A mutation in stratifin is responsible for the repeated epilation (Er) phenotype in mice

Stratifin (Sfn, also called 14-3-3sigma) is highly expressed in differentiating epidermis and mediates cell cycle arrest. Sfn is repressed in cancer, but its function during development is uncharacterized. We identified an insertion mutation in the gene Sfn in repeated epilation (Er) mutant mice by positional cloning. Er/+ mice expressed a truncated Sfn protein, which probably contributes to the defects in Er/Er and Er/+ epidermis and to cancer development in Er/+ mice.     

A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis

Smith-Lemli-Opitz syndrome (SLOS), desmosterolosis and lathosterolosis are human syndromes caused by defects in the final stages of cholesterol biosynthesis. Many of the developmental malformations in these syndromes occur in tissues and structures whose embryonic patterning depends on signaling by the Hedgehog (Hh) family of secreted proteins. Here we report that response to the Hh signal is compromised in mutant cells from mouse models of SLOS and lathosterolosis and in normal cells pharmacologically depleted of sterols. We show that decreasing levels of cellular sterols correlate with diminishing responsiveness to the Hh signal. This diminished response occurs at sterol levels sufficient for normal autoprocessing of Hh protein, which requires cholesterol as cofactor and covalent adduct. We further find that sterol depletion affects the activity of Smoothened (Smo), an essential component of the Hh signal transduction apparatus.     

Population choice in mapping genes for complex diseases

The difficulty of identifying susceptibility genes for common diseases has polarized geneticists' views on what disease models are appropriate and how best to proceed once high-density genome maps become available. Different disease models have different implications for using linkage or linkage-disequilibrium-based approaches for mapping complex disease genes. We argue that the choice of study population is a critical factor when designing a study, and that genetically simplified isolates are more useful than diverse continental populations under most assumptions.     

'Racial' differences in genetic effects for complex diseases

'Racial' differences are frequently debated in clinical, epidemiological and molecular research and beyond. In particular, there is considerable controversy regarding the existence and importance of 'racial' differences in genetic effects for complex diseases influenced by a large number of genes. An important question is whether ancestry influences the impact of each gene variant on the disease risk. Here, we addressed this question by examining the genetic effects for 43 validated gene-disease associations across 697 study populations of various descents. The frequencies of the genetic marker of interest in the control populations often (58%) showed large heterogeneity (statistical variability) between 'races'. Conversely, we saw large heterogeneity in the genetic effects (odds ratios) between 'races' in only 14% of cases. Genetic markers for proposed gene-disease associations vary in frequency across populations, but their biological impact on the risk for common diseases may usually be consistent across traditional 'racial' boundaries.     

Mutations in KANSL1 cause the 17q21.31 microdeletion syndrome phenotype

The chromosome 17q21.31 deletion syndrome is a genomic disorder characterized by highly distinctive facial features, moderate-to-severe intellectual disability, hypotonia and friendly behavior. Here, we show that de novo loss-of-function mutations in KANSL1 (also called KIAA1267) cause a full del(17q21.31) phenotype in two unrelated individuals that lack deletion at 17q21.31. These findings indicate that 17q21.31 deletion syndrome is a monogenic disorder caused by haploinsufficiency of KANSL1.     

Efficient and accurate replication in the presence of 7,8-dihydro-8-oxoguanine by DNA polymerase eta

Oxidative damage to DNA has been proposed to have a role in cancer and ageing. Oxygen-free radicals formed during normal aerobic cellular metabolism attack bases in DNA, and 7, 8-dihydro-8-oxoguanine (8-oxoG) is one of the adducts formed. Eukaryotic replicative DNA polymerases replicate DNA containing 8-oxoG by inserting an adenine opposite the lesion; consequently, 8-oxoG is highly mutagenic and causes G:C to T:A transversions. Genetic studies in yeast have indicated a role for mismatch repair in minimizing the incidence of these mutations. In Saccharomyces cerevisiae, deletion of OGG1, encoding a DNA glycosylase that functions in the removal of 8-oxoG when paired with C, causes an increase in the rate of G:C to T:A transversions. The ogg1Delta msh2Delta double mutant displays a higher rate of CAN1S to can1r forward mutations than the ogg1Delta or msh2Delta single mutants, and this enhanced mutagenesis is primarily due to G:C to T:A transversions. The gene RAD30 of S. cerevisiae encodes a DNA polymerase, Poleta, that efficiently replicates DNA containing a cis-syn thymine-thymine (T-T) dimer by inserting two adenines across from the dimer. In humans, mutations in the yeast RAD30 counterpart, POLH, cause the variant form of xeroderma pigmentosum (XP-V), and XP-V individuals suffer from a high incidence of sunlight-induced skin cancers. Here we show that yeast and human POLeta replicate DNA containing 8-oxoG efficiently and accurately by inserting a cytosine across from the lesion and by proficiently extending from this base pair. Consistent with these biochemical studies, a synergistic increase in the rate of spontaneous mutations occurs in the absence of POLeta in the yeast ogg1Delta mutant. Our results suggest an additional role for Poleta in the prevention of internal cancers in humans that would otherwise result from the mutagenic replication of 8-oxoG in DNA.     

Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex

Carney complex (CNC) is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumours and psammomatous melanotic schwannomas. CNC is inherited as an autosomal dominant trait and the genes responsible have been mapped to 2p16 and 17q22-24 (refs 6, 7). Because of its similarities to the McCune-Albright syndrome and other features, such as paradoxical responses to endocrine signals, genes implicated in cyclic nucleotide-dependent signalling have been considered candidates for causing CNC (ref. 10). In CNC families mapping to 17q, we detected loss of heterozygosity (LOH) in the vicinity of the gene (PRKAR1A) encoding protein kinase A regulatory subunit 1-alpha (RIalpha), including a polymorphic site within its 5' region. We subsequently identified three unrelated kindreds with an identical mutation in the coding region of PRKAR1A. Analysis of additional cases revealed the same mutation in a sporadic case of CNC, and different mutations in three other families, including one with isolated inherited cardiac myxomas. Analysis of PKA activity in CNC tumours demonstrated a decreased basal activity, but an increase in cAMP-stimulated activity compared with non-CNC tumours. We conclude that germline mutations in PRKAR1A, an apparent tumour-suppressor gene, are responsible for the CNC phenotype in a subset of patients with this disease.     

A genome-wide association study identifies two susceptibility loci for duodenal ulcer in the Japanese population

Through a genome-wide association analysis with a total of 7,035 individuals with duodenal ulcer and 25,323 controls from Japan, we identified two susceptibility loci at the PSCA gene (encoding prostate stem cell antigen) at 8q24 and at the ABO blood group locus at 9q34. The C allele of rs2294008 at PSCA was associated with increased risk of duodenal ulcer (odds ratio (OR) = 1.84; P = 3.92 × 10(-33)) in a recessive model but was associated with decreased risk of gastric cancer (OR = 0.79; P = 6.79 × 10(-12)), as reported previously. The T allele of rs2294008 encodes a translation initiation codon upstream of the reported site and changes protein localization from the cytoplasm to the cell surface. rs505922 at ABO was also associated with duodenal ulcer in a recessive model (OR = 1.32; P = 1.15 × 10(-10)). Our findings demonstrate a role for genetic variants in the pathogenesis of duodenal ulcer.     

A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population

Lung adenocarcinoma is the most common histological type of lung cancer, and its incidence is increasing worldwide. To identify genetic factors influencing risk of lung adenocarcinoma, we conducted a genome-wide association study and two validation studies in the Japanese population comprising a total of 6,029 individuals with lung adenocarcinoma (cases) and 13,535 controls. We confirmed two previously reported risk loci, 5p15.33 (rs2853677, P(combined) = 2.8 × 10(-40), odds ratio (OR) = 1.41) and 3q28 (rs10937405, P(combined) = 6.9 × 10(-17), OR = 1.25), and identified two new susceptibility loci, 17q24.3 (rs7216064, P(combined) = 7.4 × 10(-11), OR = 1.20) and 6p21.3 (rs3817963, P(combined) = 2.7 × 10(-10), OR = 1.18). These data provide further evidence supporting a role for genetic susceptibility in the development of lung adenocarcinoma.     

Position of a 'green-red' hybrid gene in the visual pigment array determines colour-vision phenotype.

The X-linked red- and green-pigment genes are arranged in a head-to-tail tandem array. The colour-vision defect of deuteranomaly (in 5% of males of European descent) is associated with a 5'-green-red-3' visual-pigment hybrid gene, which may also exist in males with normal colour vision. To explain why males with a normal red, a normal green and a green-red hybrid gene may have either normal or deutan colour vision, we hypothesized that only the first two genes are expressed and deuteranomaly results only if the green-red hybrid gene occupies the second position and is expressed preferentially over normal green-pigment genes occupying more distal positions. We used long-range PCR amplification and studied 10 deutan males (8 deuteranomalous and 2 deuteranopic) with 3 visual pigment genes (red, green and green-red hybrid) to investigate whether position of the hybrid gene in the array determined gene expression. The green-red hybrid gene was always at the second position (and the first position was always occupied by the red gene). Conversely, in two men with red, green and green-red hybrid genes and normal colour vision, the hybrid gene occupied the third position. When pigment gene mRNA expression was assessed in post-mortem retinae of three men with the red, green and green-red genotype, the green-red hybrid gene was expressed only when located in the second position. We conclude that the green-red hybrid gene will only cause deutan defects when it occupies the second position of the pigment gene array.     

Mutations in the pre-replication complex cause Meier-Gorlin syndrome

Meier-Gorlin syndrome (ear, patella and short-stature syndrome) is an autosomal recessive primordial dwarfism syndrome characterized by absent or hypoplastic patellae and markedly small ears1?3. Both pre- and post-natal growth are impaired in this disorder, and although microcephaly is often evident, intellect is usually normal in this syndrome. We report here that individuals with this disorder show marked locus heterogeneity, and we identify mutations in five separate genes: ORC1, ORC4, ORC6, CDT1 and CDC6. All of these genes encode components of the pre-replication complex, implicating defects in replication licensing as the cause of a genetic syndrome with distinct developmental abnormalities.     

A genome-wide association study identifies susceptibility loci for Wilms tumor

Wilms tumor is the most common renal malignancy of childhood. To identify common variants that confer susceptibility to Wilms tumor, we conducted a genome-wide association study in 757 individuals with Wilms tumor (cases) and 1,879 controls. We evaluated ten SNPs in regions significantly associated at P < 5 × 10(-5) in two independent replication series from the UK (769 cases and 2,814 controls) and the United States (719 cases and 1,037 controls). We identified clear significant associations at 2p24 (rs3755132, P = 1.03 × 10(-14); rs807624, P = 1.32 × 10(-14)) and 11q14 (rs790356, P = 4.25 × 10(-15)). Both regions contain genes that are plausibly related to Wilms tumorigenesis. We also identified candidate association signals at 5q14, 22q12 and Xp22.     

The Collaborative Cross, a community resource for the genetic analysis of complex traits

The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.     

A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis

To identify susceptibility loci for ankylosing spondylitis, we performed a two-stage genome-wide association study in Han Chinese. In the discovery stage, we analyzed 1,356,350 autosomal SNPs in 1,837 individuals with ankylosing spondylitis and 4,231 controls; in the validation stage, we analyzed 30 suggestive SNPs in an additional 2,100 affected individuals and 3,496 controls. We identified two new susceptibility loci between EDIL3 and HAPLN1 at 5q14.3 (rs4552569; P = 8.77 × 10(-10)) and within ANO6 at 12q12 (rs17095830; P = 1.63 × 10(-8)). We also confirmed previously reported associations in Europeans within the major histocompatibility complex (MHC) region (top SNP, rs13202464; P < 5 × 10(-324)) and at 2p15 (rs10865331; P = 1.98 × 10(-8)). We show that rs13202464 within the MHC region mainly represents the risk effect of HLA-B*27 variants (including HLA-B*2704, HLA-B*2705 and HLA-B*2715) in Chinese. The two newly discovered loci implicate genes related to bone formation and cartilage development, suggesting their potential involvement in the etiology of ankylosing spondylitis.