ABSTRACT
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.
Subject(s)
Alleles , Arteriosclerosis/genetics , DNA Helicases/genetics , Gene Expression , Immunologic Deficiency Syndromes/genetics , Mutation , Nephrotic Syndrome/genetics , Osteochondrodysplasias/genetics , Pulmonary Embolism/genetics , Animals , Arteriosclerosis/metabolism , Chromatin/metabolism , DNA Helicases/metabolism , Disease Models, Animal , Drosophila/enzymology , Embryo, Nonmammalian/metabolism , Environment , Humans , Immunologic Deficiency Syndromes/metabolism , Mice , Nephrotic Syndrome/metabolism , Osteochondrodysplasias/metabolism , Penetrance , Primary Immunodeficiency Diseases , Pulmonary Embolism/metabolismABSTRACT
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.
Subject(s)
Arteriosclerosis/metabolism , Glomerulosclerosis, Focal Segmental/metabolism , Immunologic Deficiency Syndromes/metabolism , Kidney Diseases/metabolism , Nephrotic Syndrome/metabolism , Osteochondrodysplasias/metabolism , Pulmonary Embolism/metabolism , Receptors, Notch/metabolism , Wnt Proteins/metabolism , Animals , Arteriosclerosis/genetics , Child , Child, Preschool , DNA Helicases/genetics , DNA Helicases/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Fluorescent Antibody Technique, Indirect , Glomerulosclerosis, Focal Segmental/genetics , Humans , Immunologic Deficiency Syndromes/genetics , Kidney Diseases/genetics , Male , Nephrotic Syndrome/genetics , Osteochondrodysplasias/genetics , Primary Immunodeficiency Diseases , Pulmonary Embolism/genetics , Wnt Proteins/geneticsABSTRACT
The posterior bed nuclei of the stria terminalis (BST) are important neural substrate for relaying limbic influences to the paraventricular nucleus (PVN) of the hypothalamus to inhibit hypothalamic-pituitary-adrenal (HPA) axis responses to emotional stress. Androgen receptor-expressing cells within the posterior BST have been identified as projecting to the PVN region. To test a role for androgen receptors in the posterior BST to inhibit PVN motor neurons, we compared the effects of the non-aromatizable androgen dihydrotestosterone (DHT), the androgen receptor antagonist hydroxyflutamide (HF), or a combination of both drugs implanted unilaterally within the posterior BST. Rats bearing unilateral implants were analyzed for PVN Fos induction in response to acute-restraint stress and relative levels of corticotrophin-releasing hormone and arginine vasopressin (AVP) mRNA. Glutamic acid decarboxylase (GAD) 65 and GAD 67 mRNA were analyzed in the posterior BST to test a local involvement of GABA. There were no changes in GAD expression to support a GABA-related mechanism in the BST. For PVN neuropeptide expression and Fos responses, basic effects were lateralized to the sides of the PVN ipsilateral to the implants. However, opposite to our expectations of an inhibitory influence of androgen receptors in the posterior BST, PVN AVP mRNA and stress-induced Fos were augmented in response to DHT and attenuated in response to HF. These results suggest that a subset of androgen receptor-expressing cells within the posterior BST region may be responsible for increasing the biosynthetic capacity and stress-induced drive of PVN motor neurons.