Medicine (Baltimore) ; 98(30): e16485, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348255

RESUMO

RATIONALE: Spondylometaphyseal dysplasia (SMD) is an extremely rare disorder of irregular development of spine and metaphyses of long tubular bones. Mutations in the collagen type X alpha 1 gene were found to underlie this condition. Previously reported mutations in the N-terminal non-collagenous NC2 domain and C-terminal non-collagenous NC1 domain failed to be identified in some specific patients. PATIENT CONCERNS: A 23-year-old male was referred to us for fixed, angular thoracolumbar kyphosis with semi-paralysis, numbness, and tremor on his left lower limb. Marked hypoplasia of thoracolumbar vertebra and spinal canal stenosis were observed on radiology. DIAGNOSES: He was diagnosed with spondylometaphyseal dysplasia (Type A4). Gene sequencing was performed using normalized targeted regions sequencing (TRS). A novel heterozygous missense variant p.Gly139Cys in the triple-helical region. Multiple lines of evidence imply this mutation to be pathogenic. INTERVENTIONS: Posterior instrumentation and vertebral column resection were given to correct his fixed, angular thoracolumbar kyphosis. OUTCOMES: The correction was satisfying and the functional outcomes were good. LESSONS SUBSECTIONS AS PER STYLE: The findings corroborated that type X collagen plays a critical role in the formation of the human spine as well as the long bones, and further expanded the range of type X collagenopathy. Surgical procedure could be considered for patients with severe malformation and neurological impairments.


Assuntos
Colágeno Tipo X/genética , Coxa Valga/complicações , Osteocondrodisplasias/complicações , Osteocondrodisplasias/genética , Coxa Valga/cirurgia , Humanos , Cifose/etiologia , Cifose/cirurgia , Masculino , Osteocondrodisplasias/cirurgia , Análise de Sequência de DNA , Adulto Jovem
11.
Cytogenet Genome Res ; 158(2): 56-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31158835

RESUMO

SHOX resides in the short arm pseudoautosomal region (PAR1) of the sex chromosomes and escapes X inactivation. SHOX haploinsufficiency underlies idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). A substantial percentage of cases with SHOX haploinsufficiency arise from pseudoautosomal copy number variations (CNVs) involving putative enhancer regions of SHOX. Our previous study using peripheral blood samples showed that some CpG dinucleotides adjacent to SHOX exon 1 were hypomethylated in a healthy woman and methylated in a woman with gross X chromosomal rearrangements. However, it remains unknown whether submicroscopic pseudoautosomal CNVs cause aberrant DNA methylation of SHOX-flanking CpG islands. In this study, we examined the DNA methylation status of SHOX-flanking CpG islands in 50 healthy individuals and 10 ISS/LWD patients with pseudoautosomal CNVs. In silico analysis detected 3 CpG islands within the 20-kb region from the translation start site of SHOX. Pyrosequencing and bisulfite sequencing of genomic DNA samples revealed that these CpG islands were barely methylated in peripheral blood cells and cultured chondrocytes of healthy individuals, as well as in peripheral blood cells of ISS/LWD patients with pseudoautosomal CNVs. These results, in conjunction with our previous findings, indicate that the DNA methylation status of SHOX-flanking CpG islands can be affected by gross X-chromosomal abnormalities, but not by submicroscopic CNVs in PAR1. Such CNVs likely disturb SHOX expression through DNA methylation-independent mechanisms, which need to be determined in future studies.


Assuntos
Metilação de DNA , Doenças Genéticas Ligadas ao Cromossomo X/genética , Transtornos do Crescimento/genética , Osteocondrodisplasias/genética , Proteína de Homoeobox de Baixa Estatura/genética , Adolescente , Adulto , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Condrócitos , Ilhas de CpG , Variações do Número de Cópias de DNA , Feminino , Humanos , Análise de Sequência de DNA
12.
BMJ Case Rep ; 12(5)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151966

RESUMO

Microcephalic osteodysplastic primordial dwarfism syndrome II (MOPDII) is microcephalic primordial dwarfism and is a very rare form of disproportionate short stature. This disorder shares common features with other forms of microcephalic primordial dwarfism, including severe prenatal and postnatal growth retardation with marked microcephaly. However, it includes characteristic skeletal dysplasia, abnormal dentition and increased risk for cerebrovascular diseases. Recent reports added more features, including café-au-lait lesions, cutis marmorata, astigmatism, Moyamoya disease, insulin resistance, obesity, abnormal skin pigmentation and acanthosis nigricans around the neck. Clearly, the more MOPDII reports that are produced, the more information will be added to the spectrum of MOPDII features that can improve our understanding of this disorder. In this paper, we reported a new case of MOPDII with more severe clinical features, earlier onset of common features, in addition to a homozygous novel variant in the PCNT gene.


Assuntos
Antígenos/genética , Nanismo/genética , Retardo do Crescimento Fetal/genética , Microcefalia/genética , Osteocondrodisplasias/genética , Consanguinidade , Nanismo/diagnóstico por imagem , Transtornos da Alimentação e da Ingestão de Alimentos/congênito , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Transtornos da Alimentação e da Ingestão de Alimentos/terapia , Retardo do Crescimento Fetal/diagnóstico por imagem , Homozigoto , Humanos , Lactente , Masculino , Microcefalia/diagnóstico por imagem , Doenças do Sistema Nervoso/congênito , Doenças do Sistema Nervoso/genética , Osteocondrodisplasias/diagnóstico por imagem , Nutrição Parenteral , Doenças Raras
13.
RNA ; 25(9): 1130-1149, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31175170

RESUMO

Minor intron splicing plays a central role in human embryonic development and survival. Indeed, biallelic mutations in RNU4ATAC, transcribed into the minor spliceosomal U4atac snRNA, are responsible for three rare autosomal recessive multimalformation disorders named Taybi-Linder (TALS/MOPD1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes, which associate numerous overlapping signs of varying severity. Although RNA-seq experiments have been conducted on a few RFMN patient cells, none have been performed in TALS, and more generally no in-depth transcriptomic analysis of the ∼700 human genes containing a minor (U12-type) intron had been published as yet. We thus sequenced RNA from cells derived from five skin, three amniotic fluid, and one blood biosamples obtained from seven unrelated TALS cases and from age- and sex-matched controls. This allowed us to describe for the first time the mRNA expression and splicing profile of genes containing U12-type introns, in the context of a functional minor spliceosome. Concerning RNU4ATAC-mutated patients, we show that as expected, they display distinct U12-type intron splicing profiles compared to controls, but that rather unexpectedly mRNA expression levels are mostly unchanged. Furthermore, although U12-type intron missplicing concerns most of the expressed U12 genes, the level of U12-type intron retention is surprisingly low in fibroblasts and amniocytes, and much more pronounced in blood cells. Interestingly, we found several occurrences of introns that can be spliced using either U2, U12, or a combination of both types of splice site consensus sequences, with a shift towards splicing using preferentially U2 sites in TALS patients' cells compared to controls.


Assuntos
Nanismo/genética , Retardo do Crescimento Fetal/genética , Microcefalia/genética , Osteocondrodisplasias/genética , Processamento de RNA/genética , Transcriptoma/genética , Adulto , Idoso , Sequência de Bases/genética , Pré-Escolar , Sequência Consenso/genética , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Lactente , Íntrons/genética , Masculino , Pessoa de Meia-Idade , RNA/genética , RNA Mensageiro/genética , RNA Nuclear Pequeno/genética , Spliceossomos/genética , Adulto Jovem
14.
Biomed Res Int ; 2019: 2492590, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31218223

RESUMO

Skeletal dysplasias (SDs) comprise a series of severe congenital disorders that have strong clinical heterogeneity and usually attribute to diverse genetic variations. The pathogenesis of more than half of SDs remains unclear. Additionally, the clinical manifestations of fetal SDs are ambiguous, which poses a big challenge for accurate diagnosis. In this study, eight unrelated families with fetal SD were recruited and subjected to sequential tests including chromosomal karyotyping, chromosomal microarray analysis (CMA), and trio whole-exome sequencing (WES). Sanger sequencing and quantitative fluorescence PCR (QF-PCR) were performed as affirmative experiments. In six families, a total of six pathogenic/likely pathogenic variations were identified in four genes including SLC26A2, FGFR3, FLNB, and TMEM38B. These variations caused disorders following autosomal dominant or autosomal recessive inheritance patterns, respectively. The results provided reliable evidence for the subsequent genetic counseling and reproductive options to these families. With its advantage in variation calling and interpreting, trio WES is a promising strategy for the investigation of fetal SDs in cases with normal karyotyping and CMA results. It has considerable prospects to be utilized in prenatal diagnosis.


Assuntos
Doenças Fetais/genética , Feto , Variação Genética , Osteocondrodisplasias/genética , Sequenciamento Completo do Exoma , Adulto , Feminino , Humanos , Gravidez
15.
BMC Med Genet ; 20(1): 70, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053099

RESUMO

BACKGROUND: X-linked spondyloepiphyseal dysplasia tarda (SEDT-XL) is a skeletal disorder characterized by defective structures of vertebral bodies and/or of epiphyses of the long bones, resulting in moderately short stature and early joint degeneration. TRAPPC2 gene, which is important for collagen secretion, has been reported as causative for SEDT-XL. CASE PRESENTATION: Here, we report two variants of TRAPPC2 gene of SEDT-XL patients, a missense variant of start codon, c.1A > T, and a deletion variant, c.40delG. To understand molecular consequence of the variants, we establish an in vitro gene expression assay system and demonstrate that both mutated genes are transcribed, but are not properly translated, indicative of the pathogenic nature of those TRAPPC2 variants. CONCLUSIONS: In the current study, we provide additional experimental data showing that loss-of-function TRAPPC2 variants are probably causative for SEDT-XL phenotype. These findings further contribute to the understanding the clinical picture related to TRAPPC2 gene.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas de Membrana Transportadoras/genética , Osteocondrodisplasias/genética , Fatores de Transcrição/genética , Adolescente , Humanos , Masculino , Pessoa de Meia-Idade
16.
Genet Test Mol Biomarkers ; 23(5): 310-315, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30932712

RESUMO

Objective:Heterozygous pathogenic variants in the COL2A1 gene result in several clinical features including impaired skeletal growth, ocular and otolaryngological abnormalities. Missense mutations in the triple helical region of the COL2A1 protein have been associated with lethal spondyloepiphyseal dysplasia (SED). In this study, we aimed to identify the underlying cause of a case of SED congenita (SEDC) in a 27-month-old child. Materials and Methods: A patient who was diagnosed initially with osteochondrodysplasia underwent a detailed clinical and radiological examination to obtain a conclusive diagnosis. The patient did not show any clinical features of hypochondrogenesis. Whole exome sequencing of the COL2A1 gene was carried out to identify the underlying genetic cause of the disorder. Results: Variant annotation and filtration detected a heterozygous missense mutation c.1357G>A (p.G453S) in the exon 21 of the COL2A1 gene of the proband which was confirmed by Sanger sequencing. Neither parent carried the mvariant suggesting this was a new mutation. Conclusion: The COL2A1 mutation (c.1357G>A), identified in this case, results in more mild phenotype than other missense mutations in exon 21 which are known to cause lethal hypochondrogenesis. We showed, for the first time, that a missense mutation (p.G453S) in the triple helical region of the alpha 1 (II) chain of the COL2A1 protein underlies SEDC and is not always lethal.


Assuntos
Colágeno Tipo II/genética , Osteocondrodisplasias/congênito , Colágeno Tipo II/fisiologia , Feminino , Heterozigoto , Humanos , Lactente , Mutação , Mutação de Sentido Incorreto/genética , Osteocondrodisplasias/genética , Osteocondrodisplasias/fisiopatologia , Arábia Saudita , Sequenciamento Completo do Exoma
17.
Cytogenet Genome Res ; 157(3): 135-140, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30933954

RESUMO

We report a patient with developmental delay, brachydactyly type E, short stature, and tetralogy of Fallot. Brachydactyly-mental retardation syndrome (BDMR) was suspected based on the phenotype; however, array CGH excluded a 2q37 deletion, but identified a deletion encompassing the SHOX gene. BDMR is characterized by cognitive impairment, skeletal abnormalities involving hands and feet, short stature, and overweight. Most affected individuals carry relatively large 2q37 deletions encompassing HDAC4. This gene encodes a histone deacetylase involved in epigenetic regulation of cell growth and differentiation, specifically during endochondral bone formation in chondrocyte hypertrophy. Since SHOX haploinsufficiency can cause skeletal defects and short stature but would not fully explain the clinical picture of this patient, exome sequencing was performed, and a heterozygous HDAC8 frameshift mutation was identified. HDAC8 is a distinct histone deacetylase involved in cohesin recycling and is responsible for an X-linked dominant Cornelia de Lange-like phenotype. A new blended clinical phenotype may be explained by the result of a dual molecular diagnosis, which represents a combination of 2 independent genetic defects, with relevant implications for genetic counseling, clinical management, and prognosis.


Assuntos
Síndrome de Lange/diagnóstico , Mutação da Fase de Leitura , Deleção de Genes , Transtornos do Crescimento/diagnóstico , Histona Desacetilases/genética , Osteocondrodisplasias/diagnóstico , Proteínas Repressoras/genética , Proteína de Homoeobox de Baixa Estatura/genética , Criança , Hibridização Genômica Comparativa , Síndrome de Lange/genética , Feminino , Transtornos do Crescimento/genética , Haploinsuficiência , Humanos , Osteocondrodisplasias/genética , Linhagem , Fenótipo , Sequenciamento Completo do Exoma
18.
Int J Exp Pathol ; 100(1): 4-11, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30912609

RESUMO

This review, based on the BSMB Fell-Muir Lecture I presented in July 2018 at the Matrix Biology Europe Conference in Manchester, gives a personal perspective of my own laboratory's contributions to research into type X collagen, metaphyseal chondrodysplasia type Schmid and potential treatments for this disorder that are currently entering clinical trial. I have tried to set the advances made in the context of the scientific technologies available at the time and how these have changed over the more than three decades of this research.


Assuntos
Pesquisa Biomédica/métodos , Ensaios Clínicos como Assunto/métodos , Clonagem Molecular/métodos , Colágeno Tipo X/genética , Terapia Genética/métodos , Mutação , Osteocondrodisplasias/terapia , Animais , Pesquisa Biomédica/história , Ensaios Clínicos como Assunto/história , Colágeno Tipo X/metabolismo , Congressos como Assunto , Difusão de Inovações , Predisposição Genética para Doença , Terapia Genética/história , História do Século XX , História do Século XXI , Humanos , Osteocondrodisplasias/genética , Osteocondrodisplasias/história , Osteocondrodisplasias/metabolismo , Fenótipo
19.
Mol Genet Genomic Med ; 7(5): e648, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30916490

RESUMO

BACKGROUND: A family with skeletal and craniofacial anomalies is presented. Whole-exome sequencing (WES) analysis indicated a diagnosis of Larsen syndrome, although their clinical presentation does not include the hallmark joint dislocations typically observed in Larsen syndrome. METHODS: Patient consent for the sharing of de-identified clinical and genetic information, along with use of photographs for publication, was obtained. WES and variant segregation analysis by WES were performed by commercial laboratory, GeneDx (Gaithersburg, MD), on peripheral blood samples from the proband, her brother, and her parents using methods detailed on their website for test XomeDx Whole Exome Sequencing Trio (https://www.genedx.com/test-catalog/available-tests/xomedx-whole-exome-sequencing-trio/). WES uses next-generation sequencing (NGS) technology to assess for variants within the coding regions, or exons, of approximately 23,000 genes. For the FLNB gene (NM_001457.3), 100% of the coding region was covered at a minimum of 10x. GeneDx uses Sanger sequencing to confirm NGS variants. RESULTS: WES revealed a heterozygous pathogenic variant, p.Glu227Lys (c.679G>A), in the FLNB gene in three out of the four family members tested. This variant is associated with Larsen syndrome, a skeletal dysplasia condition with a wide range of phenotypic variability that usually includes congenital joint dislocations. CONCLUSION: This is a highly unusual presentation of Larsen syndrome in which the identifying hallmark trait is absent in the patients' phenotypes.


Assuntos
Luxações Articulares/genética , Osteocondrodisplasias/genética , Fenótipo , Adulto , Feminino , Filaminas/genética , Humanos , Lactente , Recém-Nascido , Luxações Articulares/patologia , Masculino , Osteocondrodisplasias/patologia , Linhagem
20.
Res Vet Sci ; 124: 112-117, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30878632

RESUMO

Tibial dyschondroplasia (TD) is a type of bone deformity found in fast-growing chickens, which induce inflammatory responses. Prostaglandins (PGs) implicate in bone formation and bone resorption, associated with inflammation in an autocrine/paracrine manner. This study used qRT-PCR and immunohistochemistry analysis to identify the expression patterns of PG-related genes in the erythrocytes of broiler chickens and explore the effects of thiram-induced TD and the recombinant glutathione-S-transferase A3 (rGSTA3) protein on the expression of PG-related genes: GSTA3, cyclooxygenase 2 (COX-2), prostaglandin D2 synthase (PTGDS), prostaglandin E synthase (PTGES), prostaglandin E2 receptor (PTGER) 3, PTGER4 and prostaglandin reductase 1 (PTGR1). Interestingly, the results showed that these seven PG-related genes expression was identified in the erythrocytes of broiler chicken, and thiram-induced TD suppressed the expression of these PG-related genes in the initial stage of TD and promoted their expression in TD recovery. These findings demonstrated that the immunoregulatory function of erythrocytes can be inhibited in the early stage of TD and promoted in the recovery stage by modulating the expression of PG-related genes. Further, the rGSTA3 protein can modulate the expression of PG-related genes in erythrocytes and participate in the recovery of TD.


Assuntos
Galinhas , Glutationa Transferase/farmacologia , Osteocondrodisplasias/veterinária , Doenças das Aves Domésticas/genética , Prostaglandinas/genética , Tíbia/patologia , Animais , Proteínas Aviárias/farmacologia , Eritrócitos/metabolismo , Mutagênicos/farmacologia , Osteocondrodisplasias/induzido quimicamente , Osteocondrodisplasias/genética , Doenças das Aves Domésticas/induzido quimicamente , Prostaglandinas/metabolismo , Proteínas Recombinantes/farmacologia , Tiram/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA