RESUMO
Described for the first time in 1971, Schimke immuno-osseous dysplasia (SIOD) is an autosomal-recessive multisystem disorder that is caused by bi-allelic mutations of SMARCAL1, which encodes a DNA annealing helicase. To define better the dental anomalies of SIOD, we reviewed the records from SIOD patients with identified bi-allelic SMARCAL1 mutations, and we found that 66.0% had microdontia, hypodontia, or malformed deciduous and permanent molars. Immunohistochemical analyses showed expression of SMARCAL1 in all developing teeth, raising the possibility that the malformations are cell-autonomous consequences of SMARCAL1 deficiency. We also found that stimulation of cultured skin fibroblasts from SIOD patients with the tooth morphogens WNT3A, BMP4, and TGFß1 identified altered transcriptional responses, raising the hypothesis that the dental malformations arise in part from altered responses to developmental morphogens. To the best of our knowledge, this is the first systematic study of the dental anomalies associated with SIOD.
Assuntos
Arteriosclerose/complicações , Síndromes de Imunodeficiência/complicações , Síndrome Nefrótica/complicações , Osteocondrodisplasias/complicações , Embolia Pulmonar/complicações , Anormalidades Dentárias/etiologia , Alelos , Anodontia/etiologia , Arteriosclerose/genética , Dente Pré-Molar/anormalidades , Proteína Morfogenética Óssea 4/análise , Técnicas de Cultura de Células , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , DNA Helicases/análise , DNA Helicases/genética , Fibroblastos/patologia , Humanos , Síndromes de Imunodeficiência/genética , Dente Molar/anormalidades , Mutação/genética , Síndrome Nefrótica/genética , Odontogênese/genética , Osteocondrodisplasias/genética , Doenças da Imunodeficiência Primária , Embolia Pulmonar/genética , Pele/citologia , Germe de Dente/patologia , Raiz Dentária/anormalidades , Dente Decíduo/anormalidades , Transcrição Gênica/genética , Fator de Crescimento Transformador beta1/análise , Proteína Wnt3A/análiseRESUMO
BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive pleiotropic disorder caused by mutations in SMARCAL1. SMARCAL1 encodes an enzyme with homology to the SNF2 chromatin remodelling proteins. METHODS: To assess the affect of SMARCAL1 mutations associated with SIOD on SMARCAL1 expression and function, we characterised the effects of various mutations on mRNA and protein expression in patient tissues and cell lines, and the ATPase activity, subcellular localisation, and chromatin binding of SMARCAL1 missense mutants. RESULTS: The SIOD associated SMARCAL1 mutations affected SMARCAL1 protein expression, stability, subcellular localisation, chromatin binding, and enzymatic activity. Further, expressing SMARCAL1 missense mutants in Drosophila melanogaster showed that disease severity was inversely proportionate to overall SMARCAL1 activity. CONCLUSION: Our results show for the first time that SMARCAL1 binds chromatin in vivo and that SIOD arises from impairment of diverse SMARCAL1 functions.
