The general lack of pain experience is a rare occurrence in humans, and the molecular causes for this phenotype are not well understood. Here we have studied a Canadian family from Newfoundland with members who exhibit a congenital inability to experience pain. We have mapped the locus to a 13.7 Mb region on chromosome 2q (2q24.3-2q31.1). Screening of candidate genes in this region identified a protein-truncating mutation in SCN9A, which encodes for the voltage-gated sodium channel Na(v)1.7. The mutation is a C-A transversion at nucleotide 984 transforming the codon for tyrosine 328 to a stop codon. The predicted product lacks all pore-forming regions of Na(v)1.7. Indeed, expression of this altered gene in a cell line did not produce functional responses, nor did it cause compensatory effects on endogenous voltage-gated sodium currents when expressed in ND7/23 cells. Because a homozygous knockout of Na(v)1.7 in mice has been shown to be lethal, we explored why a deficiency of Na(v)1.7 is non-lethal in humans. Expression studies in monkey, human, mouse and rat tissue indicated species-differences in the Na(v)1.7 expression profile. Whereas in rodents the channel was strongly expressed in hypothalamic nuclei, only weak mRNA levels were detected in this area in primates. Furthermore, primate pituitary and adrenal glands were devoid of signal, whereas these two glands were mRNA-positive in rodents. This species difference may explain the non-lethality of the observed mutation in humans. Our data further establish Na(v)1.7 as a critical element of peripheral nociception in humans.

BackgroundTo determine the prevalence of RET rearrangement genes, RET copy number gains and expression in tumor samples from four Phase III non-small-cell lung cancer (NSCLC) trials of vandetanib, a selective inhibitor of VEGFR, RET and EGFR signaling, and to determine any association with outcome to vandetanib treatment.MethodsArchival tumor samples from the ZODIAC (NCT00312377, vandetanib ± docetaxel), ZEAL (NCT00418886, vandetanib ± pemetrexed), ZEPHYR (NCT00404924, vandetanib vs placebo) and ZEST (NCT00364351, vandetanib vs erlotinib) studies were evaluated by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in 944 and 1102 patients.ResultsThe prevalence of RET rearrangements by FISH was 0.7% (95% CI 0.3–1.5%) among patients with a known result. Seven tumor samples were positive for RET rearrangements (vandetanib, n = 3; comparator, n = 4). 2.8% (n = 26) of samples had RET amplification (innumerable RET clusters, or ≥7 copies in > 10% of tumor cells), 8.1% (n = 76) had low RET gene copy number gain (4–6 copies in ≥40% of tumor cells) and 8.3% (n = 92) were RET expression positive (signal intensity ++ or +++ in >10% of tumor cells). Of RET-rearrangement-positive patients, none had an objective response in the vandetanib arm and one patient responded in the comparator arm. Radiologic evidence of tumor shrinkage was observed in two patients treated with vandetanib and one treated with comparator drug. The objective response rate was similar in the vandetanib and comparator arms for patients positive for RET copy number gains or RET protein expression.ConclusionsWe have identified prevalence for three RET biomarkers in a population predominated by non-Asians and smokers. RET rearrangement prevalence was lower than previously reported. We found no evidence of a differential benefit for efficacy by IHC and RET gene copy number gains. The low prevalence of RET rearrangements (0.7%) prevents firm conclusions regarding association of vandetanib treatment with efficacy in the RET rearrangement NSCLC subpopulation.Trial registrationRandomized Phase III clinical trials (NCT00312377, ZODIAC; NCT00418886, ZEAL; NCT00364351, ZEST; NCT00404924, ZEPHYR).Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1146-8) contains supplementary material, which is available to authorized users.

We have studied the genetics of susceptibility to infection by Streptococcus pneumoniae in mice. Linkage analysis of the F(2) generation from a cross between resistant BALB/cO1aHsd and susceptible CBA/CaO1aHsd strains allowed us to map a major locus controlling the development of bacteremia and survival after intranasal infection.

The gene encoding the melatonin-related receptor (GPR50) is highly expressed within hypothalamic nuclei concerned with the control of body weight and metabolism. We screened GPR50 for mutations in an obese cohort and identified an insertion of four amino acid residues (TTGH) at position 501, two common coding polymorphisms (T528A and V602I), and one noncoding polymorphism (C-16X2GPR50T). Single-nucleotide polymorphisms were then typed in 500 English Caucasian subjects, and associations were sought to intermediate obesity phenotypes. Although no association was seen with body mass index, carriers of two copies of the mutant allele at C-16X2GPR50T, Ins501Del, and A1582G had significantly higher fasting circulating triglyceride levels (P , 0.05). In a separate set of 585 subjects, the associations were replicated, with statistically significant effects of similar magnitude and direction. The association of C-16X2GPR50T with fasting triglycerides was highly significant (P , 0.001). In addition, a significant association between C-16X2GPR50T and circulating HDL levels was observed in the combined population, with C-16X2GPR50T carriers having significantly lower circulating HDL-cholesterol levels (1.39 mM) than wild-type subjects (1.47 mM) (P , 0.01). These findings suggest a previously unexpected role for this orphan receptor in the regulation of lipid metabolism that warrants further investigation. Mutations in at least six different genes expressed in, or acting on, the hypothalamus have been shown to result in severe early-onset human obesity (1). Indeed, there is as yet no compelling instance of a monogenic form of obesity that does not involve a disturbance of hypothalamic function. In our own large cohort of patients with severe earlyonset obesity, ,10% of subjects have a mutation in any of these known genes. It is plausible, therefore, that dysfunction of other signaling molecules expressed in the hypothalamus might underlie some as yet uncharacterized cases of severe human obesity. The orphan G proteincoupled receptor GPR50 (also known as the melatoninrelated receptor) is expressed within the dorsal medial hypothalamus, lateral hypothalamus, and arcuate nucleus within the rodent brain (2). The human gene is located on the X chromosome. Other than the site of its expression and its structural similarity to the melatonin receptor (3), little is known of its biology (4). In this study, we have examined the coding region and immediate 59 and 39 flanking sequences of GPR50 for mutations in a cohort of subjects with severe early-onset obesity (mean age of onset of obesity, 5 years; mean body mass index standard deviation score, 4.2). Having detected common singlenucleotide polymorphisms (SNPs) within this gene and determined their allele frequency in 100 alleles from control subjects, we examined their association with quantitative metabolic traits in a population-based study. Having found a surprising association of certain polymorphisms with plasma triglyceride levels, we undertook a replication study, w...

The human aldose reductase (AR) gene has been mapped to chromosome 7 using the polymerase chain reaction to specifically amplify the human AR sequence in hamster/human hybrid DNA and also in mouse/human monochromosome hybrids. The assignment to chromosome 7 was confirmed by in situ hybridisation to human metaphase chromosomes using a novel, rapid hybridisation, method giving a regional localisation at 7q35.