Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.     

Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas

To identify somatic mutations in pediatric diffuse intrinsic pontine glioma (DIPG), we performed whole-genome sequencing of DNA from seven DIPGs and matched germline tissue and targeted sequencing of an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). We found that 78% of DIPGs and 22% of non-BS-PGs contained a mutation in H3F3A, encoding histone H3.3, or in the related HIST1H3B, encoding histone H3.1, that caused a p.Lys27Met amino acid substitution in each protein. An additional 14% of non-BS-PGs had somatic mutations in H3F3A causing a p.Gly34Arg alteration.     

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ～10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.     

Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration

Leber congenital amaurosis (LCA) is a blinding retinal disease that presents within the first year after birth. Using exome sequencing, we identified mutations in the nicotinamide adenine dinucleotide (NAD) synthase gene NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 in eight families with LCA, including the family in which LCA was originally linked to the LCA9 locus. Notably, all individuals with NMNAT1 mutations also have macular colobomas, which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors. Functional assays of the proteins encoded by the mutant alleles identified in our study showed that the mutations reduce the enzymatic activity of NMNAT1 in NAD biosynthesis and affect protein folding. Of note, recent characterization of the slow Wallerian degeneration (Wld(s)) mouse model, in which prolonged axonal survival after injury is observed, identified NMNAT1 as a neuroprotective protein when ectopically expressed. Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous system disorder.     

Stimulation of olfactory ensheathing cell motility enhances olfactory axon growth

Axons of primary olfactory neurons are intimately associated with olfactory ensheathing cells (OECs) from the olfactory epithelium until the final targeting of axons within the olfactory bulb. However, little is understood about the nature and role of interactions between OECs and axons during development of the olfactory nerve pathway. We have used high resolution time-lapse microscopy to examine the growth and interactions of olfactory axons and OECs in vitro. Transgenic mice expressing fluorescent reporters in primary olfactory axons (OMP-ZsGreen) and ensheathing cells (S100ß-DsRed) enabled us to selectively analyse these cell types in explants of olfactory epithelium. We reveal here that rather than providing only a permissive substrate for axon growth, OECs play an active role in modulating the growth of pioneer olfactory axons. We show that the interactions between OECs and axons were dependent on lamellipodial waves on the shaft of OEC processes. The motility of OECs was mediated by GDNF, which stimulated cell migration and increased the apparent motility of the axons, whereas loss of OECs via laser ablation of the cells inhibited olfactory axon outgrowth. These results demonstrate that the migration of OECs strongly regulates the motility of axons and that stimulation of OEC motility enhances axon extension and growth cone activity.     

List of Idaho Scolytidae (Coleoptera) and notes on new records

Reported are 105 species of Scolytidae (Coleoptera) from Idaho. About one-third of these are rarely collected, of which 22 species are known from a single locality each. Twelve species reported from Idaho for the first time are: Carphoborus carri Swaine, C. sansoni Swaine, Phloeosinus hoferi Blackman, Conophthorus monophyllae Hopkins, Dryocoetes betulae Hopkins, Ips confuses (LeConte), Pityophthorus absonus Blackman, P. aquilus Blackman , P. blandus Blackman, P. deletus LeConte, P. sculptor Blackman, and Xyleborinus saxeseni (Ratzeburg). Significant extensions of the known distributions in Idaho are reported for seven other scolytids; Alniphagus aspericollis (LeConte), Dendroctonus murrayanae Hopkins, Phloeotribus lecontei Schedl, Procryphalus mucronatus (LeConte), Trypophloeus populi Hopkins, Xyleborus dispar (Fabricius), and X. intrusus Blandford. Xyleborus dispar especially needs study in anticipation that it may become increasingly important in Idaho fruit trees and other woody plants including ornamentals and shade trees.     

Seedling size and survival for Chrysothamnus nauseosus

Seedling size and survival in relation to summer drought were examined for Chrysothamnus nauseosus growing under field and greenhouse conditions. In the field, summer survival rates were less than 2% annually for the three years monitored. The effect of initial seedling height on subsequent survival was examined in both the field and greenhouse by grouping seedlings into live and dead categories on each census date and comparing initial heights for seedlings in these categories. For a majority of the census dates, the initial height of surviving seedlings was greater than the initial height of those that subsequently died (significant differences ranged from 1 to 8 mm), indicating that seedlings that were taller at the initiation of the drought period had a higher probability of survival. In the greenhouse, taller seedlings had greater shoot and root biomass and rooting depth. Seedlings that are larger (i.e., taller and have greater aboveground biomass) in late spring appear to have a higher probability of surviving summer drought due to greater rooting depth and hence increased access to moisture in deeper soil layers. Seed availability and safe sites for germination were probably not limiting since large numbers of seedlings successfully germinated in a patchy pattern during the study period. Seedling size and probability of survival were not related to either seedling density or the distance to nearest seedling neighbor. Survival through summer drought appears to be the main limitation to seedling recruitment in this population.     

Dynamic landforms and plant communities in a pluvial lake basin

Mapping units were developed based on landform, soils, and plant communities for the 40,000 ha of salt desert vegetation located below the maximum level of pluvial Lake Gilbert in Grass Valley, Nevada. Lake plain, beach, and bar features of the pluvial lake provide the dominant landforms. Fine textured lake sediments have produced salt- and Na-affected soils. The distribution and structure of plant communities are related to depth of the groundwater table, fluctuations in this depth, and the salt content of the groundwater. Wind and water erosion combine to continually evolve new environments for colonization by plants in this ecosystem.