We investigated the genome of a 5-year old male who presented with global developmental delay (motor, cognitive, and speech), hypotonia, possibly ataxia, and cerebellar hypoplasia of unknown origin. Whole genome sequencing and mRNA-sequencing were performed on a family containing an affected proband, his unaffected parents and maternal grandfather. To explore the molecular and functional consequences of the variant, we performed cell proliferation assays, qRT-PCR array, immunoblotting, calcium imaging, and neurite outgrowth experiments in SH-SY5Y neuroblastoma cells to compare the properties of the wild type TAF1, deletion of TAF1, and TAF1 variant p.Ser1600Gly samples. The whole genome data identified several gene variants. However, the genome sequence data failed to implicate a candidate gene as many of the variants were of unknown significance. By combining genome sequence data with transcriptomic data, a probable candidate variant, p.Ser1600Gly, emerged in TAF1. Moreover, the RNA-seq data revealed a 90:10 extremely skewed X-chromosome inactivation in the mother. Our results show that neuronal ion channel genes were differentially expressed between TAF1 deletion and TAF1 variant p.Ser1600Gly cells, when compared to their respective controls, and that the TAF1 variant may impair neuronal differentiation and cell proliferation. Taken together, our data suggests that this novel variant in TAF1 plays a key role in the development of a recently described X-linked syndrome, TAF1 intellectual disability syndrome, and further extends our knowledge of a potential link between TAF1 deficiency and defects in neuronal cell function.

Atp10c is a strong candidate gene for diet-induced obesity and type 2 diabetes. To identify molecular and cellular targets of ATP10C, Atp10c expression was altered in vitro in C2C12 skeletal muscle myotubes by transient transfection with an Atp10c-specific siRNA. Glucose uptake assays revealed that insulin stimulation caused a significant 2.54-fold decrease in 2-deoxyglucose uptake in transfected cells coupled with a significant upregulation of native mitogen-activated protein kinases (MAPKs), p38, and p44/42. Additionally, glucose transporter-1 (GLUT1) was significantly upregulated; no changes in glucose transporter-4 (GLUT4) expression were observed. The involvement of MAPKs was confirmed using the specific inhibitor SB203580, which downregulated the expression of native and phosphorylated MAPK proteins in transfected cells without any changes in insulin-stimulated glucose uptake. Results indicate that Atp10c regulates glucose metabolism, at least in part via the MAPK pathway, and, thus, plays a significant role in the development of insulin resistance and type 2 diabetes.

Abstract:We have shown that Atp10c, a type 4 P-type ATPase, is a strong candidate affecting glucose and lipid metabolism in humans and mice. Atp10c is a putative phospholipid translocase associated with cell signaling and intracellular protein trafficking. In order to examine the biological role of Atp10c, semiquantitative reverse transcriptasepolymerase chain reaction was carried out. Atp10c mRNA is expressed in 3T3-L1 cells and in primary preadipocytes and adipocytes generated from mice. Atp10c mRNA is regulated during fat cell differentiation and modulated by PPAR agonists and antagonists as well as by hormonal factors (insulin and dexamethasone). Atp10c expression is regulated by both the process of adipocyte differentiation and by effectors of fat and glucose metabolism. Taken together these data along with the published phenotype of the Atp10c heterozygote mice suggest that ATP10C is a newly identified protein with a possible biological role in the development of obesity and obesity-related metabolic disorders.

No abstract

PP-ice produces clinically and statistically greater muscle and skin cooling compared with PP-gel and control.