Congenital indifference to pain (CIP) is a rare condition in which patients have severely impaired pain perception, but are otherwise essentially normal. We identified and collected DNA from individuals from nine families of seven different nationalities in which the affected individuals meet the diagnostic criteria for CIP. Using homozygosity mapping and haplotype sharing methods, we narrowed the CIP locus to chromosome 2q24-q31, a region known to contain a cluster of voltage-gated sodium channel genes. From these prioritized candidate sodium channels, we identified 10 mutations in the SCN9A gene encoding the sodium channel protein Nav1.7. The mutations completely co-segregated with the disease phenotype, and nine of these SCN9A mutations resulted in truncation and loss-of-function of the Nav1.7 channel. These genetic data further support the evidence that Nav1.7 plays an essential role in mediating pain in humans, and that SCN9A mutations identified in multiple different populations underlie CIP.
The increased risk of colorectal cancer associated with a high BMI might be largely restricted to tumors that display the more common MS-stable phenotype, suggesting further that colorectal cancer etiology differs by tumor MSI status.
Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder characterized by impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons. We identified two large pedigrees segregating the disorder in an isolated population living in Newfoundland and performed a 5-cM genome scan. Linkage analysis identified a locus mapping to 12p13.33 with a maximum LOD score of 8.4. Haplotype sharing defined a candidate interval of 1.06 Mb containing all or part of seven annotated genes, sequencing of which failed to detect causative mutations. Comparative genomics revealed a conserved ORF corresponding to a novel gene in which we found three different truncating mutations among five families including patients from rural Quebec and Nova Scotia. This gene, termed "HSN2," consists of a single exon located within intron 8 of the PRKWNK1 gene and is transcribed from the same strand. The HSN2 protein may play a role in the development and/or maintenance of peripheral sensory neurons or their supporting Schwann cells.
Background and aims-Colorectal cancer (CRC) is the second most frequent cancer in developed countries. Newfoundland has the highest incidence of CRC in Canada and the highest rate of familial CRC yet reported in the world. To determine the impact of mutations in known CRC susceptibility genes and the contribution of the known pathways to the development of hereditary CRC, an incident cohort of 750 patients with CRC (708 different families) from the Newfoundland population was studied.
We have previously isolated long-range acting enhancer elements from the HeLa genome by functional selection. In this report, the structural and functional characteristics of one (GA1) of the enhancers are reported. By cloning various restriction fragments and by deletion mutagenesis, the activity of GAl was located in a 230-bp region. The nucleotide sequence of GAl and genomic Southern blot analysis indicated that GAl is derived from human papilloma virus (HPV) 18 DNA that had been integrated into the HeLa genome. The enhancer is located in the non-coding region of the HPV 18 genome. The HPV 18 enhancer consists of two functional domains, both of which have full enhancer activity in HeLa cells. The enhancer does not contain enhancer core sequences but contains several blocks of potential Z-DNA sequence. Like SV40 and polyoma virus enhancers, the activity of the HPV 18 enhancer was repressed by adenovirus Ela products. The HPV 18 enhancer shows a narrow cell type specificity: it is active in some cervical carcinoma cell lines, but inactive in all non-cervical cells except for one neuroblastoma cell line. These results suggest that the HPV 18 enhancer plays an important role in regulation of the viral genes.
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