Showing papers by "French Institute of Health and Medical Research published in 1998"
TL;DR: The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in bRCA2 carriers <50 years of age.
Abstract: The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.
2,892 citations
TL;DR: The Clustal series of programs as mentioned in this paper have been widely used for multiple alignment and for preparing phylogenetic trees, and the most popular of these programs is the Clusteral W 1.7.
2,682 citations
TL;DR: In this article, the authors compared the SF-12 and SF-36 summary measures in nine European countries (Denmark, France, Germany, Italy, Netherlands, Norway, Spain, Sweden, and the United Kingdom).
2,471 citations
TL;DR: A homozygous mutation in the human leptin receptor gene results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains, which indicates that leptin is an important physiological regulator of several endocrine functions in humans.
Abstract: The adipocyte-specific hormone leptin, the product of the obese (ob) gene, regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family In rodents, homozygous mutations in genes encoding leptin or the leptin receptor cause early-onset morbid obesity, hyperphagia and reduced energy expenditure These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadisms In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced These results indicate that leptin is an important physiological regulator of several endocrine functions in humans
2,291 citations
TL;DR: It is clear that there are multiple actions associated with PRL, and the technique of gene targeting in mice has been used to develop the first experimental model in which the effect of the complete absence of any lactogen or PRL-mediated effects can be studied.
Abstract: PRL is an anterior pituitary hormone that, along with GH and PLs, forms a family of hormones that probably resulted from the duplication of an ancestral gene. The PRLR is also a member of a larger family, known as the cytokine class-1 receptor superfamily, which currently has more than 20 different members. PRLRs or binding sites are widely distributed throughout the body. In fact, it is difficult to find a tissue that does not express any PRLR mRNA or protein. In agreement with this wide distribution of receptors is the fact that now more than 300 separate actions of PRL have been reported in various vertebrates, including effects on water and salt balance, growth and development, endocrinology and metabolism, brain and behavior, reproduction, and immune regulation and protection. Clearly, a large proportion of these actions are directly or indirectly associated with the process of reproduction, including many behavioral effects. PRL is also becoming well known as an important regulator of immune function. A number of disease states, including the growth of different forms of cancer as well as various autoimmune diseases, appear to be related to an overproduction of PRL, which may act in an endocrine, autocrine, or paracrine manner, or via an increased sensitivity to the hormone. The first step in the mechanism of action of PRL is the binding to a cell surface receptor. The ligand binds in a two-step process in which site 1 on PRL binds to one receptor molecule, after which a second receptor molecule binds to site 2 on the hormone, forming a homodimer consisting of one molecule of PRL and two molecules of receptor. The PRLR contains no intrinsic tyrosine kinase cytoplasmic domain but associates with a cytoplasmic tyrosine kinase, JAK2. Dimerization of the receptor induces tyrosine phosphorylation and activation of the JAK kinase followed by phosphorylation of the receptor. Other receptor-associated kinases of the Src family have also been shown to be activated by PRL. One major pathway of signaling involves phosphorylation of cytoplasmic State proteins, which themselves dimerize and translocate to nucleus and bind to specific promoter elements on PRL-responsive genes. In addition, the Ras/Raf/MAP kinase pathway is also activated by PRL and may be involved in the proliferative effects of the hormone. Finally, a number of other potential mediators have been identified, including IRS-1, PI-3 kinase, SHP-2, PLC gamma, PKC, and intracellular Ca2+. The technique of gene targeting in mice has been used to develop the first experimental model in which the effect of the complete absence of any lactogen or PRL-mediated effects can be studied. Heterozygous (+/-) females show almost complete failure to lactate after the first, but not subsequent, pregnancies. Homozygous (-/-) females are infertile due to multiple reproductive abnormalities, including ovulation of premeiotic oocytes, reduced fertilization of oocytes, reduced preimplantation oocyte development, lack of embryo implantation, and the absence of pseudopregnancy. Twenty per cent of the homozygous males showed delayed fertility. Other phenotypes, including effects on the immune system and bone, are currently being examined. It is clear that there are multiple actions associated with PRL. It will be important to correlate known effects with local production of PRL to differentiate classic endocrine from autocrine/paracrine effects. The fact that extrapituitary PRL can, under some circumstances, compensate for pituitary PRL raises the interesting possibility that there may be effects of PRL other than those originally observed in hypophysectomized rats. The PRLR knockout mouse model should be an interesting system by which to look for effects activated only by PRL or other lactogenic hormones. On the other hand, many of the effects reported in this review may be shared with other hormones, cytokines, or growth factors and thus will be more difficult to study. (ABSTRACT TRUNCATED)
1,838 citations
TL;DR: It is suggested that mutant huntingtin acts within the nucleus to induce neurodegeneration, however, intranuclear inclusions may reflect a cellular mechanism to protect against huntingtin-induced cell death.
1,646 citations
TL;DR: The molecular background of the Peutz–Jeghers syndrome, a rare hereditary disease in which there is predisposition to benign and malignant tumours of many organ systems, is investigated and truncating germline mutations in a gene residing on chromosome 19p are identified.
Abstract: Studies of hereditary cancer syndromes have contributed greatly to our understanding of molecular events involved in tumorigenesis. Here we investigate the molecular background of the Peutz-Jeghers syndrome (PJS), a rare hereditary disease in which there is predisposition to benign and malignant tumours of many organ systems. A locus for this condition was recently assigned to chromosome 19p. We have identified truncating germline mutations in a gene residing on chromosome 19p in multiple individuals affected by PJS. This previously identified but unmapped gene, LKB1, has strong homology to a cytoplasmic Xenopus serine/threonine protein kinase XEEK1, and weaker similarity to many other protein kinases. Peutz-Jeghers syndrome is therefore the first cancer-susceptibility syndrome to be identified that is due to inactivating mutations in a protein kinase.
1,608 citations
TL;DR: The mouse gene for mitochondrial transcription factor A (Tfam), formerly known as m-mtTFA, is disrupted by gene targetting of loxP-sites followed by cre-mediated excision in vivo and is the first mammalian protein demonstrated to regulate mtDNA copy number in vivo.
Abstract: The regulation of mitochondrial DNA (mtDNA) expression is crucial for mitochondrial biogenesis during development and differentiation. We have disrupted the mouse gene for mitochondrial transcription factor A (Tfam; formerly known as m-mtTFA) by gene targetting of loxP-sites followed by cre-mediated excision in vivo. Heterozygous knockout mice exhibit reduced mtDNA copy number and respiratory chain deficiency in heart. Homozygous knockout embryos exhibit a severe mtDNA depletion with abolished oxidative phosphorylation. Mutant embryos proceed through implantation and gastrulation, but die prior to embryonic day (E)10.5. Thus, Tfam is the first mammalian protein demonstrated to regulate mtDNA copy number in vivo and is essential for mitochondrial biogenesis and embryonic development.
1,473 citations
TL;DR: An anatomical parameter, the pelvic incidence, appears to be the main axis of the sagittal balance of the spine, which controls spinal curves in accordance with the adaptability of the other parameters.
Abstract: This paper proposes an anatomical parameter, the pelvic incidence, as the key factor for managing the spinal balance. Pelvic and spinal sagittal parameters were investigated for normal and scoliotic adult subjects. The relation between pelvic orientation, and spinal sagittal balance was examined by statistical analysis. A close relationship was observed, for both normal and scoliotic subjects, between the anatomical parameter of pelvic incidence and the sacral slope, which strongly determines lumbar lordosis. Taking into account the Cobb angle and the apical vertebral rotation confers a three-dimensional aspect to this chain of relations between pelvis and spine. A predictive equation of lordosis is postulated. The pelvic incidence appears to be the main axis of the sagittal balance of the spine. It controls spinal curves in accordance with the adaptability of the other parameters.
1,458 citations
TL;DR: The develop-ment of functional foods for the gut is in its infancy and will be successful only if more fundamental research is done on digestive physiology, the gut microflora, immune system and mucosal function.
Abstract: The gut is an obvious target for the development of functional foods, acting as it does as the interface between diet and the metabolic events which sustain life. The key processes in digestive physiology which can be regulated by modifying diet are satiety, the rate and extent of macronutrient breakdown and absorption from the small bowel, sterol metabolism, the colonic microflora, fermentation, mucosal function and bowel habit, and the gut immune system. The intestinal microflora is the main focus of many current functional foods. Probiotics are foods which contain live bacteria which are beneficial to health whilst prebiotics, such as certain non-digestible oligosaccharides which selectively stimulate the growth of bifidobacteria in the colon, are already on the market. Their claimed benefits are to alleviate lactose maldigestion, increase resistance to invasion by pathogenic species of bacteria in the gut, stimulate the immune system and possibly protect against cancer. There are very few reports of well-designed human intervention studies with prebiotics as yet. Certain probiotic species have been shown to shorten the duration of rotavirus diarrhoea in children but much more work is needed on the mechanism of immunomodulation and of competitive exclusion and microflora modification. The development of functional foods for the gut is in its infancy and will be successful only if more fundamental research is done on digestive physiology, the gut microflora, immune system and mucosal function.
1,416 citations
TL;DR: It is shown that leptin messenger RNA and leptin protein are present in rat gastric epithelium, and that cells in the glands of the gastric fundic mucosa are immunoreactive for leptin, indicating that gastric leptin may be involved in early CCK-mediated effects activated by food intake, possibly including satiety.
Abstract: The circulating peptide leptin, which is the product of the ob gene, provides feedback information on the size of fat stores to central Ob receptors that control food intake and body-weight homeostasis. Leptin has so far been reported to be secreted only by adipocytes and the placenta. Here we show that leptin messenger RNA and leptin protein are present in rat gastric epithelium, and that cells in the glands of the gastric fundic mucosa are immunoreactive for leptin. The physiological function of this previously unsuspected source of leptin is unknown. However, both feeding and administration of CCK-8 (the biologically active carboxy-terminal end of cholecystokinin) result in a rapid and large decrease in both leptin cell immunoreactivity and the leptin content of the fundic epithelium, with a concomitant increase in the concentration of leptin in the plasma. These results indicate that gastric leptin may be involved in early CCK-mediated effects activated by food intake, possibly including satiety.
TL;DR: It is concluded that activators of PPARα inhibit the inflammatory response of aortic smooth-muscle cells and decrease the concentration of plasma acute-phase proteins, indicating that PPAR α in the vascular wall may influence the process of atherosclerosis and re-stenosis.
Abstract: Peroxisome proliferator-activated receptors (PPARs) are key players in lipid and glucose metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as dyslipidaemia and diabetes. Whereas PPARgamma promotes lipid storage by regulating adipocyte differentiation, PPARalpha stimulates the beta-oxidative degradation of fatty acids. PPARalpha-deficient mice show a prolonged response to inflammatory stimuli, suggesting that PPARalpha is also a modulator of inflammation. Hypolipidaemic fibrate drugs are PPARalpha ligands that inhibit the progressive formation of atherosclerotic lesions, which involves chronic inflammatory processes, even in the absence of their atherogenic lipoprotein-lowering effect. Here we show that PPARalpha is expressed in human aortic smooth-muscle cells, which participate in plaque formation and post-angioplasty re-stenosis. In these smooth-muscle cells, we find that PPARalpha ligands, and not PPARgamma ligands, inhibit interleukin-1-induced production of interleukin-6 and prostaglandin and expression of cyclooxygenase-2. This inhibition of cyclooxygenase-2 induction occurs transcriptionally as a result of PPARalpha repression of NF-kappaB signalling. In hyperlipidaemic patients, fenofibrate treatment decreases the plasma concentrations of interleukin-6, fibrinogen and C-reactive protein. We conclude that activators of PPARalpha inhibit the inflammatory response of aortic smooth-muscle cells and decrease the concentration of plasma acute-phase proteins, indicating that PPARalpha in the vascular wall may influence the process of atherosclerosis and re-stenosis.
TL;DR: In this paper, the authors examined the status of the β-catenin gene in different transgenic mouse lines of HCC obtained with the oncogenes c-myc or H-ras.
Abstract: Hepatocellular carcinoma (HCC) is the major primary malignant tumor in the human liver, but the molecular changes leading to liver cell transformation remain largely unknown. The Wnt-β-catenin pathway is activated in colon cancers and some melanoma cell lines, but has not yet been investigated in HCC. We have examined the status of the β-catenin gene in different transgenic mouse lines of HCC obtained with the oncogenes c-myc or H-ras. Fifty percent of the hepatic tumors in these transgenic mice had activating somatic mutations within the β-catenin gene similar to those found in colon cancers and melanomas. These alterations in the β-catenin gene (point mutations or deletions) lead to a disregulation of the signaling function of β-catenin and thus to carcinogenesis. We then analyzed human HCCs and found similar mutations in eight of 31 (26%) human liver tumors tested and in HepG2 and HuH6 hepatoma cells. The mutations led to the accumulation of β-catenin in the nucleus. Thus alterations in the β-catenin gene frequently are selected for during liver tumorigenesis and suggest that disregulation of the Wnt-β-catenin pathway is a major event in the development of HCC in humans and mice.
TL;DR: These results are the first to identify a defect in a molecular chaperone as a cause for an inherited human muscle disorder, and an R120G missense mutation in CRYAB that co-segregates with the disease phenotype in this family.
Abstract: Desmin-related myopathies (DRM) are inherited neuromuscular disorders characterized by adult onset and delayed accumulation of aggregates of desmin, a protein belonging to the type III intermediate filament family, in the sarcoplasma of skeletal and cardiac muscles. In this paper, we have mapped the locus for DRM in a large French pedigree to a 26-cM interval in chromosome 11q21-23. This region contains the alphaB-crystallin gene (CRYAB), a candidate gene encoding a 20-kD protein that is abundant in lens and is also present in a number of non-ocular tissues, including cardiac and skeletal muscle. AlphaB-crystallin is a member of the small heat shock protein (shsp) family and possesses molecular chaperone activity. We identified an R120G missense mutation in CRYAB that co-segregates with the disease phenotype in this family. Muscle cell lines transfected with the mutant CRYAB cDNA showed intracellular aggregates that contain both desmin and alphaB-crystallin as observed in muscle fibers from DRM patients. These results are the first to identify a defect in a molecular chaperone as a cause for an inherited human muscle disorder.
TL;DR: A minimal hypothesis is proposed concerning the brain processes underlying effortful tasks and predictions for spatio-temporal activation patterns during brain imaging are outlined, particularly about the contribution of dorsolateral cortex and anterior cingulate to the workspace.
Abstract: A minimal hypothesis is proposed concerning the brain processes underlying effortful tasks. It distinguishes two main computational spaces: a unique global workspace composed of distributed and heavily interconnected neurons with long-range axons, and a set of specialized and modular perceptual, motor, memory, evaluative, and attentional processors. Workspace neurons are mobilized in effortful tasks for which the specialized processors do not suffice. They selectively mobilize or suppress, through descending connections, the contribution of specific processor neurons. In the course of task performance, workspace neurons become spontaneously coactivated, forming discrete though variable spatio-temporal patterns subject to modulation by vigilance signals and to selection by reward signals. A computer simulation of the Stroop task shows workspace activation to increase during acquisition of a novel task, effortful execution, and after errors. We outline predictions for spatio-temporal activation patterns during brain imaging, particularly about the contribution of dorsolateral prefrontal cortex and anterior cingulate to the workspace.
TL;DR: The results indicate that masked stimuli have a measurable influence on electrical and haemodynamic measures of brain activity and a stream of perceptual, semantic and motor processes can occur without awareness.
Abstract: Visual words that are masked and presented so briefly that they cannot be seen may nevertheless facilitate the subsequent processing of related words, a phenomenon called masked priming It has been debated whether masked primes can activate cognitive processes without gaining access to consciousness Here we use a combination of behavioural and brain-imaging techniques to estimate the depth of processing of masked numerical primes Our results indicate that masked stimuli have a measurable influence on electrical and haemodynamic measures of brain activity When subjects engage in an overt semantic comparison task with a clearly visible target numeral, measures of covert motor activity indicate that they also unconsciously apply the task instructions to an unseen masked numeral A stream of perceptual, semantic and motor processes can therefore occur without awareness
TL;DR: It is shown that the PPARα and PPARγ forms are expressed in differentiated human monocyte-derived macrophages, which participate in inflammation control and atherosclerotic plaque formation and demonstrate a novel function of PPAR in human macrophage with likely consequences in inflammation and Atherosclerosis.
TL;DR: It is shown that feedback connections facilitate responses to objects moving within the classical receptive field; enhance suppression evoked by background stimuli in the surrounding region; and have the strongest effects for stimuli of low salience.
Abstract: A single visual stimulus activates neurons in many different cortical areas. A major challenge in cortical physiology is to understand how the neural activity in these numerous active zones leads to a unified percept of the visual scene. The anatomical basis for these interactions is the dense network of connections that link the visual areas. Within this network, feedforward connections transmit signals from lower-order areas such as V1 or V2 to higher-order areas. In addition, there is a dense web of feedback connections which, despite their anatomical prominence1,2,3,4, remain functionally mysterious5,6,7,8. Here we show, using reversible inactivation of a higher-order area (monkey area V5/MT), that feedback connections serve to amplify and focus activity of neurons in lower-order areas, and that they are important in the differentiation of figure from ground, particularly in the case of stimuli of low visibility. More specifically, we show that feedback connections facilitate responses to objects moving within the classical receptive field; enhance suppression evoked by background stimuli in the surrounding region; and have the strongest effects for stimuli of low salience.
TL;DR: The most difficult items to translate were physical functioning items, which used examples of activities and distances that are not common outside of the United States; items that used colloquial expressions such as pep or blue; and the social functioning items.
TL;DR: The positive effect found for both sensorimotor and more cognitive spatial functions suggests that they share or depend on a common level of space representation linked to multisensory integration.
Abstract: A large proportion of right-hemisphere stroke patients show hemispatial neglect-a neurological deficit of perception, attention, representation, and/or performing actions within their left-sided space, inducing many functional debilitating effects on everyday life, and responsible for poor functional recovery and ability to benefit from treatment. The frequent parietal locus of the lesion producing neglect reflects the impairment of coordinate transformation used by the nervous system to represent extrapersonal space. Given that adaptation to a visual distortion can provide an efficient way to stimulate neural structures responsible for the transformation of sensorimotor coordinates, the aim of our study was to investigate the effect of prism adaptation on various neglect symptoms, including the pathological shift of the subjective midline to the right. All patients exposed to the optical shift of the visual field to the right were improved on their manual body-midline demonstration and on classical neuropsychological tests. Unlike other physiological manipulations used to improve neglect, this improvement lasted for at least two hours after prism removal and thus could be useful in rehabilitation programmes. The positive effect found for both sensorimotor and more cognitive spatial functions suggests that they share or depend on a common level of space representation linked to multisensory integration.
TL;DR: The concomitant identification and functional analysis of co-regulators (transcriptional intermediary factors [TIFs], comprising co-activators and co-repressors) previously predicted from squelching studies have deepened this understanding.
Journal Article•
TL;DR: It is demonstrated that AOPP act as a mediator of oxidative stress and monocyte respiratory burst, which points to monocytes as both target and actor in the immune dysregulation associated with chronic uremia.
Abstract: We previously demonstrated the presence of advanced oxidation protein products (AOPP), a novel marker of oxidative stress in the plasma of uremic patients receiving maintenance dialysis. The present study in a cohort of 162 uremic patients showed that plasma concentrations of AOPP increased with progression of chronic renal failure and were closely related to advanced glycation end products (AGE)-pentosidine (r = 0.52, p < 0.001), taken as a marker of AGE. In vivo, the relevance of AOPP and AGE-pentosidine in monocyte-mediated inflammatory syndrome associated with uremia was evidenced by close correlations between AOPP or AGE-pentosidine and monocyte activation markers, including neopterin, IL-1R antagonist, TNF-alpha, and TNF soluble receptors (TNF-sR55 and TNF-sR75). To determine the mechanisms by which AOPP and AGE could be directly involved in monocyte activation, AOPP-human serum albumin (HSA) and AGE-HSA were produced in vitro by treating HSA with oxidants or glucose, respectively. Spectroscopic analysis confirmed that AOPP-HSA contains carbonyls and dityrosine. Both AOPP-HSA and AGE-HSA, but not purified dityrosine, were capable of triggering the oxidative burst of human monocytes in cultures. The AOPP-HSA-induced respiratory burst was dependent on the chlorinated nature of the oxidant and on the molar ratio HSA/HOCI. Collectively, these data first demonstrate that AOPP act as a mediator of oxidative stress and monocyte respiratory burst, which points to monocytes as both target and actor in the immune dysregulation associated with chronic uremia.
TL;DR: Sustained γ-band activity during the rehearsal of the first stimulus representation in short-term memory peaked at both occipitotemporal and frontal electrodes, and fits with the idea of a synchronized cortical network centered on prefrontal and ventral visual areas.
Abstract: It has been hypothesized that visual objects could be represented in the brain by a distributed cell assembly synchronized on an oscillatory mode in the γ-band (20–80 Hz). If this hypothesis is correct, then oscillatory γ-band activity should appear in any task requiring the activation of an object representation, and in particular when an object representation is held active in short-term memory: sustained γ-band activity is thus expected during the delay of a delayed-matching-to-sample task. EEG was recorded while subjects performed such a task. Induced (e.g., appearing with a jitter in latency from one trial to the next) γ-band activity was observed during the delay. In a control task, in which no memorization was required, this activity disappeared. Furthermore, this γ-band activity during the rehearsal of the first stimulus representation in short-term memory peaked at both occipitotemporal and frontal electrodes. This topography fits with the idea of a synchronized cortical network centered on prefrontal and ventral visual areas. Activities in the α band, in the 15–20 Hz band, and in the averaged evoked potential were also analyzed. The γ-band activity during the delay can be distinguished from all of these other components of the response, on the basis of either its variations or its topography. It thus seems to be a specific functional component of the response that could correspond to the rehearsal of an object representation in short-term memory.
TL;DR: The number domain is a prime example where strong evidence points to an evolutionary endowment of abstract domain-specific knowledge in the brain because there are parallels between number processing in animals and humans.
TL;DR: It is shown that patients from four families with WS4 have mutations in SOx10, whereas no mutation could be detected in patients with HSCR alone, and this point to an essential role ofSOx10 in the development of two neural crest-derived human cell lineages.
Abstract: Waardenburg syndrome (WS; deafness with pigmentary abnormalities) and Hirschsprung's disease (HSCR; aganglionic megacolon) are congenital disorders caused by defective function of the embryonic neural crest. WS and HSCR are associated in patients with Waardenburg-Shah syndrome (WS4), whose symptoms are reminiscent of the white coat-spotting and aganglionic megacolon displayed by the mouse mutants Dom (Dominant megacolon), piebald-lethal (sl) and lethal spotting (ls). The sl and ls phenotypes are caused by mutations in the genes encoding the Endothelin-B receptor (Ednrb) and Endothelin 3 (Edn3), respectively. The identification of Sox10 as the gene mutated in Dom mice (B.H. et al., manuscript submitted) prompted us to analyse the role of its human homologue SOX10 in neural crest defects. Here we show that patients from four families with WS4 have mutations in SOX10, whereas no mutation could be detected in patients with HSCR alone. These mutations are likely to result in haploinsufficiency of the SOX10 product. Our findings further define the locus heterogeneity of Waardenburg-Hirschsprung syndromes, and point to an essential role of SOX10 in the development of two neural crest-derived human cell lineages.
TL;DR: Analysis of muscle biopsies from two patients carrying Paraplegin mutations showed typical signs of mitochondrial OXPHOS defects, thus suggesting a mechanism for neurodegeneration in HSP-type disorders.
TL;DR: It is concluded that polymers but not cationic lipids promote gene delivery from the cytoplasm to the nucleus and that transgene expression in the nucleus is prevented by complexation with cationIC lipids but not with cATIONic polymers.
TL;DR: The complete disorganization observed in lissencephaly and heterotopia seems to reflect a failure of early events associated with neuron dispersion.
TL;DR: Pathological expansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filament inclusions in nuclei to cause autosomal recessive OPMD.
Abstract: Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease with a world-wide distribution. It usually presents in the sixth decade with progressive swallowing difficulties (dysphagia), eyelid drooping (ptosis) and proximal limb weakness. Unique nuclear filament inclusions in skeletal muscle fibres are its pathological hallmark. We isolated the poly(A) binding protein 2 gene (PABP2) from a 217-kb candidate interval on chromosome 14q11 (B.B. et al., manuscript submitted). A (GCG)6 repeat encoding a polyalanine tract located at the N terminus of the protein was expanded to (GCG)8-13 in the 144 OPMD families screened. More severe phenotypes were observed in compound heterozygotes for the (GCG)9 mutation and a (GCG)7 allele that is found in 2% of the population, whereas homozygosity for the (GCG)7 allele leads to autosomal recessive OPMD. Thus the (GCG)7 allele is an example of a polymorphism which can act either as a modifier of a dominant phenotype or as a recessive mutation. Pathological expansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filament inclusions in nuclei.
University College London1, French Institute of Health and Medical Research2, University of Liverpool3, University of Edinburgh4, Netherlands Cancer Institute5, University of Pennsylvania6, University of Melbourne7, University of Cambridge8, Western General Hospital9, University of St Andrews10, University of Aberdeen11, International Agency for Research on Cancer12, University of Utah13, Trinity College, Dublin14, Curie Institute15, St James's University Hospital16, Leiden University17
TL;DR: Key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCa2 genes are identified and this information may improve the classification of breast cancer in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.
Abstract: BACKGROUND: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. METHODS: Specimens of tumor tissue (5-microm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. RESULTS: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. CONCLUSIONS: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.