Six novel rare non-synonymous mutations for migraine without aura identified by exome sequencing

Abstract

Migraine without aura (MWO) is the most common among migraine group, and is mainly associated with genetic, physical and chemical factors, and hormonal changes. We aimed to identify novel non-synonymous mutations predisposing to the susceptibility to MWO in a Chinese sample using exome sequencing. Four patients with MWO from a family and four non-migraine subjects unrelated with these patients were genotyped using whole-exome sequencing. Bioinformatics analysis was used to screen possible susceptibility gene mutations, which were then verified by PCR. In four patients with MWO, six novel rare non-synonymous mutations were observed, including EDA2R (G170A), UBE2NL (T266G), GBP2 (A907G), EMR1 (C264G), CLCNKB (A1225G), and ARHGAP28 (C413G). It is worth stressing that GBP2 (A907G) was absent in any control subject. Multiple genes predispose to the susceptibility to MWO. ARHGAP28-, EMR1-, and GBP2-encoded proteins may affect angiokinesis, which supports vasogenic theory for the etiological hypothesis of this disease. CLCNKB-encoded protein may affect cell membrane potential, which is consistent with the cortical spreading depression theory. UBE2NL-encoded protein may regulate cellular responses to 5-hydroxytryptamine, which is in accordance with trigeminovascular reflex theory. EDA2R and UBE2NL are located on the X chromosome, which supports that this disease may have gender differences in genetic predisposition. Replication in larger sample size would significantly strengthen these findings.     

Can one stop nucleic acid sampling (OSNA) predict nodal positivity following neoadjuvant chemotherapy? A prospective cohort study of 293 patients

Until recently, axillary node clearance had long been the standard of care in patients with axillary node-positive disease. One stop nucleic acid sampling (OSNA) has been used to guide intraoperative decision-making regarding suitability for axillary node clearance (ANC). The aim of this study is to evaluate the use of OSNA following neoadjuvant chemotherapy (NACT) and whether it can predict lymph node burden in ANC. A single center, prospective cohort study was performed on 297 patients having OSNA between 2016 and 2019. Patients were sub-classified according to node positivity at diagnosis and those treated with NACT and outcomes included copy number and lymph node harvest. Axillary complete pathological response was observed in 24/36 patients (67%) following NACT. 14/16 patients (87%) having axillary node clearance had axillary node disease limited to 4 nodes. OSNA copy numbers were significantly higher in patients showing disease progression following NACT. Overall, 73% of patients with lymph node positivity at diagnosis could be successfully treated with a combination of NACT and lymph node excision of four nodes. De-escalating axillary surgical treatment to resection of four nodes following NACT may be effective in balancing oncological resection and limiting treatment morbidity. ONSA can correctly identify patients experiencing disease progression who would benefit from traditional three-level ANC.     

Identification of Genetic Causes of Focal Segmental Glomerulosclerosis Increases With Proper Patient Selection

ObjectiveTo increase the likelihood of finding a causative genetic variant in patients with a focal segmental glomerulosclerosis (FSGS) lesion, clinical and histologic characteristics were analyzed.Patients and MethodsIndividuals 18 years and older with an FSGS lesion on kidney biopsy evaluated at Mayo Clinic from November 1, 1999, through October 31, 2019, were divided into 4 groups based on clinical and histologic characteristics: primary FSGS, secondary FSGS with known cause, secondary FSGS without known cause, and undetermined FSGS. A targeted gene panel and a customized gene panel retrieved from exome sequencing were performed.ResultsThe overall rate of detection of a monogenic cause was 42.9% (21/49). Individuals with undetermined FSGS had the highest rate of positivity (87.5%; 7/8) followed by secondary FSGS without an identifiable cause (61.5%; 8/13) and secondary FSGS with known cause (33.3%; 5/15). Four of 5 (80%) individuals in the latter group who had positive genetic testing results also had a family history of kidney disease. Univariate analysis showed that family history of kidney disease (odds ratio [OR], 13.8; 95% CI, 3.7 to 62.4; P<.001), absence of nephrotic syndrome (OR, 8.2; 95% CI, 1.9 to 58.1; P=.004), and female sex (OR, 5.1; 95% CI, 1.5 to 19.9; P=.01) were strong predictors of finding a causative genetic variant in the entire cohort. The most common variants were in the collagen genes (52.4%; 11/21), followed by the podocyte genes (38.1%; 8/21).ConclusionIn adults with FSGS lesions, proper selection of patients increases the rate of positive genetic testing significantly. The majority of individuals with undetermined FSGS in whom the clinical presentation and histologic parameters are discordant had a genetic diagnosis.     

A case of corneal cystinosis in a patient with rickets and chronic renal failure

A 22-year-old man diagnosed with nephropathic cystinosis at the age of 4 years was found to have progressive bilateral corneal crystal deposition. He presented with severe photophobia and decreased visual acuity. Ocular cystinosis was diagnosed on observing the typical crystals. Optical coherence tomography showed multiple areas of stromal hyperreflectivity due to crystal deposits within the corneal stroma. Ex vivo transmission electron microscopy of the cornea showed pathognomonic crystal deposits in corneal stromal keratocytes. Using polymerase chain reaction sequencing of the entire coding region, we identified five gene mutations, including two unreported mutations.     

Crystal structure and functional mapping of human ASMT,the last enzyme of the melatonin synthesis pathway

Abstract: Melatonin is a synchronizer of many physiological processes. Abnormal melatonin signaling is associated with human disorders related to sleep, metabolism, and neurodevelopment. Here, we present the X‐ray crystal structure of human N‐acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. The polypeptide chain of ASMT consists of a C‐terminal domain, which is typical of other SAM‐dependent O‐methyltransferases, and an N‐terminal domain, which intertwines several helices with another monomer to form the physiologically active dimer. Using radioenzymology, we analyzed 20 nonsynonymous variants identified through the 1000 genomes project and in patients with neuropsychiatric disorders. We found that the majority of these mutations reduced or abolished ASMT activity including one relatively frequent polymorphism in the Han Chinese population (N17K, rs17149149). Overall, we estimate that the allelic frequency of ASMT deleterious mutations ranges from 0.66% in Europe to 2.97% in Asia. Mapping of the variants on to the 3‐dimensional structure clarifies why some are harmful and provides a structural basis for understanding melatonin deficiency in humans.     

不同评价方法对介入放射工作人员个人剂量监测结果的影响

结核分枝杆菌（Mycobacterium tuberculosis, MTB）感染人体后，有两种不同的发病类型，即原发性结核病和原发后（继发性）结核病。本文重点回顾近几年结核病发病学的重要进展，包括以肺泡巨噬细胞、脂质体、泡沫巨噬细胞、肉芽肿等为结构特点的原发性结核病，在结核发病过程中所起到的保护性免疫作用，以及结核空洞等继发性结核病所造成的组织破坏性免疫反应，导致MTB释放、逃离并播散。局部组织MTB抗原持续存在与宿主高致敏淋巴细胞游走，是形成结核免疫独具特色koch现象的基础，决定潜伏性MTB感染向活动性结核病的转化。当前MTB潜伏感染人群很大，因此加强筛查仍是结核病防控的首要措施。