Fibroblast growth factor 23 (FGF23) is a phosphate-regulating hormone produced by osteocytes. In iron deficiency anemia (IDA) and in chronic kidney disease (CKD), FGF23 is also produced by erythroid c Show more
Fibroblast growth factor 23 (FGF23) is a phosphate-regulating hormone produced by osteocytes. In iron deficiency anemia (IDA) and in chronic kidney disease (CKD), FGF23 is also produced by erythroid cells. Recent studies have suggested that rising circulating FGF23 is negatively associated with erythropoiesis in IDA and CKD. However, the distinct contributions of bone- and erythroid-produced FGF23 to anemia in IDA remain unclear. Using the conditional deletion of Fgf23 in osteocytes (Fgf23Dmp1-cKO) and in erythroid cells (Fgf23HbB-cKO) in mice fed a control (Ctr) or an iron deficient (ID) diet, we first determined that in ID, osteocytes and erythroid cells are distinct sources of circulating intact FGF23 (iFGF23) and FGF23 cleaved peptides, respectively. We further show that erythroid-specific deletion of Fgf23 corrected anemia in ID mice, and overexpression induced anemia in Ctr mice unlike osteocyte-specific deletion or overexpression of Fgf23. Importantly, erythroid-specific deletion of Furin (FurinHbB-cKO), the enzyme responsible for FGF23 cleavage, led to increased production of iFGF23 from erythroid cells and aggravated ID-induced anemia. iFGF23 also dose-dependently blocked the differentiation of erythroid progenitors in culture triggering mitochondrial dysfunction leading to impaired erythropoiesis. These effects were fully suppressed by co-treatment with an FGFR1 inhibitor. Finally, erythroid-specific deletion of Fgf23 in an animal model of progressive CKD prevented the development of anemia of CKD. In aggregate, our results show that erythroid-expressed FGF23 is a negative regulator of erythropoiesis that contributes to anemia via direct paracrine FGFR1 activation in erythroid precursors. Show less
Autism is a genetic neurodevelopmental disorder of unknown cause and pathogenesis. The identification of genes involved in autism is expected to increase our understanding of its pathogenesis. Infrequ Show more
Autism is a genetic neurodevelopmental disorder of unknown cause and pathogenesis. The identification of genes involved in autism is expected to increase our understanding of its pathogenesis. Infrequently, neurodevelopmental disorders like autism are associated with chromosomal anomalies. To identify candidate genes for autism, we initiated a positional cloning strategy starting from individuals with idiopathic autism carrying a de novo chromosomal anomaly. We report on the clinical, cytogenetic and molecular findings in a male person with autism, no physical abnormalities and normal IQ, carrying a de novo balanced paracentric inversion 46,XY,inv(10)(q11.1;q21.3). The distal breakpoint disrupts the TRIP8 gene, which codes for a protein predicted to be a transcriptional regulator associated with nuclear thyroid hormone receptors. However, no link between thyroid gland and autism has been reported so far. In addition, the same breakpoint abolishes expression of a nearby gene, REEP3, through a position effect. Receptor Expression-Enhancing Proteins (REEP) 3 is one of the six human homologs of yeast Yop1p, a probable regulator of cellular vesicle trafficking between the endoplasmatic reticulum and the Golgi network. These observations suggest that TRIP8 and REEP3 are both positional candidate genes for autism. In addition, our data indicate that in the selection of positional candidate genes when studying chromosomal aberrations, position effects should be taken into account. Show less