Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration

RNA exosomes are multi-subunit complexes conserved throughout evolution and are emerging as the major cellular machinery for processing, surveillance and turnover of a diverse spectrum of coding and noncoding RNA substrates essential for viability. By exome sequencing, we discovered recessive mutations in EXOSC3 (encoding exosome component 3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 (PCH1; MIM 607596). We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment, resulting in small brain size and poor motility, reminiscent of human clinical features, and these defects were largely rescued by co-injection with wild-type but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome core component gene that is responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.     

Identification of renal Cd36 as a determinant of blood pressure and risk for hypertension

To identify renally expressed genes that influence risk for hypertension, we integrated expression quantitative trait locus (QTL) analysis of the kidney with genome-wide correlation analysis of renal expression profiles and blood pressure in recombinant inbred strains derived from the spontaneously hypertensive rat (SHR). This strategy, together with renal transplantation studies in SHR progenitor, transgenic and congenic strains, identified deficient renal expression of Cd36 encoding fatty acid translocase as a genetically determined risk factor for spontaneous hypertension.     

Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations

Mutations in BRCA1 and BRCA2 confer a high risk of breast and ovarian cancer, but account for only a small fraction of breast cancer susceptibility. To find additional genes conferring susceptibility to breast cancer, we analyzed CHEK2 (also known as CHK2), which encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes involving BRCA1 and p53 (refs 3,4,5). We show that CHEK2(*)1100delC, a truncating variant that abrogates the kinase activity, has a frequency of 1.1% in healthy individuals. However, this variant is present in 5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003), including 13.5% of individuals from families with male breast cancer (P = 0.00015). We estimate that the CHEK2(*)1100delC variant results in an approximately twofold increase of breast cancer risk in women and a tenfold increase of risk in men. By contrast, the variant confers no increased cancer risk in carriers of BRCA1 or BRCA2 mutations. This suggests that the biological mechanisms underlying the elevated risk of breast cancer in CHEK2 mutation carriers are already subverted in carriers of BRCA1 or BRCA2 mutations, which is consistent with participation of the encoded proteins in the same pathway.     

Cellularity and composition of epididymal adipose tissue from cold-acclimatized rats

Summary Cold acclimatization induces morphological and compositional modifications of rat epididymal adipose tissue: a decrease in fat cell size, an increase of fat cell number per g of tissue, but no significant increase in total fat cell number in the tissue; finally, an increase in protein content and a decrease in triglyceride content.Acknowledgments. We especially thank Mr M. Joliff for his very valuable help for fat cell size determination (Hospital Bichat, Paris).     

Gene therapy: is IL2RG oncogenic in T-cell development?

The gene IL2RG encodes the gamma-chain of the interleukin-2 receptor and is mutated in patients with X-linked severe combined immune deficiency (X-SCID). Woods et al. report the development of thymus tumours in a mouse model of X-SCID after correction by lentiviral overexpression of IL2RG and claim that these were caused by IL2RG itself. Here we find that retroviral overexpression of IL2RG in human CD34+ cells has no effect on T-cell development, whereas overexpression of the T-cell acute lymphoblastic leukaemia (T-ALL) oncogene LMO2 leads to severe abnormalities. Retroviral expression of IL2RG may therefore not be directly oncogenic--rather, the restoration of normal signalling by the interleukin-7 receptor to X-SCID precursor cells allows progression of T-cell development to stages that are permissive for the pro-leukaemic effects of ectopic LMO2.     

Dynamic resource allocation for efficient patient scheduling: A data-driven approach

Efficient staff rostering and patient scheduling to meet outpatient demand is a very complex and dynamic task. Due to fluctuations in demand and specialist availability, specialist allocation must be very flexible and non-myopic. Medical specialists are typically restricted in sub-specialization, serve several patient groups and are the key resource in a chain of patient visits to the clinic and operating room (OR). To overcome a myopic view of once-off appointment scheduling, we address the patient flow through a chain of patient appointments when allocating key resources to different patient groups. We present a new, data-driven algorithmic approach to automatic allocation of specialists to roster activities and patient groups. By their very nature, simplified mathematical models cannot capture the complexity that is characteristic to the system being modeled. In our approach, the allocation of specialists to their day-to-day activities is flexible and responsive to past and present key resource availability, as well as to past resource allocation. Variability in roster activities is actively minimized, in order to enhance the supply chain flow. With discrete-event simulation of the application case using empirical data, we illustrate how our approach improves patient Service Level (SL, percentage of patients served on-time) as well as Wait Time (days), without change in resource capacity.     

MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia.

Acute lymphoblastic leukemias carrying a chromosomal translocation involving the mixed-lineage leukemia gene (MLL, ALL1, HRX) have a particularly poor prognosis. Here we show that they have a characteristic, highly distinct gene expression profile that is consistent with an early hematopoietic progenitor expressing select multilineage markers and individual HOX genes. Clustering algorithms reveal that lymphoblastic leukemias with MLL translocations can clearly be separated from conventional acute lymphoblastic and acute myelogenous leukemias. We propose that they constitute a distinct disease, denoted here as MLL, and show that the differences in gene expression are robust enough to classify leukemias correctly as MLL, acute lymphoblastic leukemia or acute myelogenous leukemia. Establishing that MLL is a unique entity is critical, as it mandates the examination of selectively expressed genes for urgently needed molecular targets.     

Les glycoprotéines sériques dans le granulome expérimental provoqué par la carrageenine

Summary We studied serum glycoproteins in rats and guinea pigs during the development of granulomas, provoked by carrageenin injection. In rats total serum sialic acid was raised as well as sialic acid soluble in sulfosalicylic acid and haptoglobin. The rise of these 2 fractions, seromucoid and haptoglobine accounts quantitatively for the rise of the total sialic acid. In guinea pigs total serum sialic acid was unchanged, but sulfosalicylosoluble sialic acid as well as haptoglobin were much higher than basal values. Quantitatively the serum glycoprotein reaction was much higher in rats than in guinea pigs.