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Morris Brown and colleagues identify somatic mutations in ATP1A1 and CACNA1D in aldosterone-producing adenomas with features resembling zonaglomerulosa cells. They further show that the ATP1A1 mutations cause inward leak currents under physiological conditions, whereas the CACNA1D mutations induce a shift of voltage-dependent gating to more negative potentials and suppress channel inactivation. At least 5% of individuals with hypertension have adrenal aldosterone-producing adenomas (APAs). Gain-of-function mutations in KCNJ5 and apparent loss-of-function mutations in ATP1A1 and ATP2A3 were reported to occur in APAs 1 , 2 . We find that KCNJ5 mutations are common in APAs resembling cortisol-secreting cells of the adrenal zona fasciculata but are absent in a subset of APAs resembling the aldosterone-secreting cells of the adrenal zona glomerulosa 3 . We performed exome sequencing of ten zona glomerulosa–like APAs and identified nine with somatic mutations in either ATP1A1 , encoding the Na + /K + ATPase α1 subunit, or CACNA1D , encoding Ca v 1.3. The ATP1A1 mutations all caused inward leak currents under physiological conditions, and the CACNA1D mutations induced a shift of voltage-dependent gating to more negative voltages, suppressed inactivation or increased currents. Many APAs with these mutations were <1 cm in diameter and had been overlooked on conventional adrenal imaging. Recognition of the distinct genotype and phenotype for this subset of APAs could facilitate diagnosis.

Craniofrontonasal syndrome (CFNS) is an X-linked developmental disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Females have frontonasal dysplasia and coronal craniosynostosis (fusion of the coronal sutures); in males, hypertelorism is the only typical manifestation. Here, we show that the classical female CFNS phenotype is caused by heterozygous loss-of-function mutations in EFNB1, which encodes a member of the ephrin family of transmembrane ligands for Eph receptor tyrosine kinases. In mice, the orthologous Efnb1 gene is expressed in the frontonasal neural crest and demarcates the position of the future coronal suture. Although EFNB1 is X-inactivated, we did not observe markedly skewed X-inactivation in either blood or cranial periosteum from females with CFNS, indicating that lack of ephrin-B1 does not compromise cell viability in these tissues. We propose that in heterozygous females, patchwork loss of ephrin-B1 disturbs tissue boundary formation at the developing coronal suture, whereas in males deficient in ephrin-B1, an alternative mechanism maintains the normal boundary. This is the only known mutation in the ephrin/Eph receptor signaling system in humans and provides clues to the biogenesis of craniosynostosis.

Tourette syndrome (TS) is a neuropsychiatric disorder with a strong genetic component. However, the genetic architecture of TS remains uncertain. Copy number variation (CNV) has been shown to contribute to the genetic make-up of several neurodevelopmental conditions, including schizophrenia and autism. Here we describe CNV calls using SNP chip genotype data from an initial sample of 210 TS cases and 285 controls ascertained in two Latin American populations. After extensive quality control, we found that cases (N = 179) have a significant excess (P = 0.006) of large CNV (>500 kb) calls compared to controls (N = 234). Amongst 24 large CNVs seen only in the cases, we observed four duplications of the COL8A1 gene region. We also found two cases with ∼400 kb deletions involving NRXN1, a gene previously implicated in neurodevelopmental disorders, including TS. Follow-up using multiplex ligation-dependent probe amplification (and including 53 more TS cases) validated the CNV calls and identified additional patients with rearrangements in COL8A1 and NRXN1, but none in controls. Examination of available parents indicates that two out of three NRXN1 deletions detected in the TS cases are de-novo mutations. Our results are consistent with the proposal that rare CNVs play a role in TS aetiology and suggest a possible role for rearrangements in the COL8A1 and NRXN1 gene regions.

Sadaf Farooqi, Inês Barroso and colleagues report genome-wide SNP and CNV association analyses for severe obesity in children, selected at the extreme of the distribution for body mass index. They identify four loci newly associated with severe obesity, an enrichment of rare CNVs in severely obese cases and overlap in the loci associated with severe obesity in children and with BMI and obesity in the general population. Common and rare variants associated with body mass index (BMI) and obesity account for <5% of the variance in BMI. We performed SNP and copy number variation (CNV) association analyses in 1,509 children with obesity at the extreme tail (>3 s.d. from the mean) of the BMI distribution and 5,380 controls. Evaluation of 29 SNPs ( P < 1 × 10 −5 ) in an additional 971 severely obese children and 1,990 controls identified 4 new loci associated with severe obesity ( LEPR , PRKCH , PACS1 and RMST ). A previously reported 43-kb deletion at the NEGR1 locus was significantly associated with severe obesity ( P = 6.6 × 10 −7 ). However, this signal was entirely driven by a flanking 8-kb deletion; absence of this deletion increased risk for obesity ( P = 6.1 × 10 −11 ). We found a significant burden of rare, single CNVs in severely obese cases ( P < 0.0001). Integrative gene network pathway analysis of rare deletions indicated enrichment of genes affecting G protein–coupled receptors (GPCRs) involved in the neuronal regulation of energy homeostasis.

Genetic link to obesity Obesity is a highly heritable disorder but the genetic associations reported to date account for only a small percentage of the inherited variation in body mass index. Two groups report deletions on chromosome16p11.2 that may explain part of the 'missing heritability' in terms of 'high-penetrance' mutations that are rare but when present are very often associated with severe obesity. This is in contrast to more common gene defects that are less closely associated with clinical symptoms. Bochukova et al . identified rare recurrent copy number variants in 300 patients with severe early-onset obesity, caused by deletions involving several genes including SH2B1 , known to be involved in leptin and insulin signalling. Many of the patients also suffered neurodevelopmental disorders. Walters et al . identified deletions of at least 593 kilobases on chromosome 16p11.2 in 31 patients with a previously unrecognized type of extreme obesity. The strategy they used to identify the lesion — using small well-phenotyped cohorts of extreme phenotypes with targeted follow-up in genome-wide association studies and population cohorts — shows promise as a means of identifying 'missing heritability' in complex metabolic diseases more generally. The contribution of copy number variation to obesity — a highly heritable and genetically heterogeneous disorder — is investigated in 300 Caucasian patients to reveal that large, rare deletions are significantly enriched in patients compared to controls. Several rare copy number variants are identified that are recurrent in patients but absent or at much lower prevalence in controls. Obesity is a highly heritable and genetically heterogeneous disorder 1 . Here we investigated the contribution of copy number variation to obesity in 300 Caucasian patients with severe early-onset obesity, 143 of whom also had developmental delay. Large (>500 kilobases), rare (<1%) deletions were significantly enriched in patients compared to 7,366 controls ( P  < 0.001). We identified several rare copy number variants that were recurrent in patients but absent or at much lower prevalence in controls. We identified five patients with overlapping deletions on chromosome 16p11.2 that were found in 2 out of 7,366 controls ( P  < 5 × 10 -5 ). In three patients the deletion co-segregated with severe obesity. Two patients harboured a larger de novo 16p11.2 deletion, extending through a 593-kilobase region previously associated with autism 2 , 3 , 4 and mental retardation 5 ; both of these patients had mild developmental delay in addition to severe obesity. In an independent sample of 1,062 patients with severe obesity alone, the smaller 16p11.2 deletion was found in an additional two patients. All 16p11.2 deletions encompass several genes but include SH2B1 , which is known to be involved in leptin and insulin signalling 6 . Deletion carriers exhibited hyperphagia and severe insulin resistance disproportionate for the degree of obesity. We show that copy number variation contributes significantly to the genetic architecture of human obesity.

Src homology 2 B adapter protein 1 (SH2B1) modulates signaling by a variety of ligands that bind to receptor tyrosine kinases or JAK-associated cytokine receptors, including leptin, insulin, growth hormone (GH), and nerve growth factor (NGF). Targeted deletion of Sh2b1 in mice results in increased food intake, obesity, and insulin resistance, with an intermediate phenotype seen in heterozygous null mice on a high-fat diet. We identified SH2B1 loss-of-function mutations in a large cohort of patients with severe early-onset obesity. Mutation carriers exhibited hyperphagia, childhood-onset obesity, disproportionate insulin resistance, and reduced final height as adults. Unexpectedly, mutation carriers exhibited a spectrum of behavioral abnormalities that were not reported in controls, including social isolation and aggression. We conclude that SH2B1 plays a critical role in the control of human food intake and body weight and is implicated in maladaptive human behavior.

Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of SRC-1 in Pomc neurons in mice attenuates their depolarization by leptin, decreases Pomc expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in SRC-1 found in severely obese individuals impair leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function human variant (SRC-1 L1376P ), leptin-induced depolarization of Pomc neurons and Pomc expression are significantly reduced, and food intake and body weight are increased. In summary, we demonstrate that SRC-1 modulates the function of hypothalamic Pomc neurons, and suggest that targeting SRC-1 may represent a useful therapeutic strategy for weight loss. Neurons expressing pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here the authors show that Steroid Receptor Coactivator-1 (SRC-1) regulates the function of Pomc expressing neurons, and that rare heterozygous variants found in obese individuals lead to loss of SRC-1 function.

Single-minded 1 (SIM1) is a basic helix-loop-helix transcription factor involved in the development and function of the paraventricular nucleus of the hypothalamus. Obesity has been reported in Sim1 haploinsufficient mice and in a patient with a balanced translocation disrupting SIM1. We sequenced the coding region of SIM1 in 2,100 patients with severe, early onset obesity and in 1,680 controls. Thirteen different heterozygous variants in SIM1 were identified in 28 unrelated severely obese patients. Nine of the 13 variants significantly reduced the ability of SIM1 to activate a SIM1-responsive reporter gene when studied in stably transfected cells coexpressing the heterodimeric partners of SIM1 (ARNT or ARNT2). SIM1 variants with reduced activity cosegregated with obesity in extended family studies with variable penetrance. We studied the phenotype of patients carrying variants that exhibited reduced activity in vitro. Variant carriers exhibited increased ad libitum food intake at a test meal, normal basal metabolic rate, and evidence of autonomic dysfunction. Eleven of the 13 probands had evidence of a neurobehavioral phenotype. The phenotypic similarities between patients with SIM1 deficiency and melanocortin 4 receptor (MC4R) deficiency suggest that some of the effects of SIM1 deficiency on energy homeostasis are mediated by altered melanocortin signaling.

BackgroundCraniosynostosis can be caused by both genetic and environmental factors, the relative contributions of which vary between patients. Genetic testing identifies a pathogenic mutation or chromosomal abnormality in ∼21% of cases, but it is likely that further causative mutations remain to be discovered.ObjectiveTo identify a shared signature of genetically determined craniosynostosis by comparing the expression patterns in three monogenic syndromes with a control group of patients with non-syndromic sagittal synostosis.MethodsFibroblasts from 10 individuals each with Apert syndrome (FGFR2 substitution S252W), Muenke syndrome (FGFR3 substitution P250R), Saethre–Chotzen syndrome (various mutations in TWIST1) and non-syndromic sagittal synostosis (no mutation detected) were cultured. The relative expression of ∼47 000 transcripts was quantified on Affymetrix arrays.Results435, 45 and 46 transcripts were identified in the Apert, Muenke and Saethre–Chotzen groups, respectively, that differed significantly from the controls. Forty-six of these transcripts were shared between two or more syndromes and, in all but one instance, showed the same direction of altered expression level compared with controls. Pathway analysis showed over-representation of the shared transcripts in core modules involving cell-to-cell communication and signal transduction. Individual samples from the Apert syndrome cases could be reliably distinguished from non-syndromic samples based on the gene expression profile, but this was not possible for samples from patients with Muenke and Saethre–Chotzen syndromes.ConclusionsCommon modules of altered gene expression shared by genetically distinct forms of craniosynostosis were identified. Although the expression profiles cannot currently be used to classify individual patients, this may be overcome by using more sensitive assays and sampling additional tissues.

Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS , which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1 , BBS9 , GNAS , MKKS , CLOCK and ANGPTL6 . The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10 −3 ), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.