Volume 41 Issue 7, July 2009

Two genome-wide association studies for testicular cancer report associations at three new loci, including two candidate genes previously implicated in testicular development, KITLG (ligand for the receptor tyrosine kinase) and SPRY4 (sprouty 4). These studies are notable for the high effect sizes detected and the biological plausibility of the candidate genes.

The genetic basis of myelodysplasia has long been enigmatic, with few common targets of mutation known. A new study reports common mutations in the TET2 gene in myelodysplasia and related myeloid malignancies, suggesting that TET2 has an important role in hematopoiesis and in the pathogenesis of this disease.

MicroRNAs (miRNAs) and the pathways that regulate their expression have critical functions during normal development. A new study demonstrates that select cancer cells have appropriated one developmental mechanism of miRNA regulation, the inhibition of let-7 biogenesis by the Lin-28 and Lin-28B RNA binding proteins, to rid themselves of an antitumorigenic miRNA.

Jutta Gartner and colleagues identify five pathologic mutant alleles in the RNASET2 gene that compromise its enzymatic activity and that are responsible for the CMV infection–like neurological disorder cystic leukoencephalopathy without megalencephaly (CLM).

Philip De Jager and colleagues report results of a large genome-wide association and replication study for multiple sclerosis. The work uncovers three new susceptibility loci for MS, including common and rare variants at TNFRSF1A and common variants at IRF8 and CD6.

Shaoguang Li and colleagues identify Alox5 as a key gene that regulates the function of leukemia stem cells but not normal hematopoietic stem cells in mice, highlighting how cancer and normal stem cells distinctly self-renew and differentiate.

Thomas Carroll and colleagues show that attenuation of Wnt9b signaling during kidney morphogenesis affects planar cell polarity and causes an increase in tubule diameter. Their analyses suggest that tubule diameter is established by convergent extension movements and subsequently maintained by polarized cell divisions.

Jasper Rine and colleagues examine the silencing of the HML locus in synchronous S. cerevisiae cells at single-cell resolution. They demonstrate that the establishment of silencing under native conditions occurs rapidly, within two cell cycles.

Michael Stratton and colleagues report a genome-wide association study for testicular germ cell tumor (TGCT) in a UK population, identifying three associated loci.

Katherine Nathanson and colleagues report a genome-wide association study identifying two loci associated with susceptibility to testicular germ cell tumor.

Ann Daly and colleagues report results of a genome-wide association study to identify common variants associated with drug-induced liver injury due to flucloxacillin. They show that carriers of the HLA-B*5701 allele in the MHC region are at 80-fold increased risk of developing this severe adverse drug reaction.

Peter Gregersen and colleagues report that common variants at the REL locus are associated with risk of rheumatoid arthritis. REL encodes a member of the NF-κB family of transcription factors, which play key roles in coordinating immune and inflammatory responses.

Justin Rubio and colleagues report results of a genome-wide association study of multiple sclerosis using cases from Australia and New Zealand. Their findings confirm several published risk loci for MS and identify two new risk loci on chromosomes 12 and 20.

Aicardi-Goutieres syndrome is a genetically determined encephalopathy that is associated with an increased production of interferon alpha, which in turn is central to the pathogenesis of systemic lupus erythematosus. Yanick Crow and colleagues now identify homozygous mutations in an interferon-inducible nuclear gene encoding SAMHD1 in AGS-affected individuals across several pedigrees and characterize its function in modulating an innate immune response.

Eric Shoubridge and colleagues report the identification of a mutation in the CCDC44 gene that is causal in a Leigh syndrome pedigree. The CCDC44 gene product, TACO1, is involved in mitochondrial translation and is the first specific mitochondrial translational activator identified in mammals.

Joop Jansen and colleagues show that myelodysplastic syndromes frequently harbor somatic mutations in TET2. Analysis of lineage markers suggests that TET2 mutations are early events contributing to malignant transformation.

George Daley and colleagues show that Lin28 and Lin28B promote cellular transformation by repressing let-7 family members, leading to derepression of let-7 targets. They also find that LIN28 and LIN28B are overexpressed in ∼15% of primary human tumors and cancer cell lines and that their expression is associated with aggressive disease and poor prognosis across multiple tumor types.

James Lupski and colleagues provide evidence that a replication-based mechanism termed FoSTeS/MMBIR can mediate rearrangements in humans ranging in size from a few hundred base pairs to several megabases. They propose that FoSTeS/MMBIR could be an important mechanism for generating structural variation.

William Talbot and colleagues show that a kinesin motor protein, Kif1b, is required for the specific localization of mRNAs that encode myelin proteins in central nervous system glia and mediates the development of myelinated axons. Kif1b has previously been linked to the susceptibility of multiple sclerosis, and damage to myelinated axons is central to the symptoms associated with multiple sclerosis. This suggests mechanisms by which defects in Kif1b may contribute to the disease.