FGFs (fibroblast growth factors) play major roles in a number of developmental processes. Recent studies of several human disorders, and concurrent analysis of gene knock-out and properties of the corresponding recombinant proteins have shown that FGFs and their receptors are prominently involved in the development of the skeletal system in mammals. We have compared the sequences of the nine known mammalian FGFs, FGFs from other vertebrates, and three additional sequences that we extracted from existing databases: two human FGF sequences that we tentatively designated FGF10 and FGF11, and an FGF sequence from Caenorhabditis elegans. Similarly, we have compared the sequences of the four FGF receptor paralogs found in chordates with four non-chordate FGF receptors, including one recently identified in C. elegans. The comparison of FGF and FGF receptor sequences in vertebrates and nonvertebrates shows that the FGF and FGF receptor families have evolved through phases of gene duplications, one of which may have coincided with the emergence of vertebrates, in relation with their new system of body scaffold.

Acquired aplastic anemia (aAA) is a non-malignant disease caused by autoimmune destruction of early hematopoietic cells. Clonal hematopoiesis is a late complication, seen in 20–25% of older patients. We hypothesized that clonal hematopoiesis in aAA is a more general phenomenon, which can arise early in disease even in younger patients. To evaluate clonal hematopoiesis in aAA, we used comparative whole exome sequencing of paired bone marrow and skin in 22 patients. We found somatic mutations in sixteen patients (72.7%) with a median disease duration of 1 year; twelve (66.7%) were patients with pediatriconset aAA. Fifty-eight mutations in 51 unique genes were primarily in pathways of immunity and transcriptional regulation. Most frequently mutated was PIGA, with 7 mutations. Only two mutations were in genes recurrently-mutated in MDS. Two patients had oligoclonal loss of HLA alleles, linking immune escape to clone emergence. Two patients had activating mutations in key signaling pathways (STAT5B(p.N642H), CAMK2G(p.T306M)). Our results suggest that clonal hematopoiesis in aAA is common, with two mechanisms emerging― immune escape and increased proliferation. Our findings expand conceptual understanding of this non-neoplastic blood disorder. Future prospective studies of clonal hematopoiesis in aAA will be critical for understanding outcomes, and for designing personalized treatment strategies.

The molecular cloning of cDNAs encoding murine fibroblast growth factor-13 (FGF-13/FHF-2) and three isoforms of murine FGF-12 (FHF-1) is described. Like their highly conserved human counterparts, murine FGF-12 and FGF-13 are part of a distinct subfamily of FGF-like proteins characterized by a greater degree of amino acid sequence cross-homology and by conserved N-terminal domains which do not include secretion signal sequences. In addition to their expression in several adult tissues, both of these FGF genes are prominently and regionally expressed in midgestation mouse embryos, as revealed by in situ hybridization. Fgf12 and fgf13. RNAs were detected in developing central nervous system in cells outside the proliferating ependymal layer, and fgf13 RNA was also found throughout the peripheral nervous system. Fgf12 is expressed in developing soft connective tissue of the limb skeleton and in presumptive connective tissue linking vertebrae and ribs. Both FGF genes are also expressed in the myocardium of the heart, with fgf12 RNA found only in the atrial chamber and fgf13 RNA detected in both atrium and ventricle. On the basis of their novel structure and patterns of expression, FGF-12 and FGF-13 are anticipated to perform embryonic functions distinct from other known FGF molecules.

SYNOPSIS This article provides a practice-based and concise review of the etiology, diagnosis, and management of acquired aplastic anemia in children. Bone marrow transplantation, immunosuppressive therapy, and supportive care are discussed in detail. The aim is to provide the clinician with a better understanding of the disease and to offer guidelines for the management of children with this uncommon yet serious disorder.

Epigenetic silencing plays an important role in cancer development. An attractive hypothesis is that local DNA features may participate in differential predisposition to gene hypermethylation. We found that, compared with methylationresistant genes, methylation-prone genes have a lower frequency of SINE and LINE retrotransposons near their transcription start site. In several large testing sets, this distribution was highly predictive of promoter methylation. Genomewide analysis showed that 22% of human genes were predicted to be methylation-prone in cancer; these tended to be genes that are down-regulated in cancer and that function in developmental processes. Moreover, retrotransposon distribution marks a larger fraction of methylation-prone genes compared to Polycomb group protein (PcG) marking in embryonic stem cells; indeed, PcG marking and our predictive model based on retrotransposon frequency appear to be correlated but also complementary. In summary, our data indicate that retrotransposon elements, which are widespread in our genome, are strongly associated with gene promoter DNA methylation in cancer and may in fact play a role in influencing epigenetic regulation in normal and abnormal physiological states.