Letters in 2008

Hannie Kremer and colleagues report the identification of mutations in LROMT associated with profound nonsyndromic hearing loss. LRTOMT has two alternative reading frames and encodes two different proteins, LRTOMT1 and LRTOMT2.

Hadi Al-Hasani and colleagues report that a frameshift deletion in Tbc1d1 in lean SJL mice underlies a quantitative trait locus conferring protection against high-fat diet-induced obesity. TBC1D1 seems to influence metabolism by regulating fatty acid uptake and oxidation in skeletal muscle cells.

Simon Stacey and colleagues report results of a genome-wide association study for cutaneous basal cell carcinoma. They identify two loci, at 1p36 and 1q42, associated with BCC risk, and show that neither is associated with melanoma or pigmentation traits.

Stefan Schreiber and colleagues report the results of a genome-wide association study for ulcerative colitis. Variants flanking the gene encoding the cytokine IL10 are associated with increased risk of disease, as are several other loci.

Nonsyndromic cleft lip with or without cleft palate has been associated with SNPs in the IRF6 gene. Now Jeff Murray and colleagues report the identification of a common variant in a previously unknown IRF6 enhancer that shows strong evidence of association with cleft lip only and disrupts the binding site of transcription factor AP-2α.

Nazneen Rahman and colleagues report the identification of constitutional imprinting center mutations, epimutations and uniparental disomy in individuals with nonsyndromic Wilms tumors.

Doug Epstein and colleagues present biochemical and transgenic studies implicating Six3 in the regulation of Shh forebrain expression through direct binding to a remote enhancer. The work was driven by the discovery of a rare variant in this enhancer in an individual with holoprosencephaly

Katsushi Tokunaga and colleagues report the results of a genome-wide association study for narcolepsy. A variant on chromosome 22 between CPT1B and CHKB is associated with increased risk of the disorder. Both gene products have previously been linked to the physiology of sleep, making each a potential susceptibility factor.

Chuanqing Sun and colleagues show that the gene PROG1, encoding a zinc-finger protein, determines the erect growth habit in rice. Sequencing of 182 varieties of cultivated rice reveals an identical mutation in the PROG1 coding region, suggesting a common origin for erect growth during rice domestication.

Hong-Xuan Lin and colleagues report that the gene PROG1 has an important role in determining the architecture of wild rice, including tiller angle and number of tillers. PROG1 encodes a zinc-finger transcription factor, and the authors suggest that selection of an amino acid substitution in PROG1 during domestication facilitated the transition to the architecture of domesticated rice.

Zuhua He and colleagues identify the gene underlying a quantitative trait locus for grain-filling in rice, which contributes to grain weight. The gene, GIF1, encodes a protein with cell-wall invertase activity and may have been under selection during rice domestication.

Helen Hobbs and colleagues report an association between coding variation in PNPLA3 and susceptibility to nonalcoholic fatty liver disease. The associated alleles vary in frequency among Hispanics, African Americans and European Americans and contribute to differences in disease prevalence among these ancestry groups.

Thaddeus Dryja and colleagues identify homozygous loss-of-function mutations in IDH3B, encoding the beta subunit of the NAD-specific isocitrate dehydrogenase enzyme, in two families with retinitis pigmentosa. The absence of obvious clinical phenotypes outside of the retina suggests that the NADP-specific form of this enzyme can compensate for the absence of the NAD-specific form in most human tissues.

Edward Patterson and colleagues report that a missense mutation in the gene encoding dynamin 1 (DNM1) is associated with exercise-induced collapsed in Labrador retriever dogs. This is the first documented mutation in DNM1 in mammals and suggests a critical role for dynamin 1 in maintaining proper neurotransmission under conditions of high synaptic activity.

Kazuhiko Yamamoto and colleagues report an association of two SNPs in CD244 with increased risk of rheumatoid arthritis. These variants promote increased expression of CD244 in luciferase reporter assays.

Kari Stefansson and colleagues report results of a genome-wide association study for urinary bladder cancer. The strongest association was with a variant on 8q24, located 30 kb upstream of MYC in a haplotype block distinct from previously reported 8q24 cancer risk variants.

Robert Plenge and colleagues report the results of a meta-analysis of published genome-wide association studies that led to the identification of two previously unknown variants associated with rheumatoid arthritis.

Evan Eichler and colleagues present an analysis of how well current commercial SNP platforms accurately capture copy number variants (CNVs). Although they were able accurately predict from Illumina Human 1M genotype data many sites identified in their recent study assessing CNVs in nine human individuals with a fosmid paired-end sequence approach, they find that commonly used platforms offer limited coverage for a large fraction of CNVs.

Hakon Hakonarson and colleagues report the identification of two new susceptibility loci for inflammatory bowel disease (IBD). One variant is near a gene encoding tumor necrosis factor receptor subfamily member 6B and is associated with increased levels of this protein in serum from individuals with IBD.

Ras family genes are common targets for somatic mutations in human cancer: KRAS is frequently mutated in lung carcinomas, whereas HRAS mutations are common in skin tumors. Allan Balmain and colleagues use genetic engineering of ras genes in mice to show that specificity for ras mutations is determined by local regulatory elements, and that Kras 4A is the major oncogenic isoform of Kras.