The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy

Neutral lipid storage disease comprises a heterogeneous group of autosomal recessive disorders characterized by systemic accumulation of triglycerides in cytoplasmic droplets. Here we report a neutral lipid storage disease subgroup characterized by mild myopathy, absence of ichthyosis and mutations in both alleles of adipose triglyceride lipase (PNPLA2, also known as ATGL). Three of these mutations are predicted to lead to a truncated ATGL protein with an intact patatin domain containing the active site, but with defects in the hydrophobic domain. The block in triglyceride degradation was mimicked by short interfering RNA directed against ATGL. NLSDM is distinct from Chanarin-Dorfman syndrome, which is characterized by neutral lipid storage disease with ichthyosis, mild myopathy and hepatomegaly due to mutations in ABHD5 (also known as CGI-58).     

The power of VEGF (vascular endothelial growth factor) family molecules

Vascular endothelial growth factors (VEGFs) and their high-affinity tyrosine kinase VEGF receptors (VEGFRs) are key regulators of both angiogenesis and neurogenesis. The current issue of CMLS discusses recent literature and work implementing these signals in nervous system development, maintenance and disease pathology.     

Newly identified loci that influence lipid concentrations and risk of coronary artery disease

To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.     

Evolutionary differentiation within the northern Great Basin pocket gopher, Thomomys townsendii II. Genetic variation and biogeographic considerations

Geographic and nongeographic variation in morphology was examined in Thomomys townsendii . A univariate analysis of external and cranial characters from a large population sample (66 adults; fusion of cranial sutures used as aging criteria) was used to assess variation among three adult age classes and between sexes. Only minor variation is apparent among age classes; however, sexual dimorphism is pronounced. Univariate and multivariate techniques were used to analyze external and cranial measurements and pelage characters for adults throughout the species range. These analyses show little to support the seven subspecific designations recognized by Davis (1937). The general pattern is one of homogeneity throughout the range of Thomomys townsendii . With the possible exception of T. t. nevadensis samples, current subspecies are not defined as morphological units. In fact, differentiation is found among populations within some subspecies. The most apparent pattern seen in these analyses is the divergence between the Humboldt River (including Honey Lake Valley samples) and Snake River systems. These results will be considered with those of a companion paper on the genetic variation in this species to more adequately assess the patterns of differentiation in Thomomys townsendii .     

The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells

A therapeutic strategy for treating cancer is to target and eradicate cancer stem cells (CSCs) without harming their normal stem cell counterparts. The success of this approach relies on the identification of molecular pathways that selectively regulate CSC function. Using BCR-ABL-induced chronic myeloid leukemia (CML) as a disease model for CSCs, we show that BCR-ABL downregulates the Blk gene (encoding B-lymphoid kinase) through c-Myc in leukemic stem cells (LSCs) in CML mice and that Blk functions as a tumor suppressor in LSCs but does not affect normal hematopoietic stem cells (HSCs) or hematopoiesis. Blk suppresses LSC function through a pathway involving an upstream regulator, Pax5, and a downstream effector, p27. Inhibition of this Blk pathway accelerates CML development, whereas increased activity of the Blk pathway delays CML development. Blk also suppresses the proliferation of human CML stem cells. Our results show the feasibility of selectively targeting LSCs, an approach that should be applicable to other cancers.     

Spatial and Temporal Variability in Perennial and Annual Vegetation at Chaco Canyon, New Mexico

Annual plant populations in norhtwestern New Mexico were found to be spatially and temporally highly variable. During favorable years annual plant species have patterns of dominance and diversity that are different from those of perennial species. Measurement of perennial plant diversity in plant communities is a poor predictor of productivity. Both perennial and annual components of plant communities should be considered in measurements of diversity and productivity.     

The associated beetle fauna of Hohenbergia augusta and Vriesea friburgensis (Bromeliaceae) in southern Brazil

This work presents the first list of Coleoptera species found in Hohenbergia augusta (Vell.) E. Morren and Vriesea friburgensis Mez. (Bromeliaceae), in Santa Catarina state, Brazil, most of them identified to the species level. Beetle species richness and composition were compared between the bromeliad species and between Atlantic forest and restinga habitats. Biological information on some beetle species is reported for the first time. We also discuss the aquatic habit of the hydrophilid Lachnodacnum luederwaldti Orchymont, 1937 (Sphaeridinae) inside bromeliad phytotelms.     

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ～ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10??), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.