Infevers: an evolving mutation database for auto-inflammatory syndromes

The Infevers database (http://fmf.igh.cnrs.fr/infevers/) was established in 2002 to provide investigators with access to a central source of information about all sequence variants associated with periodic fevers: Familial Mediterranean fever (FMF), TNF Receptor Associated Periodic Syndrome (TRAPS), Hyper IgD Syndrome (HIDS), Familial Cold Autoinflammatory Syndrome/Muckle-Wells Syndrome/Chronic Infantile Neurological Cutaneous and Articular Syndrome (FCAS/MWS/CINCA). The prototype of this group of disorders is FMF, a recessive disease characterized by recurrent bouts of unexplained inflammation. FMF is the pivotal member of an expanding family of autoinflammatory disorders, a new term coined to describe illnesses resulting from a defect of the innate immune response. Therefore, we decided to extend the Infevers database to genes connected with autoinflammatory diseases. We present here the biological content of the Infevers database, including the introduction of two new entries: Crohn/Blau and Pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA syndrome). Infevers has a range of query capabilities, allowing for simple or complex interrogation of the database. Currently, the database contains 291 sequence variants in related genes (MEFV, TNFRSF1A, MVK, CARD15, PSTPIP1, and CIAS1), consisting of published data and personal communications, which has revealed or refined the preferential mutational sites for each gene. This database will continue to evolve in its content and to improve in its presentation.     

Bioassays of shortened duration for drugs: statistical implications.

Declining survival rates in rodent carcinogenesis bioassays have raised a concern that continuing the practice of terminating such studies at 24 months could result in too few live animals at termination for adequate pathological evaluation. One option for ensuring sufficient numbers of animals at the terminal sacrifice is to shorten the duration of the bioassay, but this approach is accompanied by a reduction in statistical power for detecting carcinogenic potential. The present study was conducted to evaluate the loss of power associated with early termination. Data from drug studies in rats were used to formulate biologically based dose-response models of carcinogenesis using the 2-stage clonal expansion model as a context. These dose-response models, which were chosen to represent 6 variations of the initiation-promotion-completion cancer model, were employed to generate a large number of representative bioassay data sets using Monte Carlo simulation techniques. For a variety of tumor dose-response trends, tumor lethality, and competing risk-survival rates, the power of age-adjusted statistical tests to assess the significance of carcinogenic potential was evaluated at 18 and 21 months, and compared to the power at the normal 24-month stopping time. The results showed that stopping at 18 months would reduce power to an unacceptable level for all 6 submodels of the 2-stage clonal expansion model, with the pure-promoter and pure-completer models being most adversely affected. For the 21-month stopping time, the results showed that, unless pure promotion can be ruled out a priori as a potential carcinogenic mode of action, the loss of power is too great to warrant early stopping.     

双下肢浅表播散型汗孔角化症一例基因突变检测

目的：检测一例局限于双下肢的散发浅表播散型汗孔角化症患者致病基因突变。方法：提取患者外周血DNA,在Illumina HiSeq测序平台进行全基因组外显子测序,将测序结果与既往报道的汗孔角化症致病基因比对,采用Sanger测序对发现的突变位点在100例患者中进行验证。结果：最终将DSP的致病基因锁定为位于12号染色体的MVK基因,检测到10号内含子c.1040-2A>C突变位点,在全部正常对照中未检测到该位点。经检索,该突变为浅表播散型和播散性浅表性光线型汗孔角化症的共同突变位点。结论：本家系中MVK基因突变位点(c.1040-2A>C)与浅表播散型汗孔角化症发病相关。     

Analysis of retinoblastoma age incidence data using a fully stochastic cancer model

Retinoblastoma (RB) is an important ocular malignancy of childhood. It has been commonly accepted for some time that knockout of the two alleles of the RB1 gene is the principal molecular target associated with the occurrence of RB. In this article, we examine the validity of the two-hit theory for RB by comparing the fit of a stochastic model with two or more mutational stages. Unlike many such models, our model assumes a fully stochastic stem cell compartment, which is crucial to its behavior. Models are fitted to a population-based dataset comprising 1,553 cases of RB for the period 1962-2000 in Great Britain (England, Scotland and Wales). The population incidence of RB is best described by a fully stochastic model with two stages, although models with a deterministic stem cell compartment yield equivalent fit; models with three or more stages fit much less well. The results strongly suggest that knockout of the two alleles of the RB1 gene is necessary and may be largely sufficient for the development of RB, in support of Knudson's two-hit hypothesis.     

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??Mevalonate kinase deficiency??MKD?? is a rare autosomal recessive autoinflammatory disease. There are two phenotypes of MKD based on the degree of the mevalonate kinase??MVK?? deficiency and clinical symptoms??including hyperimmunoglobulinemia D with periodic fever syndrome??HIDS??and mevalonic aciduria??MA??. This article will systematically review the pathogenesis??manifestations??diagnosis??treatment??and prognosis of this rare disease.     

Patient with neonatal-onset chronic hepatitis presenting with mevalonate kinase deficiency with a novel MVK gene mutation

Abstract

A Japanese girl with neonatal-onset chronic hepatitis and systemic inflammation was diagnosed with hyper-immunoglobulinemia D and periodic fever syndrome (HIDS). However, she lacked the typical HIDS features until the age of 32 months. She had compound heterozygous MVK mutations, H380R and A262P, the latter of which was novel. These findings suggest that HIDS patients could lack typical episodes of recurrent fever at the onset and that HIDS should be considered as a possible cause of neonatal-onset chronic hepatitis.     

斑块型汗孔角化症一家系MVK基因突变检测

目的：检测1家系7例中国汉族斑块型汗孔角化症（PM）患者MVK基因上的突变位点。方法：收集家系成员7例患者及3名正常成员的临床资料及血液样本,提取外周血DNA,PCR技术扩增MVK全部外显子及其侧翼序列,并采用Sanger测序法对纯化后的PCR产物进行检测。并将检测结果与既往测得676例健康对照的全部外显子进行对比。结果：在7例患者中检测出突变位点（c.604G>A）,此突变曾在播散性浅表性光化性汗孔角化症（DSAP）患者中报道。正常家系成员及健康对照中未检测到此突变。结论：本家系中MVK基因突变（c.604 G>A）与PM发病有关,且为DSAP与PM的共同突变位点。     

甲羟戊酸激酶缺乏症

甲羟戊酸激酶缺乏症（MKD）是一种罕见的自身炎症性疾病,属常染色体隐性遗传病。根据甲羟戊酸激酶（MVK）活性和临床表现不同,MKD又分高IgD伴周期性发热综合征（HIDS）和甲羟戊酸尿症（MA）两种亚型。文章系统阐述MKD发病机制、临床表现、诊断标准、治疗原则及预后,以提高临床医生对疾病的认识。     

Adaptive changes in renal mitochondrial redox status in diabetic nephropathy

Nephropathy is a serious and common complication of diabetes. In the streptozotocin (STZ)-treated rat model of diabetes, nephropathy does not typically develop until 30 to 45 days post-injection, although hyperglycemia occurs within 24 h. We tested the hypothesis that chronic hyperglycemia results in a modest degree of oxidative stress that is accompanied by compensatory changes in certain antioxidants and mitochondrial redox status. We propose that as kidneys progress to a state of diabetic nephropathy, further adaptations occur in mitochondrial redox status. Basic parameters of renal function in vivo and several parameters of mitochondrial function and glutathione (GSH) and redox status in isolated renal cortical mitochondria from STZ-treated and age-matched control rats were examined at 30 days and 90 days post-injection. While there was no effect of diabetes on blood urea nitrogen, measurement of other, more sensitive parameters, such as urinary albumin and protein, and histopathology showed significant and progressive worsening in diabetic rats. Thus, renal function is compromised even prior to the onset of frank nephropathy. Changes in mitochondrial respiration and enzyme activities indicated existence of a hypermetabolic state. Higher mitochondrial GSH content and rates of GSH transport into mitochondria in kidneys from diabetic rats were only partially due to changes in expression of mitochondrial GSH carriers and were mostly due to higher substrate supply. Although there are few clear indicators of oxidative stress, there are several redox changes that occur early and change further as nephropathy progresses, highlighting the complexity of the disease.     

Detection of a novel missense mutation in the mevalonate kinase gene in one Chinese family with DSAP

Disseminated superficial actinic porokeratosis (DSAP) is the most common form of porokeratosis and a severe chronic autosomal dominant cutaneous disorder with high genetic heterogeneity. Recently, the mevalonate kinase (MVK) gene has been identified as a candidate gene responsible for DSAP and multiple mutations have been reported. Here, we report identification of a novel missense mutation in the MVK gene in a Chinese family with DSAP. A 50-year-old male was diagnosed as proband of DSAP based on the clinical and histological findings, which show numerous hyperpigmented macules by physical examination and cornoid lamella by skin biopsy. Similar skin symptoms were also observed in his father, who died many years ago. We prepared genomic DNA from the proband, unaffected individuals from his family members, as well as 100 unrelated healthy controls. PCR was then conducted using the above genomic DNA as template and the MVK gene-specific primers. The PCR product was subjected to direct sequencing and the sequence was compared to that of MVK gene within the NCBI database. We detected a heterozygous C to G transition at nucleotide 643 in exon 7 of MVK gene of the proband. This will result in an amino acid change at codon 215 (P.Arg215Gly.), which is from an arginine codon (CGA) to a Glycine codon (GGA). We did not detect any mutation in the unaffected family members or the 100 unrelated healthy controls, demonstrating that this is a novel missense mutation in MVK gene and therefore, contributes to the molecular diagnosis of DSAP.