Whole exome sequencing to identify genetic causes of short stature

BACKGROUND/AIMS: Short stature is a common reason for presentation to pediatric endocrinology clinics. However, for most patients, no cause for the short stature can be identified. As genetics plays a strong role in height, we sought to identify known and novel genetic causes of short stature. METHODS: We recruited 14 children with severe short stature of unknown etiology. We conducted whole exome sequencing of the patients and their family members. We used an analysis pipeline to identify rare non-synonymous genetic variants that cause the short stature. RESULTS: We identified a genetic cause of short stature in 5 of the 14 patients. This included cases of floating-harbor syndrome, Kenny-Caffey syndrome, the progeroid form of Ehlers-Danlos syndrome, as well as 2 cases of the 3-M syndrome. For the remaining patients, we have generated lists of candidate variants. CONCLUSIONS: Whole exome sequencing can help identify genetic causes of short stature in the context of defined genetic syndromes, but may be less effective in identifying novel genetic causes of short stature in individual families. Utilized in the clinic, whole exome sequencing can provide clinically relevant diagnoses for these patients. Rare syndromic causes of short stature may be underrecognized and underdiagnosed in pediatric endocrinology clinics

Impaired degranulation but enhanced cytokine production after FcɛRI stimulation of diacylglycerol kinase ζ–deficient mast cells

Calcium and diacylglycerol are critical second messengers that together effect mast cell degranulation after allergen cross-linking of immunoglobulin (Ig)E-bound FcɛRI. Diacylglycerol kinase (DGK)ζ is a negative regulator of diacylglycerol-dependent signaling that acts by converting diacylglycerol to phosphatidic acid. We reported previously that DGKζ−/− mice have enhanced in vivo T cell function. Here, we demonstrate that these mice have diminished in vivo mast cell function, as revealed by impaired local anaphylactic responses. Concordantly, DGKζ−/− bone marrow–derived mast cells (BMMCs) demonstrate impaired degranulation after FcɛRI cross-linking, associated with diminished phospholipase Cγ activity, calcium flux, and protein kinase C–βII membrane recruitment. In contrast, Ras-Erk signals and interleukin-6 production are enhanced, both during IgE sensitization and after antigen cross-linking of FcɛRI. Our data demonstrate dissociation between cytokine production and degranulation in mast cells and reveal the importance of DGK activity during IgE sensitization for proper attenuation of FcɛRI signals

CANDELS Observations Of The Structural Properties Of Cluster Galaxies At Z=1.62

We discuss the structural and morphological properties of galaxies in a z = 1.62 proto-cluster using near-IR imaging data from Hubble Space Telescope Wide Field Camera 3 data of the Cosmic Assembly Near-IR Deep Extragalactic Legacy Survey (CANDELS). The cluster galaxies exhibit a clear color-morphology relation: galaxies with colors of quiescent stellar populations generally have morphologies consistent with spheroids, and galaxies with colors consistent with ongoing star formation have disk-like and irregular morphologies. The size distribution of the quiescent cluster galaxies shows a deficit of compact (less than or similar to 1 kpc), massive galaxies compared to CANDELS field galaxies at z = 1.6. As a result, the cluster quiescent galaxies have larger average effective sizes compared to field galaxies at fixed mass at greater than 90% significance. Combined with data from the literature, the size evolution of quiescent cluster galaxies is relatively slow from z similar or equal to 1.6 to the present, growing as (1 + z)(-0.6 +/- 0.1). If this result is generalizable, then it implies that physical processes associated with the denser cluster region seem to have caused accelerated size growth in quiescent galaxies prior to z = 1.6 and slower subsequent growth at z < 1.6 compared to galaxies in the lower density field. The quiescent cluster galaxies at z = 1.6 have higher ellipticities compared to lower redshift samples at fixed mass, and their surface-brightness profiles suggest that they contain extended stellar disks. We argue that the cluster galaxies require dissipationless (i.e., gas-poor or "dry") mergers to reorganize the disk material and to match the relations for ellipticity, stellar mass, size, and color of early-type galaxies in z < 1 clusters.NASA NAS5-26555HST GO-12060NASA through from the Space Telescope Science Institute GO-12060European Research CouncilRoyal SocietyTexas AM UniversityGeorge P. and Cynthia Woods Institute for Fundamental Physics and AstronomyAstronom

The timescale of early land plant evolution

Establishing the timescale of early land plant evolution is essential for testing hypotheses on the coevolution of land plants and Earth's System. The sparseness of early land plant megafossils and stratigraphic controls on their distribution make the fossil record an unreliable guide, leaving only the molecular clock. However, the application of molecular clock methodology is challenged by the current impasse in attempts to resolve the evolutionary relationships among the living bryophytes and tracheophytes. Here, we establish a timescale for early land plant evolution that integrates over topological uncertainty by exploring the impact of competing hypotheses on bryophyte-tracheophyte relationships, among other variables, on divergence time estimation. We codify 37 fossil calibrations for Viridiplantae following best practice. We apply these calibrations in a Bayesian relaxed molecular clock analysis of a phylogenomic dataset encompassing the diversity of Embryophyta and their relatives within Viridiplantae. Topology and dataset sizes have little impact on age estimates, with greater differences among alternative clock models and calibration strategies. For all analyses, a Cambrian origin of Embryophyta is recovered with highest probability. The estimated ages for crown tracheophytes range from Late Ordovician to late Silurian. This timescale implies an early establishment of terrestrial ecosystems by land plants that is in close accord with recent estimates for the origin of terrestrial animal lineages. Biogeochemical models that are constrained by the fossil record of early land plants, or attempt to explain their impact, must consider the implications of a much earlier, middle Cambrian-Early Ordovician, origin

CANDELS/GOODS-S, CDFS, ECDFS: Photometric Redshifts For Normal and for X-Ray-Detected Galaxies

We present photometric redshifts and associated probability distributions for all detected sources in the Extended Chandra Deep Field South (ECDFS). The work makes use of the most up-to-date data from the Cosmic Assembly Near-IR Deep Legacy Survey (CANDELS) and the Taiwan ECDFS Near-Infrared Survey (TENIS) in addition to other data. We also revisit multi-wavelength counterparts for published X-ray sources from the 4Ms-CDFS and 250ks-ECDFS surveys, finding reliable counterparts for 1207 out of 1259 sources ($\sim 96\%$). Data used for photometric redshifts include intermediate-band photometry deblended using the TFIT method, which is used for the first time in this work. Photometric redshifts for X-ray source counterparts are based on a new library of AGN/galaxy hybrid templates appropriate for the faint X-ray population in the CDFS. Photometric redshift accuracy for normal galaxies is 0.010 and for X-ray sources is 0.014, and outlier fractions are $4\%$ and $5.4\%$ respectively. The results within the CANDELS coverage area are even better as demonstrated both by spectroscopic comparison and by galaxy-pair statistics. Intermediate-band photometry, even if shallow, is valuable when combined with deep broad-band photometry. For best accuracy, templates must include emission lines.Comment: The paper has been accepted by ApJ. The materials we provide are available under [Surveys] > [CDFS] through the portal http://www.mpe.mpg.de/XraySurvey

Exome sequencing reveals independent SGCD deletions causing limb girdle muscular dystrophy in Boston terriers

Background: Limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of inherited autosomal myopathies that preferentially affect voluntary muscles of the shoulders and hips. LGMD has been clinically described in several breeds of dogs, but the responsible mutations are unknown. The clinical presentation in dogs is characterized by marked muscle weakness and atrophy in the shoulder and hips during puppyhood. Methods: Following clinical evaluation, the identification of the dystrophic histological phenotype on muscle histology, and demonstration of the absence of sarcoglycan-sarcospan complex by immunostaining, whole exome sequencing was performed on five Boston terriers: one affected dog and its three family members and one unrelated affected dog. Results: Within sarcoglycan-delta (SGCD), a two base pair deletion segregating with LGMD in the family was discovered, and a deletion encompassing exons 7 and 8 was found in the unrelated dog. Both mutations are predicted to cause an absence of SGCD protein, confirmed by immunohistochemistry. The mutations are private to each family. Conclusions: Here, we describe the first cases of canine LGMD characterized at the molecular level with the classification of LGMD2F.Peer reviewe

DHODH modulates transcriptional elongation in the neural crest and melanoma

Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma1. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation