The ATM gene and breast cancer: is it really a risk factor?

The genetic determinants for most breast cancer cases remain elusive. Whilst mutations in BRCA1 and BRCA2 significantly contribute to familial breast cancer risk, their contribution to sporadic breast cancer is low. In such cases genes frequently altered in the general population, such as the gene mutated in Ataxia telangiectasia (AT), ATM may be important risk factors. The initial interest in studying ATM heterozygosity in breast cancer arose from the findings of epidemiological studies of AT families in which AT heterozygote women had an increased risk of breast cancer and estimations that 1% of the population are AT heterozygotes. One of the clinical features of AT patients is extreme cellular sensitivity to ionising radiation. This observation, together with the finding that a significant proportion of breast cancer patients show an exaggerated acute or late normal tissue reactions after radiotherapy, has lead to the suggestion that AT heterozygosity plays a role in radiosensitivity and breast cancer development. Loss of heterozygosity in the region of the ATM gene on chromosome 11, has been found in about 40% of sporadic breast tumours. However, screening for ATM mutations in sporadic breast cancer cases, showing or not adverse effects to radiotherapy, has not revealed the magnitude of involvement of the ATM gene expected. Their size and the use of the protein truncation test to identify mutations limit many of these studies. This latter parameter is critical as the profile of mutations in AT patients may not be representative of the ATM mutations in other diseases. The potential role of rare sequence variants within the ATM gene, sometimes reported as polymorphisms, also needs to be fully assessed in larger cohorts of breast cancer patients and controls in order to determine whether they represent cancer and/or radiation sensitivity predisposing mutations.     

The ATM gene and breast cancer: is it really a risk factor?

The genetic determinants for most breast cancer cases remain elusive. Whilst mutations in BRCA1 and BRCA2 significantly contribute to familial breast cancer risk, their contribution to sporadic breast cancer is low. In such cases genes frequently altered in the general population, such as the gene mutated in Ataxia telangiectasia (AT), ATM may be important risk factors. The initial interest in studying ATM heterozygosity in breast cancer arose from the findings of epidemiological studies of AT families in which AT heterozygote women had an increased risk of breast cancer and estimations that 1% of the population are AT heterozygotes. One of the clinical features of AT patients is extreme cellular sensitivity to ionising radiation. This observation, together with the finding that a significant proportion of breast cancer patients show an exaggerated acute or late normal tissue reactions after radiotherapy, has lead to the suggestion that AT heterozygosity plays a role in radiosensitivity and breast cancer development. Loss of heterozygosity in the region of the ATM gene on chromosome 11, has been found in about 40% of sporadic breast tumours. However, screening for ATM mutations in sporadic breast cancer cases, showing or not adverse effects to radiotherapy, has not revealed the magnitude of involvement of the ATM gene expected. Their size and the use of the protein truncation test to identify mutations limit many of these studies. This latter parameter is critical as the profile of mutations in AT patients may not be representative of the ATM mutations in other diseases. The potential role of rare sequence variants within the ATM gene, sometimes reported as polymorphisms, also needs to be fully assessed in larger cohorts of breast cancer patients and controls in order to determine whether they represent cancer and/or radiation sensitivity predisposing mutations.     

An unusual WPW syndrome: What is the preexcitation variant?

A 15-year-old female with WPW syndrome and normal heart underwent an electrophysiology study for paroxysmal palpitations and syncope. Intravenous adenosine produced an unexpected response of QRS changes and advanced AV block. During isoproteronol infusion, short-lasting and poorly tolerated wide QRS tachycardia was inducible, but pacing maneuvers were not feasible during tachycardia to determine its definitive mechanism. However, various electrophysiologic phenomena including adenosine response, junctional beats pattern, and multisite atrial pacing were helpful to overcome the diagnosis challenges. Finally, careful evaluation of tachycardia features and the comprehensive electrophysiology study were crucial to establish presence of unusual preexcitation variants, and thus to guide successful catheter ablation of the arrhythmic substrate.     

What is type VI secretion doing in all those bugs?

The identification of bacterial secretion systems capable of translocating substrates into eukaryotic cells via needle-like appendages has opened fruitful and exciting areas of microbial pathogenesis research. The recent discovery of the type VI secretion system (T6SS) was met with early speculation that it too acts as a 'needle' that pathogens aim at host cells. New reports demonstrate that certain T6SSs are potent mediators of interbacterial interactions. In light of these findings, we examined earlier data indicating its role in pathogenesis. We conclude that although T6S can, in rare instances, directly influence interactions with higher organisms, the broader physiological significance of the system is likely to provide defense against simple eukaryotic cells and other bacteria in the environment. The crucial role of T6S in bacterial interactions, along with its presence in many organisms relevant to disease, suggests that it might be a key determinant in the progression and outcome of certain human polymicrobial infections.     

Coral diseases: what is really known?

Reports of new and emerging coral diseases have proliferated in recent years. Such coral diseases are often cited as contributing to coral reef decline. Many of these diseases, however, have been described solely on the basis of field characteristics, and in some instances there is disagreement as to whether an observed coral condition is actually a disease. A disease pathogen has been identified for only three coral diseases, and for only two of these has the pathogen been shown (in the laboratory) to be the disease agent. In one case, the same disease name has been used for several widely varying coral syndromes, whereas in another multiple disease names have been applied to symptoms that may be caused by a single disease. Despite the current confusion, rapid progress is being made.     

Is the mismatch repair deficient type of Muir-Torre syndrome confined to mutations in the hMSH2 gene?

The Muir-Torre syndrome (MTS) is a rare autosomal-dominant condition characterized by the occurrence of sebaceous skin lesions and internal tumours in a patient. It has been demonstrated that at least a subgroup of MTS exhibits clinical and molecular genetic features of hereditary nonpolyposis colorectal cancer, including microsatellite instability in skin and visceral tumours, because of mutations in DNA mismatch repair genes. We have identified germline mutations in the hMSH2 gene in two unrelated MTS patients ascertained because of their skin tumours. Our results, together with published MTS cases, support the hypothesis that MTS with its characteristic skin lesions is confined to mutations in the hMSH2 gene. Received: 22 July 1996 / Revised: 12 August 1996     

Paraoxonase 1 and atherosclerosis: is the gene or the protein more important?

The oxidation of low-density lipoprotein (LDL) is centrally involved in the initiation and progression of atherosclerosis. High-density lipoprotein (HDL) paraoxonase 1 (PON1) retards the oxidation of LDL and is a major antiatherosclerotic component of HDL. The PON1 gene contains a number of functional polymorphisms in both the coding and the promoter regions, which affect either the level or the substrate specificity of PON1. Genetic case-control and prospective studies conducted to date have produced confusing results. Meta-analysis of these studies indicates no simple relationship between the PON1 polymorphisms and the presence of coronary heart disease (CHD). However, at the present moment in time, it seems that PON1 status, i.e., activity and/or concentration, is more closely related to CHD, and indeed, PON1 has shown to be an independent risk factor for CHD in a prospective study, compared to the genetic polymorphisms. PON1 levels can also be modulated by environmental\lifestyle and possibly pharmaceutical factors. Larger, better designed, preferably prospective studies are needed to determine further the association of PON1 genetic polymorphisms and status with CHD.     

Comparing aquatic and terrestrial grazing ecosystems: is the grass really greener?

‘Grazing ecosystem’ is typically used to describe terrestrial ecosystems with high densities of mammalian herbivores such as the Serengeti in East Africa or the Greater Yellowstone Ecosystem in North America. These abundant, large herbivores determine plant community dynamics and ecosystem processes. The general concepts that define grazing ecosystems also aptly describe many aquatic ecosystems, including coral reefs, seagrass beds, and lakes, where herbivores such as parrotfishes, turtles, and zooplankton have strong impacts on ecosystem processes. Here, I compare the ecology of grazing ecosystems in search of common concepts that transcend the terrestrial‐aquatic boundary. Specifically, I evaluate: 1) the feedbacks between herbivory and primary production, 2) the roles of herbivore richness and facilitation, 3) how predators and diet quality shape patterns of herbivory, and 4) how altering herbivory mediates alternative states.     

Why is the cystic fibrosis gene so frequent?

Summary The high incidence of cystic fibrosis (CF) in most European populations (and populations of European descent) can be explained by different hypotheses that can be tested using the available data concerning this disorder. Among the five hypotheses discussed (genetic heterogeneity, high rate of mutation, meiotic drive, drift and heterozygote advantage), only the last is supported by experimental data. The following conclusions can be drawn from the evidence that we have reviewed: (1) CF is a single gene disorder (genetically homogeneous). (2) Haplotypes associated with the CF gene suggest that only a few mutations (the same gene located in 7q13 is always affected) are responsible for the disorder. (3) CF with pancreatic insufficiency is mainly associated with a single haplotype, whereas CF with pancreatic sufficiency is more frequently associated with different haplotypes. (4) A selective advantage consisting of higher resistance to Cl^–-secreting diarrhoeas might have favored, in the past, survival of infants heterozygous for the CF gene.     

Cardiovascular disease risk prediction using genetic information (gene scores): is it really informative?

PURPOSE OF REVIEW: DNA-based tests for assessment of genetic predisposition to coronary heart disease need to provide information over and above that of conventional risk factors. The efficacy of selected 'candidate' gene loci in risk algorithms, to improve the predictive accuracy for coronary heart disease, remains to be demonstrated. RECENT FINDINGS: Although many candidate genes for coronary heart disease have been tested, the optimal set of risk genotypes has yet to be identified. There is only a relatively modest risk to be expected in association with any single genotype, published estimates are in the range of 1.12-1.73. Thus the risk associated with any one genotype is modest, but, in combination, selected genotypes may be associated with a clinically significant risk. Since the allele frequency for many of these variants is high, many individuals will carry several 'risk alleles'. A small number of selected single nucleotide polymorphisms should complement the conventional risk factors to identify high-risk individuals in whom correction of 'modifiable risk factors' through lifestyle interventions or medication would be most beneficial. SUMMARY: As our understanding of how genetic variation impacts on common diseases advances, the novel loci identified by genome-wide association scans associated with disease risk will rapidly improve these risk algorithms.     

Exclusion of the C/D box snoRNA gene cluster HBII-52 from a major role in Prader–Willi syndrome

Prader–Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurogenetic disorders caused by the loss of function of imprinted genes in 15q11–q13. The maternally expressed UBE3A gene is affected in AS. Four protein-encoding genes (MKRN3, MAGEL2, NDN and SNURF-SNRPN) and several small nucleolar (sno) RNA genes (HBII-13, HBII-436, HBII-85, HBII-438A, HBII-438B and HBII-52) are expressed from the paternal chromosome only but their contribution to PWS is unclear. To examine the role of the HBII-52 snoRNA genes, we have reinvestigated an AS family with a submicroscopic deletion spanning UBE3A and flanking sequences. By fine mapping of the centromeric deletion breakpoint in this family, we have found that the deletion affects all of the 47 HBII-52 genes. Since the complete loss of the HBII-52 genes in family members who carry the deletion on their paternal chromosome is not associated with an obvious clinical phenotype, we conclude that HBII-52 snoRNA genes do not play a major role in PWS. However, we cannot exclude the possibility that the loss of HBII-52 has a phenotypic effect when accompanied by the loss of function of other genes in 15q11–q13.Electronic Database Information: accession numbers and URLs for data presented herein are as follows: for PAR-4 (accession number AF019617), deletion junction fragment (L15422): GenBank, ; for Angelman syndrome [MIM105830]: Online Mendelian Inheritance in Man (OMIM),     

A case of ‘tachy-brady syndrome’: What is the mechanism?

A young male presented with incessant narrow QRS tachycardia and left ventricular dysfunction. 24-Holter monitoring revealed multiple episodes of sustained and nonsustained episodes of tachycardia with prolonged sinus pauses at termination. The analysis of the electrocardiogram, followed by an invasive electrophysiological study, suggested an unusual mechanism for this tachy-brady syndrome.     

Opinion: peroxisomal-protein import: is it really that complex?

Peroxisomal enzymes are synthesized in the cytoplasm and imported post-translationally across the peroxisome membrane. Unlike other organelles with a sealed membrane, peroxisomes can import folded enzymes, and they seem to lack intraperoxisomal chaperones. Here, we propose a mechanistic model for the early steps in peroxisomal-matrix-enzyme import, which might help to explain the unusual features of this process.