ABSTRACT
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.
Subject(s)
Arteriosclerosis/complications , Immunologic Deficiency Syndromes/complications , Nephrotic Syndrome/complications , Osteochondrodysplasias/complications , Pulmonary Embolism/complications , Tooth Abnormalities/etiology , Alleles , Anodontia/etiology , Arteriosclerosis/genetics , Bicuspid/abnormalities , Bone Morphogenetic Protein 4/analysis , Cell Culture Techniques , Cell Proliferation , Cell Survival , Cells, Cultured , DNA Helicases/analysis , DNA Helicases/genetics , Fibroblasts/pathology , Humans , Immunologic Deficiency Syndromes/genetics , Molar/abnormalities , Mutation/genetics , Nephrotic Syndrome/genetics , Odontogenesis/genetics , Osteochondrodysplasias/genetics , Primary Immunodeficiency Diseases , Pulmonary Embolism/genetics , Skin/cytology , Tooth Germ/pathology , Tooth Root/abnormalities , Tooth, Deciduous/abnormalities , Transcription, Genetic/genetics , Transforming Growth Factor beta1/analysis , Wnt3A Protein/analysisABSTRACT
OBJECTIVES: Our previous report showed that beta-cell antigen-specific CD56+ T-cells and cytokine TRAIL mediate destruction of human pancreatic [beta] cells in vitro. To determine whether CD56 and TRAIL are present during islet cell destruction at the onset of clinical symptoms of type 1 diabetes mellitus (T1D), we studied cell marker and cytokine expression in the pancreatic islets of 2 children who died at presentation of acute-onset T1D and in T-cell lines derived from a group of children with new-onset T1D. METHODS: TRAIL, CD56, and other T-cell markers and cytokine expression were studied using immunohistochemistry on pancreatic sections from 2 children with acute-onset T1D. TRAIL and CD56 expression was analyzed by flow cytometry in the antigen-activated T-cell lines derived from 29 children with new-onset T1D. RESULTS: TRAIL+, CD56+, CD45RO+, and CD3+ cells were present in the islets of acute-onset T1D patients, while none were present in the normal islets. T-cell lines from new-onset T1D expressed TRAIL and CD56 in response to stimulation with beta-cell antigens GAD, IA-2 and insulin beta chain. CONCLUSION: The presence of TRAIL and CD56 markers is part of the T-cell response repertoire in beta-cell destruction.