Autism Spectrum Disorders (ASD) are characterised by social and communication impairment, yet evidence for deficits in the ability to recognise facial expressions of basic emotions is conflicting. ...Many studies reporting no deficits have used stimuli that may be too simple (with associated ceiling effects), for example, 100% ‘full-blown’ expressions. In order to investigate subtle deficits in facial emotion recognition, 21 adolescent males with high-functioning Austism Spectrum Disorders (ASD) and 16 age and IQ matched typically developing control males completed a new sensitive test of facial emotion recognition which uses dynamic stimuli of varying intensities of expressions of the six basic emotions (Emotion Recognition Test; Montagne et al., 2007). Participants with ASD were found to be less accurate at processing the basic emotional expressions of disgust, anger and surprise; disgust recognition was most impaired – at 100% intensity and lower levels, whereas recognition of surprise and anger were intact at 100% but impaired at lower levels of intensity.
Pathogenic variants in BRCA1 or BRCA2 are identified in ∼20% of families with multiple individuals affected by early-onset breast and/or ovarian cancer. Extensive searches for additional highly ...penetrant genes or alternative mutational mechanisms altering BRCA1 or BRCA2 have not explained the missing heritability. Here, we report a dominantly inherited 5′ UTR variant associated with epigenetic BRCA1 silencing due to promoter hypermethylation in two families affected by breast and ovarian cancer. BRCA1 promoter methylation of ten CpG dinucleotides in families who are affected by breast and/or ovarian cancer but do not have germline BRCA1 or BRCA2 pathogenic variants was assessed by pyrosequencing and clonal bisulfite sequencing. RNA and DNA sequencing of BRCA1 from lymphocytes was undertaken to establish allelic expression and the presence of germline variants. BRCA1 promoter hypermethylation was identified in 2 of 49 families in which multiple women are affected by grade 3 breast cancer or high-grade serous ovarian cancer. Soma-wide BRCA1 promoter hypermethylation was confirmed in blood, buccal mucosa, and hair follicles. Pyrosequencing showed that DNA was ∼50% methylated, consistent with the silencing of one allele, which was confirmed by clonal bisulfite sequencing. RNA sequencing revealed the allelic loss of BRCA1 expression in both families and that this loss of expression segregated with the heterozygous variant c.−107A>T in the BRCA1 5′ UTR. Our results establish a mechanism whereby familial breast and ovarian cancer is caused by an in cis 5′ UTR variant associated with epigenetic silencing of the BRCA1 promoter in two independent families. We propose that methylation analyses be undertaken to establish the frequency of this mechanism in families affected by early-onset breast and/or ovarian cancer without a BRCA1 or BRCA2 pathogenic variant.
Meningiomas arise from the arachnoid layer of the meninges that surround the brain and spine. They account for over one third of all primary central nervous system tumors in adults and confer a ...significant risk of location-dependent morbidity due to compression or displacement. A significant increase in risk of meningiomas is associated with neurofibromatosis type 2 (NF2) disease through mutation of the NF2 gene. In addition, approximately 5% of individuals with schwannomatosis disease develop meningiomas, through mutation of the SWI/SNF chromatin remodeling complex subunit, SMARCB1 . Recently, a second SWI/SNF complex subunit, SMARCE1 , was identified as a cause of clear cell meningiomas, indicating a wider role for this complex in meningioma disease. The sonic hedgehog (SHH)-GLI1 signaling pathway gene, SUFU , has also been identified as the cause of hereditary multiple meningiomas in a large Finnish family. The recent identification of somatic mutations in components of the SHH-GLI1 and AKT1-MTOR signaling pathways indicates the potential for cross talk of these pathways in the development of meningiomas. This review describes the known meningioma predisposition genes and their links to the recently identified somatic mutations.
Background.
Schwannomatosis is a recently recognized form of neurofibromatosis characterized by multiple noncutaneous schwannomas, a histologically benign nerve sheath tumor. As more cases are ...identified, the reported phenotype continues to expand and evolve. We describe the spectrum of clinical findings in a cohort of patients meeting established criteria for schwannomatosis.
Methods.
We retrospectively reviewed the clinical records of patients seen at our institution from 1995–2011 who fulfilled either research or clinical criteria for schwannomatosis. Clinical, radiographic, and pathologic data were extracted with attention to age at onset, location of tumors, ophthalmologic evaluation, family history, and other stigmata of neurofibromatosis 1 (NF1) or NF2.
Results.
Eighty‐seven patients met the criteria for the study. The most common presentation was pain unassociated with a mass (46%). Seventy‐seven of 87 (89%) patients had peripheral schwannomas, 49 of 66 (74%) had spinal schwannomas, seven of 77 (9%) had nonvestibular intracranial schwannomas, and four of 77 (5%) had intracranial meningiomas. Three patients were initially diagnosed with a malignant peripheral nerve sheath tumor; however, following pathologic review, the diagnoses were revised in all three cases. Chronic pain was the most common symptom (68%) and usually persisted despite aggressive surgical and medical management. Other common diagnoses included headaches, depression, and anxiety.
Conclusions.
Peripheral and spinal schwannomas are common in schwannomatosis patients. Severe pain is difficult to treat in these patients and often associated with anxiety and depression. These findings support a proactive surveillance plan to identify tumors by magnetic resonance imaging scan in order to optimize surgical treatment and to treat associated pain, anxiety, and depression.
摘要
背景. 神经鞘瘤病是最近认识的一种神经纤维瘤病，其特征为多发性皮肤外神经鞘瘤，即组织学良性的神经鞘膜瘤。随着越来越多的病例被发现，见诸报道的表型仍不断在扩大和演变。本文描述了一个患者队列临床表现的特征谱，这些患者均符合已确立的神经鞘瘤病诊断标准。
方法. 回顾性分析1995 ~ 2011年本研究中心收治的患者临床病历，入组患者满足神经鞘瘤病的研究或临床标准。提取患者的临床、影像学、病理学数据，以及发病时年龄、肿瘤部位、眼科评估、家族史、神经纤维瘤病1型（NF1）或NF2的其他红斑改变。
结果. 87例患者符合研究标准。最常见的临床症状为与病变面积无关的疼痛（46%）。87例患者中有77例（89%）为外周神经鞘瘤，66例中有49例（74%）为脊髓神经鞘瘤，77例中有7例（9%）为非前庭颅内神经鞘瘤，77例中有4例（5%）为颅内脑膜瘤。3例患者最初诊断为恶性外周神经鞘膜瘤；然而，经过病理学审查后，3例患者均修正诊断。慢性疼痛为最常见的症状（68%），通常持续存在且不因手术和内科积极治疗而改变。其他常见诊断包括头痛、抑郁以及焦虑。
结论. 外周与脊髓神经鞘瘤常见于神经鞘瘤病患者。这些患者出现的严重疼痛很难治疗，且常与焦虑和抑郁相关。上述发现支持开展积极主动的监测计划，通过核磁共振成像扫描发现肿瘤，进而优化外科治疗手段并治疗相关的疼痛、焦虑以及抑郁。
The spectrum of clinical findings in a cohort of patients meeting established criteria for schwannomatosis is described.
One-third of all primary central nervous system tumors in adults are meningiomas. Rarely, meningiomas occur at multiple sites, usually occurring in individuals with type 2 neurofibromatosis (NF2). We ...sequenced the exomes of three unrelated individuals with familial multiple spinal meningiomas without NF2 mutations. We identified two individuals with heterozygous loss-of-function mutations in the SWI/SNF chromatin-remodeling complex subunit gene SMARCE1. Sequencing of SMARCE1 in six further individuals with spinal meningiomas identified two additional heterozygous loss-of-function mutations. Tumors from individuals with SMARCE1 mutations were of clear-cell histological subtype, and all had loss of SMARCE1 protein, consistent with a tumor suppressor mechanism. Our findings identify multiple-spinal-meningioma disease as a new discrete entity and establish a key role for the SWI/SNF complex in the pathogenesis of both meningiomas and tumors with clear-cell histology.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Many diseases and disorders are linked to exposure to endocrine disrupting chemicals (EDCs) that mimic the function of natural estrogen hormones. Here we present a Rapid Adaptable Portable In-vitro ...Detection biosensor platform (RAPID) for detecting chemicals that interact with the human estrogen receptor β (hERβ). This biosensor consists of an allosteric fusion protein, which is expressed using cell-free protein synthesis technology and is directly assayed by a colorimetric response. The resultant biosensor successfully detected known EDCs of hERβ (BPA, E2, and DPN) at similar or better detection range than an analogous cell-based biosensor, but in a fraction of time. We also engineered cell-free protein synthesis reactions with RNAse inhibitors to increase production yields in the presence of human blood and urine. The RAPID biosensor successfully detects EDCs in these human samples in the presence of RNAse inhibitors. Engineered cell-free protein synthesis facilitates the use of protein biosensors in complex sample matrices without cumbersome protein purification.
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•Cell-free protein synthesis (CFPS) detection of estrogenic endocrine disruptors•CFPS in blood and urine improved with addition of RNAse inhibitors.•Rapid CFPS detection of the E2 in human blood and urine
Numerous researchers have examined the effects of skin condition, including texture and color, on the perception of health, age, and attractiveness in human faces. They have focused on facial color ...distribution, homogeneity of pigmentation, or skin quality. We here investigate the role of overall skin color in determining perceptions of health from faces by allowing participants to manipulate the skin portions of color-calibrated Caucasian face photographs along CIELab color axes. To enhance healthy appearance, participants increased skin redness (a*), providing additional support for previous findings that skin blood color enhances the healthy appearance of faces. Participants also increased skin yellowness (b*) and lightness (L*), suggesting a role for high carotenoid and low melanin coloration in the healthy appearance of faces. The color preferences described here resemble the red and yellow color cues to health displayed by many species of nonhuman animals.
Schwannomatosis is a rare tumor predisposition syndrome that causes multiple schwannomas. Germline loss‐of‐function (LoF) LZTR1 variants were only recently identified as disease‐causing, so ...relatively few variants have been identified in patients. In addition, many LoF variants exist in Genome Aggregation Database (gnomAD) in people who do not have clinical symptoms of schwannomatosis. These factors, and the incomplete penetrance seen in this condition, hinder definitive interpretation of the clinical significance of novel LoF variants identified in schwannomatosis patients. We collated published LOF LZTR1 variants identified in schwannomatosis patients and classified them according to current American College of Medical Genetics and Genomics/Association for Molecular Pathology/Association of Clinical Genomic Science guidelines. Subsequently, pathogenic/likely pathogenic schwannomatosis‐associated LoF variants were compared with LoF LZTR1 variants reported in gnomAD data. Using current classification guidelines, 64/71 LoF LZTR1 variants reported in schwannomatosis patients in the literature were classified as pathogenic/likely pathogenic, and their frequency in probands 64/359 (17.8%) was significantly higher than the frequency of potential LoF variants identified in the general population (0.36%; p < 0.0001). The majority of published classifications of schwannomatosis‐associated LoF variants are robust. However, the high frequency of LoF LZTR1 variants in the general population suggests that LZTR1 variants confer a reduced risk of schwannomas compared to germline NF2 and SMARCB1 pathogenic variants, making classification of novel variants challenging.
Loss‐of‐function (LoF) LZTR1 variants have been associated with schwannomatosis. However, many LoF LZTR1 variants exist in Genome Aggregation Database (gnomAD) in people who do not have clinical symptoms of schwannomatosis. We show here that LoF LZTR1 variants are strongly enriched in schwannomatosis patients, but the high frequency of LoF LZTR1 variants in gnomAD data suggest a reduced risk of schwannomas in comparison to other schwannoma predisposing genes.
Perrault syndrome is a genetically and clinically heterogeneous autosomal-recessive condition characterized by sensorineural hearing loss and ovarian failure. By a combination of linkage analysis, ...homozygosity mapping, and exome sequencing in three families, we identified mutations in CLPP as the likely cause of this phenotype. In each family, affected individuals were homozygous for a different pathogenic CLPP allele: c.433A>C (p.Thr145Pro), c.440G>C (p.Cys147Ser), or an experimentally demonstrated splice-donor-site mutation, c.270+4A>G. CLPP, a component of a mitochondrial ATP-dependent proteolytic complex, is a highly conserved endopeptidase encoded by CLPP and forms an element of the evolutionarily ancient mitochondrial unfolded-protein response (UPRmt) stress signaling pathway. Crystal-structure modeling suggests that both substitutions would alter the structure of the CLPP barrel chamber that captures unfolded proteins and exposes them to proteolysis. Together with the previous identification of mutations in HARS2, encoding mitochondrial histidyl-tRNA synthetase, mutations in CLPP expose dysfunction of mitochondrial protein homeostasis as a cause of Perrault syndrome.
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