Introduction

Autoinflammatory disorders are multisystem periodic fever syndromes, and characterized with recurrent unprovoked inflammation of the serosal membranes. Unlike autoimmune disorders, autoinflammatory disorders lack the production of high-titer autoantibodies or antigen-specific T cells. These diseases primarily include hereditary syndromes (Table 1) Familial Mediterrenean fever (FMF), TNF receptor-associated periodic fever syndrome (TRAPS), hyperimmunoglobulinaemia D and periodic fever syndrome...

NBCel mutations and migraine

It has been known that pH in the brain shows rapid changes in response to electrical activity. These changes in local pH may have an important influence on neurobiological responses by modifying numerous enzymes, ion channels, transporters, and receptors 19 . Among several acid base transporters expressed in the brain, NBCe1 is intensively expressed in olfactory bulb, hippocampal dentate gyrus, and cerebellum, localizing in both glial cells and neurons 56 . Although a large number of...

Mutations in the LDLR gene

Mutations involving a small number of nucleotides, from point mutations to small deletions or insertions, account for 90 of all mutations in the LDLR gene, while the remaining are major rearrangements due to unequal recombination between the 30 Alu sequences identified throughout the gene (Hobbs et al. 1990). To date, more than 1400 point mutations and small deletions or insertions associated with FH have been reported in the LDLR gene (http www.ucl.ac.uk fh and www.umd.be LDLR ). The UMD-LDLR...

Genotypephenotype correlation in ASD

The presence of genetic and phenotypic heterogeneity in autism with a number of underlying pathogenic mechanisms is highlighted in this current review. There are at least three phenotypic presentations with distinct genetic underpinnings (1) autism with syndromic phenotype characterized by rare, single-gene defects (Table 2) (2) broad autistic phenotypes caused by genetic variations in single or multiple genes, each of these variations being common and distributed continually in the general...

Missense Mutation in ARCGD

Additional information is available at the end of the chapter http dx.doi.org 10.5772 35758 Chronic granulomatous disease (CGD) is an inherited disorder of the innate immune system characterized by impairment of intracellular microbicidal activity of phagocytes. Mutations in one of four known nicotinamide adenine dinucleotide phosphate (NADPH) -oxidase components preclude generation of superoxide and related antimicrobial oxidants, leading to the phenotype of CGD. Defects in gp91-phox, encoded...

Activating mutations and targeted therapies

Recent advances in molecular oncology and discoveries in genetic alterations have yielded new treatment strategies that target specific molecules and pathways in the cancer cell and thereby shed light on personalized therapy. In the past, treatment decisions were based on pathologic results. Now, diagnostic or therapeutic decisions are often also based on genetics genomic alterations. Currently, the genomic view effectively guides cancer treatment decisions and predicts therapeutic response....

NBCel mutations and pRTA

Until now, 12 homozygous mutations in NBCe1 have been identified in pRTA patients associated with ocular abnormalities as shown in Figure 2 3-11 . Figure 2. NBCe1 topology and pRTA-related mutations. Numbers in circles correspond to Q29X, R298S, S427L, T485S, G486R, R510H, W516X, L522P, N721TfsX29, A799V, R881C, and S982NfsX4. White numbers in black circles indicate mutations associated with migraine. Figure 2. NBCe1 topology and pRTA-related mutations. Numbers in circles correspond to Q29X,...

Fj

Brachydactyly type Al Brachydactyly type A2 Brachydactyly type C Du Pan syndrome Grebe syndrome Hunter-Thompson syndrome* Osteoarthritis susceptibility proximal Symphalangism 1 Multiple synostosis syndrome 1 Multiple synostosis syndrome 2** Figure 8. Localization of GDF5 mutations. Arrowheads indicate the location of all currently known mutations linked to human skeletal malformation diseases affecting the limb. The specific inherited disease caused by each mutation is displayed in the legend...

Results

We found that M694V accounted for the majority of FMF chromosomes (44 ), followed by E148Q (19 ), V726A (10 ), M680I (10 ), P369S (4 ), R408Q (3 ), K695R (2 ), M694I and R761H (1.6 ), A744S (1.4 ), and F479L (0.09 ) (Tables 2, 3). Missense disease-causing mutations and synonymous polymorphisms accounted for 38 and 54 of MEFV chromosomes, respectively. Among the Turkish general population, the most frequent healthy heterozygous carrier mutation was found E148Q (6.9 ), and the carrier rate was...

Phenotypes of NBCe1deficient mice

Two types of NBCe1-deficient mice, NBCe1 KO and W516X knockin (KI) mice, have been produced 11,14 . Both types of mice show severe acidosis and early lethality. Thus, NBCe1 KO mice exhibited severe metabolic acidosis (blood HCO3- concentration of 5.3 mM), growth retardation, hyperaldosteronism, anemia and splenomegaly, abnormal enamel mineralization, intestinal obstruction, and early death before weaning. Splenomegaly might be due to hemolytic anemia due to severe acidemia. The white pulp and...

Missense mutations

The Swiss-pdb Viewer 3.1 program ( 57 , available on http www.expasy.org spdbv ) was used to calculate atomic resolution structural models for SAR1b having missense mutations (Table 3). First, using the 1F6B model 53 and PDB for Cricetulus griseus SAR1b (which lacks the first twelve AA and the 48-55 residues), two residues were modified (I80V, V163I) in order to produce a structural module having a sequence identical to that of human SAR1b. The effects of the missense mutations of AD CMRD on...

Molecularly targeted therapies in lung cancer

Molecularly targeted drugs are directed against abnormal proteins and other molecules, specific for cancer cells, participating in metabolic pathways. Excess activation of those pathways is essential for growth and unrestrained proliferation of cancer cells. Blocking these pathways results in inhibition of cell division and in cell apoptosis. Therefore, molecularly targeted drugs show high efficacy in two groups of patients 1. if the mutation of the gene encoding a signalling pathway protein...

References

Ang SO, Chen H, HirotaK et al Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 2002 32 614-621. Ayerbes VM, Gallego AG, Prado DS, Fonseca JP, Campelo G R, Aparicio ALM. Origin of renal cell carcinomas. Clin Transl Oncol. 2008 Nov 10(11) 697-712. Bender BU, Gutsche M, Glasker S, et al. Differential genetic alterations in von Hippel-Lindau syndrome-associated and sporadic pheochromocytomas. J Clin Endocrinol Metab 2000 85 4568-4574. Beroud C, Joly D, Gallou C,...

Classifications anatomy and clinical significance

Congenital heart disease encompasses a broad category of anatomic malformations, which can range from a small septal defect or leaky valve to a severe malformation requiring extensive surgical repair or leading to death such as a single ventricle. Several classification systems exist for describing congenital heart disease. The most common classification used to describe CHD is purely clinical whereby CHD is cyanotic if the malformation results in deoxygenated blood bypassing the lung and...

Epigenetics plays an important role in autism

In addition to structural genetic factors that play causative roles for autism, environmental factors also play an important role in autism by influencing fetal or early postnatal brain development, directly or via epigenetic modifications. Epigenetic modifications include cytosine methylation, post-translational modification of histones, small interfering RNA and genomic imprinting. Involvement of epigenetic factors in autism is demonstrated by the central role of epigenetic regulatory...

Types of mutations

Oncogenesis results from mutations or alterations of genes that regulate cell functions such as proliferation, growth, invasion, angiogenesis, metastasis, death, energy metabolism, genome stability, and replication. Simple mutations can be induced in DNA by exposure to a variety of mutagens, such as radiation and chemicals, or by spontaneous errors in DNA replication and repair. Genes with mutations that cause cancer can be grouped into two classes oncogenes and tumor suppressor genes....

Syndromic congenital heart disease

Cardiac malformations are among the most prevalent malformations in congenital syndromes. A large list of syndromes with congenital heart disease as a common manifestation has known genetic defects. CHD syndromes can be either due chromosome dosage disorders, large chromosomal deletions, small micro-deletions, or single gene defects. Table 2 shows a list of CHD syndromes within each of these categories with the corresponding genetic defect. This section will discuss the most common syndromes...

Cancer and the two hits of Knudsons hypothesis

Before proceeding into missense mutation in tumor suppressor gene we ought to introduce the two hits of Knudson's hypothesis. Alfred Knudson Jr in 1971 published his inspiring statistical analysis of the childhood cancer retinoblastoma where he found that retinoblastoma tend to be multifocal in familial cases and unifocal in sporadic presentation (Knudson A. G. Jr, 1971). Knudson postulated that patients with the familial form of the cancer would be born with one mutant allele and that all...

Mutation prediction Mut Pred

In light of the above observations on the wide variety of consequences of a single mutation, we developed a large range of features for each variant and employed a popular machine learning technique, random forest, to distinguish disease-associated mutations from neutral ones. We called the model MutPred 42 . In a supervised learning scenario, we collected two sets of disease-associated mutations. One set came from the HGMD 3 , in which 95 percent of mutations were annotated to monogenic...

Nonsyndromic congenital heart disease

Isolated congenital heart disease is the most prevalent form of CHD. Evidence for the genetic basis of isolated CHD comes from familial clustering of cases as well as higher recurrence rate of CHD. Mutations in many genes have been associated with several CHD phenotypes, yet the evidence is variable for each gene. Gene mutations can best be classified as highly penetrant mutations in disease-causing genes, low-penetrance mutations in susceptibility genes, and common variants in CHD risk-genes....