Showing papers by "University of Gothenburg published in 2014"

Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence

Abstract: Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent. Methods We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling. Results Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow–biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones. Conclusions Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers. (Funded by the National Human Genome Research Institute and others.)

Global diversity and geography of soil fungi

Abstract: Fungi play major roles in ecosystem processes, but the determinants of fungal diversity and biogeographic patterns remain poorly understood. Using DNA metabarcoding data from hundreds of globally distributed soil samples, we demonstrate that fungal richness is decoupled from plant diversity. The plant-to-fungus richness ratio declines exponentially toward the poles. Climatic factors, followed by edaphic and spatial variables, constitute the best predictors of fungal richness and community composition at the global scale. Fungi show similar latitudinal diversity gradients to other organisms, with several notable exceptions. These findings advance our understanding of global fungal diversity patterns and permit integration of fungi into a general macroecological framework.

Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles.

Abstract: Secreted membrane-enclosed vesicles, collectively called extracellular vesicles (EVs), which include exosomes, ectosomes, microvesicles, microparticles, apoptotic bodies and other EV subsets, encompass a very rapidly growing scientific field in biology and medicine. Importantly, it is currently technically challenging to obtain a totally pure EV fraction free from non-vesicular components for functional studies, and therefore there is a need to establish guidelines for analyses of these vesicles and reporting of scientific studies on EV biology. Here, the International Society for Extracellular Vesicles (ISEV) provides researchers with a minimal set of biochemical, biophysical and functional standards that should be used to attribute any specific biological cargo or functions to EVs.

Personal and social factors that influence pro-environmental concern and behaviour: a review

Abstract: We review the personal and social influences on pro-environmental concern and behaviour, with an emphasis on recent research. The number of these influences suggests that understanding pro-environmental concern and behaviour is far more complex than previously thought. The influences are grouped into 18 personal and social factors. The personal factors include childhood experience, knowledge and education, personality and self-construal, sense of control, values, political and world views, goals, felt responsibility, cognitive biases, place attachment, age, gender and chosen activities. The social factors include religion, urban-rural differences, norms, social class, proximity to problematic environmental sites and cultural and ethnic variations We also recognize that pro-environmental behaviour often is undertaken based on none of the above influences, but because individuals have non-environmental goals such as to save money or to improve their health. Finally, environmental outcomes that are a result of these influences undoubtedly are determined by combinations of the 18 categories. Therefore, a primary goal of researchers now should be to learn more about how these many influences moderate and mediate one another to determine pro-environmental behaviour.

The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system

Abstract: The gastrointestinal tract is covered by mucus that has different properties in the stomach, small intestine, and colon. The large highly glycosylated gel-forming mucins MUC2 and MUC5AC are the major components of the mucus in the intestine and stomach, respectively. In the small intestine, mucus limits the number of bacteria that can reach the epithelium and the Peyer's patches. In the large intestine, the inner mucus layer separates the commensal bacteria from the host epithelium. The outer colonic mucus layer is the natural habitat for the commensal bacteria. The intestinal goblet cells secrete not only the MUC2 mucin but also a number of typical mucus components: CLCA1, FCGBP, AGR2, ZG16, and TFF3. The goblet cells have recently been shown to have a novel gate-keeping role for the presentation of oral antigens to the immune system. Goblet cells deliver small intestinal luminal material to the lamina propria dendritic cells of the tolerogenic CD103+ type. In addition to the gel-forming mucins, the transmembrane mucins MUC3, MUC12, and MUC17 form the enterocyte glycocalyx that can reach about a micrometer out from the brush border. The MUC17 mucin can shuttle from a surface to an intracellular vesicle localization, suggesting that enterocytes might control and report epithelial microbial challenge. There is communication not only from the epithelial cells to the immune system but also in the opposite direction. One example of this is IL10 that can affect and improve the properties of the inner colonic mucus layer. The mucus and epithelial cells of the gastrointestinal tract are the primary gate keepers and controllers of bacterial interactions with the host immune system, but our understanding of this relationship is still in its infancy.

Association of Bariatric Surgery With Long-term Remission of Type 2 Diabetes and With Microvascular and Macrovascular Complications

Abstract: Importance Short-term studies show that bariatric surgery causes remission of diabetes. The long-term outcomes for remission and diabetes-related complications are not known. Objectives To determine the long-term diabetes remission rates and the cumulative incidence of microvascular and macrovascular diabetes complications after bariatric surgery. Design, Setting, and Participants The Swedish Obese Subjects (SOS) is a prospective matched cohort study conducted at 25 surgical departments and 480 primary health care centers in Sweden. Of patients recruited between September 1, 1987, and January 31, 2001, 260 of 2037 control patients and 343 of 2010 surgery patients had type 2 diabetes at baseline. For the current analysis, diabetes status was determined at SOS health examinations until May 22, 2013. Information on diabetes complications was obtained from national health registers until December 31, 2012. Participation rates at the 2-, 10-, and 15-year examinations were 81%, 58%, and 41% in the control group and 90%, 76%, and 47% in the surgery group. For diabetes assessment, the median follow-up time was 10 years (interquartile range [IQR], 2-15) and 10 years (IQR, 10-15) in the control and surgery groups, respectively. For diabetes complications, the median follow-up time was 17.6 years (IQR, 14.2-19.8) and 18.1 years (IQR, 15.2-21.1) in the control and surgery groups, respectively. Interventions Adjustable or nonadjustable banding (n = 61), vertical banded gastroplasty (n = 227), or gastric bypass (n = 55) procedures were performed in the surgery group, and usual obesity and diabetes care was provided to the control group. Main Outcomes and Measures Diabetes remission, relapse, and diabetes complications. Remission was defined as blood glucose Results The diabetes remission rate 2 years after surgery was 16.4% (95% CI, 11.7%-22.2%; 34/207) for control patients and 72.3% (95% CI, 66.9%-77.2%; 219/303) for bariatric surgery patients (odds ratio [OR], 13.3; 95% CI, 8.5-20.7; P P P P = .001). Conclusions and Relevance In this very long-term follow-up observational study of obese patients with type 2 diabetes, bariatric surgery was associated with more frequent diabetes remission and fewer complications than usual care. These findings require confirmation in randomized trials. Trial Registration clinicaltrials.gov Identifier:NCT01479452

Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

Abstract: Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

FXR is a molecular target for the effects of vertical sleeve gastrectomy

Abstract: Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targets for therapeutic intervention. Substantial changes in circulating total bile acids are known to occur after VSG. Moreover, bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4). We therefore examined the results of VSG surgery applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signalling as an important molecular underpinning for the beneficial effects of this weight-loss surgery. Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are the most effective therapy for the treatment of obesity; now bile acids, and the presence of the nuclear bile acid receptor FXR, are shown to underpin the mechanism of VSG action, and the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced if FXR is absent. The use and misuse of invasive surgery to control obesity and related conditions is much debated. Whatever its merits, the associated costs and risks mean that it is inappropriate in many cases. This study challenges the notion that such surgery elicits weight loss solely by making it physically difficult to consume or absorb calories, and raises the prospect that it may be possible to develop therapies that achieve the same ends without the need for a scalpel. Vertical sleeve gastrectomy (VSG), in which some 80% of the stomach is removed to create a gastric 'sleeve' contiguous with the oesophagus and duodenum, is known to induce loss of body weight and fat mass, and improves glucose tolerance in humans and rodents. Randy Seeley and colleagues show here that the therapeutic effect of VSG in mice arises not from the mechanical restrictions of a smaller stomach but from the associated increase in the levels of circulating bile acids and changes to gut microbial communities. Moreover, in the absence of nuclear bile acid receptor FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced.

Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis

Abstract: Objective The inner mucus layer in mouse colon normally separates bacteria from the epithelium. Do humans have a similar inner mucus layer and are defects in this mucus layer a common denominator for spontaneous colitis in mice models and ulcerative colitis (UC)? Methods and results The colon mucus layer from mice deficient in Muc2 mucin, Core 1 O -glycans, Tlr5, interleukin 10 (IL-10) and Slc9a3 (Nhe3) together with that from dextran sodium sulfate-treated mice was immunostained for Muc2, and bacterial localisation in the mucus was analysed. All murine colitis models revealed bacteria in contact with the epithelium. Additional analysis of the less inflamed IL-10 −/− mice revealed a thicker mucus layer than wild-type, but the properties were different, as the inner mucus layer could be penetrated both by bacteria in vivo and by fluorescent beads the size of bacteria ex vivo. Clear separation between bacteria or fluorescent beads and the epithelium mediated by the inner mucus layer was also evident in normal human sigmoid colon biopsy samples. In contrast, mucus on colon biopsy specimens from patients with UC with acute inflammation was highly penetrable. Most patients with UC in remission had an impenetrable mucus layer similar to that of controls. Conclusions Normal human sigmoid colon has an inner mucus layer that is impenetrable to bacteria. The colon mucus in animal models that spontaneously develop colitis and in patients with active UC allows bacteria to penetrate and reach the epithelium. Thus colon mucus properties can be modulated, and this suggests a novel model of UC pathophysiology.

The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data

Abstract: The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.

Antioxidants accelerate lung cancer progression in mice.

Abstract: Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. We show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by disrupting the ROS-p53 axis. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production.

Astrocyte Reactivity and Reactive Astrogliosis: Costs and Benefits

Abstract: Astrocytes are the most abundant cells in the central nervous system (CNS) that provide nutrients, recycle neurotransmitters, as well as fulfill a wide range of other homeostasis maintaining functions During the past two decades, astrocytes emerged also as increasingly important regulators of neuronal functions including the generation of new nerve cells and structural as well as functional synapse remodeling Reactive gliosis or reactive astrogliosis is a term coined for the morphological and functional changes seen in astroglial cells/astrocytes responding to CNS injury and other neurological diseases Whereas this defensive reaction of astrocytes is conceivably aimed at handling the acute stress, limiting tissue damage, and restoring homeostasis, it may also inhibit adaptive neural plasticity mechanisms underlying recovery of function Understanding the multifaceted roles of astrocytes in the healthy and diseased CNS will undoubtedly contribute to the development of treatment strategies that will, in a context-dependent manner and at appropriate time points, modulate reactive astrogliosis to promote brain repair and reduce the neurological impairment

Cardiovascular Risk and Events in 17 Low-, Middle-, and High-Income Countries

Abstract: The mean INTERHEART Risk Score was highest in high-income countries, intermediate in middle-income countries, and lowest in low-income countries (P<0.001). However, the rates of major cardiovascular events (death from cardiovascular causes, myocardial infarction, stroke, or heart failure) were lower in high-income countries than in middle- and low-income countries (3.99 events per 1000 personyears vs. 5.38 and 6.43 events per 1000 person-years, respectively; P<0.001). Case fatality rates were also lowest in high-income countries (6.5%, 15.9%, and 17.3% in high-, middle-, and low-income countries, respectively; P = 0.01). Urban communities had a higher risk-factor burden than rural communities but lower rates of cardiovascular events (4.83 vs. 6.25 events per 1000 person-years, P<0.001) and case fatality rates (13.52% vs. 17.25%, P<0.001). The use of preventive medications and revascularization procedures was significantly more common in high-income countries than in middle- or low-income countries (P<0.001). CONCLUSIONS Although the risk-factor burden was lowest in low-income countries, the rates of major cardiovascular disease and death were substantially higher in low-income countries than in high-income countries. The high burden of risk factors in highincome countries may have been mitigated by better control of risk factors and more frequent use of proven pharmacologic therapies and revascularization. (Funded by the Population Health Research Institute and others.)

Olfactory Disorders and Quality of Life—An Updated Review

Abstract: Olfactory disorders are common and affect about one-fifth of the general population. The main causes of olfactory loss are post viral upper respiratory infection, nasal/sinus disease, and head trauma and are therefore very frequent among patients in ear, nose, and throat clinics. We have systematically reviewed the impact of quantitative, qualitative, and congenital olfactory disorders on daily life domains as well as on general quality of life and depression. From the extensive body of literature, it can be concluded that loss of the sense of smell leads to disturbances in important areas, mainly in food enjoyment, detecting harmful food and smoke, and to some extent in social situations and working life. Most patients seem to deal well and manage those restrictions. However, a smaller proportion has considerable problems and expresses a noticeable reduction in general quality of life and enhanced depression. The impact of coping strategies is discussed.

Surface area of the digestive tract – revisited

Abstract: Background. According to textbooks, the human gut mucosa measures 260–300 m2, that is, in the order of a tennis court. However, the quantitative data are incomplete and sometimes conflicting. Objectives. To review the literature regarding the mucosal surface area of the human digestive tract; to collect morphometric data from the parts of the gut where such data are missing; and to recalculate the mucosal surface area of the intestine in man. Methods. With focus on the intestine, we carried out morphometry by light and electron microscopy on biopsies from healthy adult volunteers or patients with endoscopically normal mucosae. Results. Literature review of intubation or radiological methods indicates an oroanal length of ∼5 m, two-third of which refers to the small intestine. However, there is a considerable variation between individuals. The inner diameter of the small intestine averages 2.5 cm and that of the large intestine averages 4.8 cm. The mucosa of the small intestine is enlarged ∼1.6 ti...

Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans

Abstract: Brown adipose tissue (BAT) has attracted scientific interest as an antidiabetic tissue owing to its ability to dissipate energy as heat Despite a plethora of data concerning the role of BAT in glucose metabolism in rodents, the role of BAT (if any) in glucose metabolism in humans remains unclear To investigate whether BAT activation alters whole-body glucose homeostasis and insulin sensitivity in humans, we studied seven BAT-positive (BAT+) men and five BAT-negative (BAT−) men under thermoneutral conditions and after prolonged (5–8 h) cold exposure (CE) The two groups were similar in age, BMI, and adiposity CE significantly increased resting energy expenditure, whole-body glucose disposal, plasma glucose oxidation, and insulin sensitivity in the BAT+ group only These results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose homeostasis, and insulin sensitivity in humans, and support the notion that BAT may function as an antidiabetic tissue in humans

Skillful long‐range prediction of European and North American winters

Abstract: This work was supported by the Joint DECC/Defra Met Office Hadley Centre Climate Programme (GA01101), the UK Public Weather Service research program, and the European Union Framework 7 SPECS project. Leon Hermanson was funded as part of his Research Fellowship by Willis as part of Willis Research Network (WRN).

Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity

Abstract: Alcohol dependence has traditionally been considered a brain disorder. Alteration in the composition of the gut microbiota has recently been shown to be present in psychiatric disorders, which suggests the possibility of gut-to-brain interactions in the development of alcohol dependence. The aim of the present study was to explore whether changes in gut permeability are linked to gut-microbiota composition and activity in alcohol-dependent subjects. We also investigated whether gut dysfunction is associated with the psychological symptoms of alcohol dependence. Finally, we tested the reversibility of the biological and behavioral parameters after a short-term detoxification program. We found that some, but not all, alcohol-dependent subjects developed gut leakiness, which was associated with higher scores of depression, anxiety, and alcohol craving after 3 wk of abstinence, which may be important psychological factors of relapse. Moreover, subjects with increased gut permeability also had altered composition and activity of the gut microbiota. These results suggest the existence of a gut-brain axis in alcohol dependence, which implicates the gut microbiota as an actor in the gut barrier and in behavioral disorders. Thus, the gut microbiota seems to be a previously unidentified target in the management of alcohol dependence.

Diagnostic criteria for vascular cognitive disorders: a VASCOG statement.

Abstract: Author(s): Sachdev, Perminder; Kalaria, Raj; O'Brien, John; Skoog, Ingmar; Alladi, Suvarna; Black, Sandra E; Blacker, Deborah; Blazer, Dan G; Chen, Christopher; Chui, Helena; Ganguli, Mary; Jellinger, Kurt; Jeste, Dilip V; Pasquier, Florence; Paulsen, Jane; Prins, Niels; Rockwood, Kenneth; Roman, Gustavo; Scheltens, Philip; Internationlal Society for Vascular Behavioral and Cognitive Disorders | Abstract: BackgroundSeveral sets of diagnostic criteria have been published for vascular dementia since the 1960s. The continuing ambiguity in vascular dementia definition warrants a critical reexamination.MethodsParticipants at a special symposium of the International Society for Vascular Behavioral and Cognitive Disorders (VASCOG) in 2009 critiqued the current criteria. They drafted a proposal for a new set of criteria, later reviewed through multiple drafts by the group, including additional experts and the members of the Neurocognitive Disorders Work Group of the fifth revision of Diagnostic and Statistical Manual (DSM-5) Task Force.ResultsCognitive disorders of vascular etiology are a heterogeneous group of disorders with diverse pathologies and clinical manifestations, discussed broadly under the rubric of vascular cognitive disorders (VCD). The continuum of vascular cognitive impairment is recognized by the categories of Mild Vascular Cognitive Disorder, and Vascular Dementia or Major Vascular Cognitive Disorder. Diagnostic thresholds are defined. Clinical and neuroimaging criteria are proposed for establishing vascular etiology. Subtypes of VCD are described, and the frequent cooccurrence of Alzheimer disease pathology emphasized.ConclusionsThe proposed criteria for VCD provide a coherent approach to the diagnosis of this diverse group of disorders, with a view to stimulating clinical and pathologic validation studies. These criteria can be harmonized with the DSM-5 criteria such that an international consensus on the criteria for VCD may be achieved.

Impacts of invasive alien marine species on ecosystem services and biodiversity: a pan-European review.

Abstract: Stelios Katsanevakis*, Inger Wallentinus, Argyro Zenetos, Erkki Leppakoski, Melih Ertan Cinar, Bayram Ozturk, Michal Grabowski, Daniel Golani and Ana Cristina Cardoso European Commission, Joint Research Centre (JRC), Institute for Environment and Sustainability (IES), Ispra, Italy Department of Biological and Environmental Sciences, University of Gothenburg, Sweden Institute of Marine Biological Resources and Inland Waters, Hellenic Centre for Marine Research, Ag. Kosmas, Greece Department of Biosciences, Environmental and Marine Biology, Abo Akademi University, Turku, Finland Ege University, Faculty of Fisheries, Department of Hydrobiology, Bornova, Izmir, Turkey Faculty of Fisheries, Marine Biology Laboratory, University of Istanbul, Istanbul, Turkey Department of Invertebrate Zoology & Hydrobiology, University of Lodz, Poland Department of Ecology, Evolution and Behavior and the National Natural History Collections, The Hebrew University of Jerusalem, Israel

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments

Abstract: SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.