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1.
Clin Immunol ; 161(2): 355-65, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26499378

RESUMO

Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive, fatal childhood disorder associated with skeletal dysplasia, renal dysfunction, and T-cell immunodeficiency. This disease is linked to biallelic loss-of-function mutations of the SMARCAL1 gene. Although recurrent infection, due to T-cell deficiency, is a leading cause of morbidity and mortality, the etiology of the T-cell immunodeficiency is unclear. Here, we demonstrate that the T cells of SIOD patients have undetectable levels of protein and mRNA for the IL-7 receptor alpha chain (IL7Rα) and are unresponsive to stimulation with IL-7, indicating a loss of functional receptor. No pathogenic mutations were detected in the exons of IL7R in these patients; however, CpG sites in the IL7R promoter were hypermethylated in SIOD T cells. We propose therefore that the lack of IL7Rα expression, associated with hypermethylation of the IL7R promoter, in T cells and possibly their earlier progenitors, restricts T-cell development in SIOD patients.


Assuntos
Arteriosclerose/genética , Síndromes de Imunodeficiência/genética , Síndrome Nefrótica/genética , Osteocondrodisplasias/genética , Embolia Pulmonar/genética , Receptores de Interleucina-7/genética , Linfócitos T/metabolismo , Adolescente , Adulto , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Células Cultivadas , Criança , Pré-Escolar , DNA Helicases/genética , Metilação de DNA , Citometria de Fluxo , Expressão Gênica , Humanos , Imuno-Histoquímica , Síndromes de Imunodeficiência/metabolismo , Síndromes de Imunodeficiência/patologia , Interleucina-17/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Mutação , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/patologia , Osteocondrodisplasias/metabolismo , Osteocondrodisplasias/patologia , Doenças da Imunodeficiência Primária , Regiões Promotoras Genéticas/genética , Embolia Pulmonar/metabolismo , Embolia Pulmonar/patologia , Receptores de Interleucina-7/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Adulto Jovem
2.
Pediatr Res ; 78(6): 609-17, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26309238

RESUMO

BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder caused by mutations in SMARCAL1. A frequent complication is arteriosclerosis associated with reduced elastin expression; however, the mechanism underlying the reduced elastin expression remains unknown. METHODS: Expression of transcriptional regulators of elastin (ELN) and microRNA (miRNA) regulators of ELN messenger RNA (mRNA), ELN promoter methylation, and ELN mRNA poly(A) tail length were assessed by quantitative RT-PCR, bisulfite Sanger sequencing, and the Poly(A) Tail Length Assay Kit, respectively, in unaffected developing human aortae and in an SIOD aorta. RESULTS: Comparing unaffected fetal and adult aortae, ELN precursor mRNA (pre-mRNA) levels remained nearly constant, whereas mRNA levels declined by ~10(2)-fold. This corresponded with a reduction in poly(A) tail length but not with changes in the other parameters. In contrast, compared to the unaffected fetal aortae, the SIOD aorta had 18-fold less ELN pre-mRNA and 10(4)-fold less mRNA. This corresponded with increased expression of miRNA regulators and shorter ELN mRNA poly(A) tail lengths but not with altered expression of ELN transcriptional regulators or ELN promoter methylation. CONCLUSION: Posttranscriptional mechanisms account for the reduction in ELN mRNA levels in unaffected aortae, whereas transcriptional and posttranscriptional mechanisms reduce elastin expression in SIOD aorta and predispose to arteriosclerosis.


Assuntos
Aorta/metabolismo , Arteriosclerose/genética , Elastina/genética , Síndromes de Imunodeficiência/genética , Síndrome Nefrótica/genética , Osteocondrodisplasias/genética , Embolia Pulmonar/genética , Precursores de RNA/genética , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética , Transcrição Gênica , Adolescente , Adulto , Aorta/embriologia , Aorta/patologia , Arteriosclerose/embriologia , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Metilação de DNA , Regulação para Baixo , Elastina/metabolismo , Feminino , Idade Gestacional , Humanos , Síndromes de Imunodeficiência/embriologia , Síndromes de Imunodeficiência/metabolismo , Síndromes de Imunodeficiência/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Síndrome Nefrótica/embriologia , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/patologia , Osteocondrodisplasias/embriologia , Osteocondrodisplasias/metabolismo , Osteocondrodisplasias/patologia , Doenças da Imunodeficiência Primária , Regiões Promotoras Genéticas , Embolia Pulmonar/embriologia , Embolia Pulmonar/metabolismo , Embolia Pulmonar/patologia , Precursores de RNA/metabolismo , RNA Mensageiro/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
3.
Hum Mol Genet ; 21(11): 2572-87, 2012 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-22378147

RESUMO

Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous dysplasia (SIOD, MIM 242900), an incompletely penetrant autosomal recessive disorder. Using human, Drosophila and mouse models, we show that the proteins encoded by SMARCAL1 orthologs localize to transcriptionally active chromatin and modulate gene expression. We also show that, as found in SIOD patients, deficiency of the SMARCAL1 orthologs alone is insufficient to cause disease in fruit flies and mice, although such deficiency causes modest diffuse alterations in gene expression. Rather, disease manifests when SMARCAL1 deficiency interacts with genetic and environmental factors that further alter gene expression. We conclude that the SMARCAL1 annealing helicase buffers fluctuations in gene expression and that alterations in gene expression contribute to the penetrance of SIOD.


Assuntos
Alelos , Arteriosclerose/genética , DNA Helicases/genética , Expressão Gênica , Síndromes de Imunodeficiência/genética , Mutação , Síndrome Nefrótica/genética , Osteocondrodisplasias/genética , Embolia Pulmonar/genética , Animais , Arteriosclerose/metabolismo , Cromatina/metabolismo , DNA Helicases/metabolismo , Modelos Animais de Doenças , Drosophila/enzimologia , Embrião não Mamífero/metabolismo , Meio Ambiente , Humanos , Síndromes de Imunodeficiência/metabolismo , Camundongos , Síndrome Nefrótica/metabolismo , Osteocondrodisplasias/metabolismo , Penetrância , Doenças da Imunodeficiência Primária , Embolia Pulmonar/metabolismo
4.
Eur J Pediatr ; 169(7): 801-11, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20013129

RESUMO

Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by prominent spondyloepiphyseal dysplasia, T cell deficiency, and focal segmental glomerulosclerosis. Biallelic mutations in swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD, but approximately half of patients referred for molecular studies do not have detectable mutations in SMARCAL1. We hypothesized that skeletal features distinguish between those with or without SMARCAL1 mutations. Therefore, we analyzed the skeletal radiographs of 22 patients with and 11 without detectable SMARCAL1 mutations. We found that patients with SMARCAL1 mutations have a spondyloepiphyseal dysplasia (SED) essentially limited to the spine, pelvis, capital femoral epiphyses, and possibly the sella turcica, whereas the hands and other long bones are basically normal. Additionally, we found that several of the adolescent and young adult patients developed osteoporosis and coxarthrosis. Of the 11 patients without detectable SMARCAL1 mutations, seven had a SED indistinguishable from patients with SMARCAL1 mutations. We conclude therefore that SED is a feature of patients with SMARCAL1 mutations and that skeletal features do not distinguish who of those with SED have SMARCAL1 mutations.


Assuntos
Osso e Ossos/diagnóstico por imagem , DNA Helicases/genética , Mutação , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/genética , Adolescente , Adulto , Criança , Pré-Escolar , Diagnóstico Diferencial , Heterogeneidade Genética , Glomerulosclerose Segmentar e Focal/genética , Humanos , Linfopenia/genética , Fenótipo , Radiografia , Síndrome
5.
Orphanet J Rare Dis ; 11(1): 149, 2016 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-27816064

RESUMO

BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. Changes in gene expression underlie the arteriosclerosis and T-cell immunodeficiency of SIOD; therefore, we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila. RESULTS: We found increased expression of components and targets of the Wnt and Notch signaling pathways in the SIOD patient kidney, increased levels of unphosphorylated ß-catenin and Notch1 intracellular domain in the glomeruli of most SIOD patient kidneys, and genetic interaction between the Drosophila SMARCAL1 homologue Marcal1 and genes of the Wnt and Notch signaling pathways. CONCLUSIONS: We conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients.


Assuntos
Arteriosclerose/metabolismo , Glomerulosclerose Segmentar e Focal/metabolismo , Síndromes de Imunodeficiência/metabolismo , Nefropatias/metabolismo , Síndrome Nefrótica/metabolismo , Osteocondrodisplasias/metabolismo , Embolia Pulmonar/metabolismo , Receptores Notch/metabolismo , Proteínas Wnt/metabolismo , Animais , Arteriosclerose/genética , Criança , Pré-Escolar , DNA Helicases/genética , DNA Helicases/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Técnica Indireta de Fluorescência para Anticorpo , Glomerulosclerose Segmentar e Focal/genética , Humanos , Síndromes de Imunodeficiência/genética , Nefropatias/genética , Masculino , Síndrome Nefrótica/genética , Osteocondrodisplasias/genética , Doenças da Imunodeficiência Primária , Embolia Pulmonar/genética , Proteínas Wnt/genética
6.
Orphanet J Rare Dis ; 7: 70, 2012 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-22998683

RESUMO

BACKGROUND: Arteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD), a multisystem disorder caused by biallelic mutations in SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1). However, the mechanism by which the vascular and pulmonary disease arises in SIOD remains unknown. METHODS: We reviewed the records of 65 patients with SMARCAL1 mutations. Molecular and immunohistochemical analyses were conducted on autopsy tissue from 4 SIOD patients. RESULTS: Thirty-two of 63 patients had signs of arteriosclerosis and 3 of 51 had signs of emphysema. The arteriosclerosis was characterized by intimal and medial hyperplasia, smooth muscle cell hyperplasia and fragmented and disorganized elastin fibers, and the pulmonary disease was characterized by panlobular enlargement of air spaces. Consistent with a cell autonomous disorder, SMARCAL1 was expressed in arterial and lung tissue, and both the aorta and lung of SIOD patients had reduced expression of elastin and alterations in the expression of regulators of elastin gene expression. CONCLUSIONS: This first comprehensive study of the vascular and pulmonary complications of SIOD shows that these commonly cause morbidity and mortality and might arise from impaired elastogenesis. Additionally, the effect of SMARCAL1 deficiency on elastin expression provides a model for understanding other features of SIOD.


Assuntos
Arteriosclerose/fisiopatologia , Enfisema/fisiopatologia , Síndromes de Imunodeficiência/fisiopatologia , Síndrome Nefrótica/fisiopatologia , Osteocondrodisplasias/fisiopatologia , Embolia Pulmonar/fisiopatologia , Adulto , Arteriosclerose/genética , Autopsia , Criança , Pré-Escolar , DNA Helicases/genética , Enfisema/genética , Feminino , Humanos , Imuno-Histoquímica , Síndromes de Imunodeficiência/genética , Masculino , Síndrome Nefrótica/genética , Osteocondrodisplasias/genética , Doenças da Imunodeficiência Primária , Embolia Pulmonar/genética
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