New Mutations (new + mutation)

Distribution by Scientific Domains

Selected Abstracts

New Mutations of EXT1 and EXT2 Genes in German Patients with Multiple Osteochondromas

Wolfram Heinritz
Summary Mutations in either the EXT1 or EXT2 genes lead to Multiple Osteochondromas (MO), an autosomal dominantly inherited disorder. This is a report on clinical findings and results of molecular analyses of both genes in 23 German patients affected by MO. Mutation screening was performed by using denaturing high performance liquid chromatography (dHPLC) and automated sequencing. In 17 of 23 patients novel pathogenic mutations have been identified; eleven in the EXT1 and six in the EXT2 gene. Five patients were carriers of recurrent mutations in the EXT2 gene (p.Asp227Asn, p.Gln172X, p.Gln258X) and one patient had no detectable mutation. To demonstrate their pathogenic effect on transcription, two complex mutations in EXT1 and EXT2 and three splice site mutations were characterized by mRNA investigations. The results obtained provide evidence for different aberrant splice effects , usage of new cryptic splice sites and exon skipping. Our study extends the mutational spectrum and understanding of pathogenic effects of mutations in EXT1 and EXT2. [source]

New mutation of the MPZ gene in a family with the Dejerine,Sottas disease phenotype

MUSCLE AND NERVE, Issue 5 2007
Paraskewi Floroskufi MSc
Abstract Charcot,Marie,Tooth disease type 1B is associated with mutations in the myelin protein zero gene. In the present study a new myelin protein zero gene mutation (c.89T>C,Ile30Thr) was detected in a family with the Dejerine,Sottas disease phenotype. The results support the hypothesis that severe, early-onset neuropathy may be related to either an alteration of a conserved amino acid or a disruption of the tertiary structure of myelin protein zero. Muscle Nerve, 2006 [source]

Smith-Lemli-Opitz syndrome: New mutation with a mild phenotype

Chitra Prasad
Abstract Smith-Lemli-Opitz syndrome (SLOS) (Online Mendelian Inheritance in Man, OMIMÔ, 2001, for SLOS, MIM 270400) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations of the 3,-hydroxysterol ,7 -reductase gene, DHCR7. We report on a female infant with an exceptionally mild phenotype of SLOS, in whom molecular studies identified a new mutation in DHCR7. The proposita initially presented with feeding difficulties, failure to thrive, hypotonia, mild developmental delay, and oral tactile aversion. She had minor facial anomalies and 2,3 syndactyly of her toes in both feet. The plasma cholesterol was borderline low at 2.88 mmol/L (normal 2.97,4.40 mmol/L). Elevated plasma 7-dehydrocholesterol level of 200.0 ,mol/L confirmed the clinical diagnosis of SLOS. Molecular analysis demonstrated compound heterozygosity for IVS8-1G ,C and Y280C, a new missense mutation in DHCR7. Since the other mutation in this patient is a known null mutation, this newly discovered mutation is presumably associated with significant residual enzyme activity and milder expression of clinical phenotype. © 2002 Wiley-Liss, Inc. [source]

New mutations of KIT gene in two Chinese patients with piebaldism

Z-M. Lin
No abstract is available for this article. [source]

Triose phosphate isomerase deficiency associated with two novel mutations in TPI gene

Elisa Fermo
Abstract We report the clinical, haematological and molecular characteristics of two triose phosphate isomerase deficient patients affected by haemolytic anaemia and neuromuscular impairment. The sequence of complete TPI gene showed the presence of two previously undescribed mutations: c.722 T>C (Phe240Ser) and c.28 insG; each of the two unrelated patients showed the new mutation in compound heterozygosity with the most common variant Glu104Asp. The association of Glu104Asp with c.28 insG resulted in a very severe clinical pattern. [source]

Novel point mutation in exon 12 of the glucose-6- Phosphate Dehydrogenase Gene: G6PD Flores

Maria-Odete Rodrigues
Abstract In Portugal there are a wide variety of G6PD deficiency associated mutations. In an individual from the island of Flores of the Azorean archipelago, we report a new mutation in the G6PD gene that gives rise to a "moderate rate of G6PD deficiency" (12.6% of the normal activity) according to WHO criteria. Direct sequencing revealed a C,A point mutation at position 1387 with the consequent substitution of an Argine by Serine. We designated this new mutation as G6PD FLORES. The mutation is associated with haplotype I ( , , + + , , ), using six intragenic RFLPs. This information may also be seen as contributing to the clarification of the genetic makeup of the Azorean population, founder mutations, and/or gene flow. J. Clin. Lab. Anal. 18:129,131, 2004. © 2004 Wiley-Liss, Inc. [source]

Early emergence of raltegravir resistance mutations in patients receiving HAART salvage regimens

Fausto Baldanti
Abstract The emergence of drug-resistance mutations in HIV-1 integrase of patients receiving HAART salvage regimens including raltegravir was investigated in 11 heavily pretreated patients (median number of treatment failures 12, range 5,22) within an expanded access program in Pavia, Italy. HIV-1 RNA levels in plasma, CD4+ T-cell counts and sequencing of HIV-1 reverse transcriptase (RT), protease (PR), gp41, and integrase genes were performed at baseline and after 1, 2, 3, 6, and 12 months. The treatment baseline median HIV-1 RNA levels in plasma decreased from 7,510 (range 118,407,107) to <50,copies/ml (range <50,7,562), while median CD4+ T-cell counts remained unchanged (from 212,cells/µl, range 10,764 to 262,cells/µl, range 13,760). Mutations at positions involved in raltegravir resistance (E92G, G140S, Q148H, and N155H) were detected in 4 of 11 (36.3%) patients as early as 1 month after initiating salvage HAART. Of note, the E,,,G change at codon 92 was not reported previously. In two patients with raltegravir resistance, the simultaneous appearance of additional mutations (Y143R and E170A) with an unclear impact on susceptibility to raltegravir or on integrase activity was observed. It is concluded that raltegravir resistant HIV-1 strains may emerge as early as 1 month after initiating HAART salvage regimens. A new mutation associated with the emergence of raltegravir resistance is described, and the simultaneous appearance of primary and secondary mutations was observed. The effect of single and multiple mutations on integrase activity, raltegravir susceptibility, and on the capacity of viral replication remains to be elucidated. J. Med. Virol. 82:116,122, 2010. © 2009 Wiley-Liss, Inc. [source]

Bullous Congenital Ichthyosiform Erythroderma: A Sporadic Case Produced by a New KRT10 Gene Mutation

We report the case of a girl with typical clinical and histopathologic findings of bullous congenital ichthyosiform erythroderma, who was found to have a new mutation in KRT10 gene, Glu445Lys at position 445, affecting the 2B region of the KRT10 protein, the end of the rod domain, where many other keratin mutations associated with hereditary skin disease have been reported. This new mutation contributes to add to the catalog of bullous congenital ichthyosiform erythroderma mutations known. [source]

Isolated erythrocytosis in V617F negative patients with JAK2 exon 12 mutations: Report of a new mutation

Martina Bernardi
No abstract is available for this article. [source]

Prenatal diagnosis of glycogen storage disease type Ia, presenting a new mutation in the glucose-6-phosphatase gene

Dong-Zhi Li
No abstract is available for this article. [source]

Smith-Lemli-Opitz syndrome: New mutation with a mild phenotype

Chitra Prasad
Abstract Smith-Lemli-Opitz syndrome (SLOS) (Online Mendelian Inheritance in Man, OMIMÔ, 2001, for SLOS, MIM 270400) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations of the 3,-hydroxysterol ,7 -reductase gene, DHCR7. We report on a female infant with an exceptionally mild phenotype of SLOS, in whom molecular studies identified a new mutation in DHCR7. The proposita initially presented with feeding difficulties, failure to thrive, hypotonia, mild developmental delay, and oral tactile aversion. She had minor facial anomalies and 2,3 syndactyly of her toes in both feet. The plasma cholesterol was borderline low at 2.88 mmol/L (normal 2.97,4.40 mmol/L). Elevated plasma 7-dehydrocholesterol level of 200.0 ,mol/L confirmed the clinical diagnosis of SLOS. Molecular analysis demonstrated compound heterozygosity for IVS8-1G ,C and Y280C, a new missense mutation in DHCR7. Since the other mutation in this patient is a known null mutation, this newly discovered mutation is presumably associated with significant residual enzyme activity and milder expression of clinical phenotype. © 2002 Wiley-Liss, Inc. [source]

Mosaicism in Autosomal Dominant Polycystic Kidney Disease Revealed by Genetic Testing to Enable Living Related Renal Transplantation

A. Connor
Patients with end-stage renal disease (ESRD) secondary to autosomal dominant polycystic kidney disease (ADPKD) receive fewer living-related kidney (LRK) transplants than other groups with ESRD. This relates to the difficulties in excluding the disease in potential donors. We report a case which highlights these difficulties and, by discovery of mosaicism for a new mutation, illustrates the role of clinical and molecular genetic resources in assessing young related kidney donors for patients with ADPKD. [source]

A novel mutation in the mitochondrial tRNA for tryptophan causing a late-onset mitochondrial encephalomyopathy

P. S. Sanaker
Sanaker PS, Nakkestad HL, Downham E, Bindoff LA. A novel mutation in the mitochondrial tRNA for tryptophan causing a late-onset mitochondrial encephalomyopathy. Acta Neurol Scand: 2010: 121: 109,113. © 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Background,,, Mitochondrial DNA (mtDNA) mutations are increasingly being recognized as causes of late-onset disease. We report a patient with a late-onset mitochondrial encephalomyopathy caused by a novel G > C transition in mtDNA at position 5556 in the gene encoding the tRNA for tryptophan (MTTW). Aims,,, To investigate the cause of disease and assess the pathogenicity of this new mutation. Methods,,, Clinical, histopathological and gene sequencing studies. Quantification of the mutation was performed in different tissues from the patient and two relatives and in single muscle fibres. Results,,, The mutation was heteroplasmic, segregated in biochemically affected muscle fibres and was absent in blood. The level of mutation in skeletal muscle was higher than in brain, although the brain was clinically the most affected tissue. Discussion,,, The 5556G > C mutation appears sporadic. It was not found in any of the family members tested, although some of them manifested disorders that can be associated with mtDNA disease. In addition to reporting the eighth mutation in MTTW, our case illustrates the challenges posed when assigning pathogenicity to mtDNA mutations. [source]

A new mutation in the linker 12 domain of keratin 5 in a Chinese family with Weber,Cockayne epidermolysis bullosa simplex

J.-G. Li
Summary A previously undescribed missense mutation was detected in the L12 domain of keratin 5 (K5) in a Chinese family with Weber,Cockayne epidermolysis bullosa simplex. Direct sequencing of the PCR products identified a single base substitution (983A,G) that changes the aspartic acid residue at codon 328 to glycine in all affected family members, while no mutation was observed either in the healthy individual or 50 unrelated control samples. Asp328 of K5 is remarkably conserved among all type II keratins. D328G is the fourth mutation found to affect this residue in K5-related epidermolysis bullosa simplex, indicating the importance of Asp328 for K5 structure and the dramatic effect that fine changes can have on keratin intermediate filament integrity. [source]

SDHC mutation in an elderly patient without familial antecedents

Elena López-Jiménez
Summary Head and neck paragangliomas are usually asymptomatic and benign tumours arising mainly from the carotid body and the vagal, tympanic or jugular glomus. The majority of patients develop sporadic masses, and around 30% of cases harbour germline mutations in one of the succinate dehydrogenase genes: SDHB, SDHC or SDHD. In these hereditary cases, the presence of familial antecedents of the disease, multiplicity/bilaterality, young age at onset, and more recently, presence of gastrointestinal stromal tumours, are main factors to be considered. Here we describe a new mutation (c.256,257insTTT) affecting the SDHC gene in a 60-year-old-patient with a single head and neck paraganglioma, and without familial antecedents of the disease. In silico splice site analysis showed that this variant created a cryptic splice acceptor site and loss of heterozygosity (LOH) supported the pathogenic role of the mutation. Control population analyses did not detect this variant but revealed a novel SDHC polymorphism that exhibited a frequency of 0·3% (3/1020). This latter finding highlights the importance of assessing the clinical relevance of variants of unknown significance by means of analysing sufficient controls. Despite having found a germline mutation in an older, apparently sporadic patient, we consider that the high costs of analysing all susceptibility genes related to the disease support the recommendation of screening for mutations only in patients fulfilling the above criteria. [source]

A mitochondrial ATPase 6 mutation is associated with Leigh syndrome in a family and affects proton flow and adenosine triphosphate output when modeled in Escherichia coli

R Carrozzo
A multidisciplinary strategy was used to identify the molecular defect in a family with Leigh syndrome (LS). The propositus presented severe developmental delay, an ataxic-spastic gait and seizures. She died at 3.5 y of age from cardiorespiratory arrest. Postmortem examination disclosed pathological features typical of LS. A 12-y-old sister is affected with the same disease. Respiratory chain enzyme complex activities in skeletal muscle biopsy were normal. Adenosine triphosphate (ATP) synthesis during oxidative phosphorylation in skin fibroblasts mitochondria showed a severely hampered ATP production. Mitochondrial DNA sequencing revealed a new mutation in the ATPase 6 gene (T9176G). Site-directed mutagenesis in Escherichia coli strains was used to measure H+ pumping and ATP synthesis. Results were comparable to findings obtained in human cells. These data corroborate the use of E. coli strains as a feasible "animal" model for functional studies in pathogenic mutations of the ATPase 6 gene. [source]

A new approach to long QT syndrome mutation detection by Sequenom MassARRAY® system

Catarina Allegue
Abstract Congenital long QT syndrome is an inherited cardiac disorder characterized by a prolonged QT interval and polymorphic ventricular arrhythmias that could result in recurrent syncope, seizures or sudden death as the most dramatic event. Until now QT interval mutations have been described in 12 genes, where the majority of mutations reside in three genes KCNQ1, KCNH2, and SCN5A. Diagnosis and prognosis are directly related with the gene and mutation involved. We have developed a diagnostic approach for long QT syndrome and Brugada syndrome based on published mutations and Sequenom MassArray® system. Three diagnostic tests have been developed, oriented to each of the three most prevalent genes in the long QT syndrome. A total of 433 mutations are analyzed in 38 multiplex reactions, allowing their detection in about 48,h. Tests were validated on 502 samples from individuals with different clinical conditions and family history. The average call rates obtained for each of the tests were 93, 83, and 73% in KCNQ1, KCNH2, and SCNA, respectively. Sequenom MassARRAY mutation detection is a reliable, highly flexible, and cost-efficient alternative to conventional methods for genetic testing in long QT syndrome and Brugada syndrome, facilitating flexible upgrades of the version of the test presented here with the inclusion of new mutations. [source]


EVOLUTION, Issue 11 2009
John Novembre
Estimating dispersal distances from population genetic data provides an important alternative to logistically taxing methods for directly observing dispersal. Although methods for estimating dispersal rates between a modest number of discrete demes are well developed, methods of inference applicable to "isolation-by-distance" models are much less established. Here, we present a method for estimating ,,2, the product of population density (,) and the variance of the dispersal displacement distribution (,2). The method is based on the assumption that low-frequency alleles are identical by descent. Hence, the extent of geographic clustering of such alleles, relative to their frequency in the population, provides information about ,,2. We show that a novel likelihood-based method can infer this composite parameter with a modest bias in a lattice model of isolation-by-distance. For calculating the likelihood, we use an importance sampling approach to average over the unobserved intraallelic genealogies, where the intraallelic genealogies are modeled as a pure birth process. The approach also leads to a likelihood-ratio test of isotropy of dispersal, that is, whether dispersal distances on two axes are different. We test the performance of our methods using simulations of new mutations in a lattice model and illustrate its use with a dataset from Arabidopsis thaliana. [source]


EVOLUTION, Issue 3 2009
Michael C. Whitlock
Healthy males are likely to have higher mating success than unhealthy males because of differential expression of condition-dependent traits such as mate searching intensity, fighting ability, display vigor, and some types of exaggerated morphological characters. We therefore expect that most new mutations that are deleterious for overall fitness may also be deleterious for male mating success. From this perspective, sexual selection is not limited to influencing those genes directly involved in exaggerated morphological traits but rather affects most, if not all, genes in the genome. If true, sexual selection can be an important force acting to reduce the frequency of deleterious mutations and, as a result, mutation load. We review the literature and find various forms of indirect evidence that sexual selection helps to eliminate deleterious mutations. However, direct evidence is scant, and there are almost no data available to address a key issue: is selection in males stronger than selection in females? In addition, the total effect of sexual selection on mutation load is complicated by possible increases in mutation rate that may be attributable to sexual selection. Finally, sexual selection affects population fitness not only through mutation load but also through sexual conflict, making it difficult to empirically measure how sexual selection affects load. Several lines of enquiry are suggested to better fill large gaps in our understanding of sexual selection and its effect on genetic load. [source]


EVOLUTION, Issue 4 2007
Adam G. Jones
Evolvability is a key characteristic of any evolving system, and the concept of evolvability serves as a unifying theme in a wide range of disciplines related to evolutionary theory. The field of quantitative genetics provides a framework for the exploration of evolvability with the promise to produce insights of global importance. With respect to the quantitative genetics of biological systems, the parameters most relevant to evolvability are the G -matrix, which describes the standing additive genetic variances and covariances for a suite of traits, and the M -matrix, which describes the effects of new mutations on genetic variances and covariances. A population's immediate response to selection is governed by the G -matrix. However, evolvability is also concerned with the ability of mutational processes to produce adaptive variants, and consequently the M -matrix is a crucial quantitative genetic parameter. Here, we explore the evolution of evolvability by using analytical theory and simulation-based models to examine the evolution of the mutational correlation, r,, the key parameter determining the nature of genetic constraints imposed by M. The model uses a diploid, sexually reproducing population of finite size experiencing stabilizing selection on a two-trait phenotype. We assume that the mutational correlation is a third quantitative trait determined by multiple additive loci. An individual's value of the mutational correlation trait determines the correlation between pleiotropic effects of new alleles when they arise in that individual. Our results show that the mutational correlation, despite the fact that it is not involved directly in the specification of an individual's fitness, does evolve in response to selection on the bivariate phenotype. The mutational variance exhibits a weak tendency to evolve to produce alignment of the M -matrix with the adaptive landscape, but is prone to erratic fluctuations as a consequence of genetic drift. The interpretation of this result is that the evolvability of the population is capable of a response to selection, and whether this response results in an increase or decrease in evolvability depends on the way in which the bivariate phenotypic optimum is expected to move. Interestingly, both analytical and simulation results show that the mutational correlation experiences disruptive selection, with local fitness maxima at ,1 and +1. Genetic drift counteracts the tendency for the mutational correlation to persist at these extreme values, however. Our results also show that an evolving M -matrix tends to increase stability of the G -matrix under most circumstances. Previous studies of G -matrix stability, which assume nonevolving M -matrices, consequently may overestimate the level of instability of G relative to what might be expected in natural systems. Overall, our results indicate that evolvability can evolve in natural systems in a way that tends to result in alignment of the G -matrix, the M -matrix, and the adaptive landscape, and that such evolution tends to stabilize the G -matrix over evolutionary time. [source]


EVOLUTION, Issue 2 2005
Christina M. Kavanaugh
Abstract It has been hypothesized that new, spontaneous mutations tend to reduce fitness more severely in more stressful environments. To address this hypothesis, we grew plants representing 20 Arabidopsis thaliana mutationaccumulation (M-A) lines, advanced to generation 17, and their progenitor, in differing light conditions. The experiment was conducted in a greenhouse, and two treatments were used: full sun and shade, in which influx of red light was reduced relative to far-red. The shade treatment was considered the more stressful because mean absolute fitness was lower in that treatment, though not significantly so. Plants from generation 17 of M-A developed significantly faster than those from generation 0 in both treatments. A significant interaction between generation and treatment revealed that, counter to the hypothesis, M-A lines tended to have higher fitness on average relative to the progenitor in the shaded conditions, whereas, in full sun, the two generations were similar in fitness. A secondary objective of this experiment was to characterize the contribution of new mutations to genotype x environment interaction. We did not, however, detect a significant interaction between M-A line and treatment. Plots of the line-specific enviromental responses indicate no tendency of new mutations to contribute to fitness trade-offs between environments. They also do not support a model of conditionally deleterious mutation, in which a mutatn reduces fitness only in a particular environment. These results suggest that interactions between genotype and light environment previously documented for A. thaliana are not explicable primarily as a consequence of steady input of spontaneous mutations having environment-specific effects. [source]


EVOLUTION, Issue 3 2003
Peter D. Keightley
Abstract Analysis of a recent mutation accumulation (MA) experiment has led to the suggestion that as many as one-half of spontaneous mutations in Arabidopsis are advantageous for fitness. We evaluate this in the light of data from other MA experiments, along with molecular evidence, that suggest the vast majority of new mutations are deleterious. [source]


EVOLUTION, Issue 6 2000
Michael C. Whitlock
Abstract With a small effective population size, random genetic drift is more important than selection in determining the fate of new alleles. Small populations therefore accumulate deleterious mutations. Left unchecked, the effect of these fixed alleles is to reduce the reproductive capacity of a species, eventually to the point of extinction. New beneficial mutations, if fixed by selection, can restore some of this lost fitness. This paper derives the overall change in fitness due to fixation of new deleterious and beneficial alleles, as a function of the distribution of effects of new mutations and the effective population size. There is a critical effective size below which a population will on average decline in fitness, but above which beneficial mutations allow the population to persist. With reasonable estimates of the relevant parameters, this critical effective size is likely to be a few hundred. Furthermore, sexual selection can act to reduce the fixation probability of deleterious new mutations and increase the probability of fixing new beneficial mutations. Sexual selection can therefore reduce the risk of extinction of small populations. [source]


EVOLUTION, Issue 4 2000
Larissa L. Vassilieva
Abstract. Spontaneous mutation to mildly deleterious alleles has emerged as a potentially unifying component of a variety of observations in evolutionary genetics and molecular evolution. However, the biological significance of hypotheses based on mildly deleterious mutation depends critically on the rate at which new mutations arise and on their average effects. A long-term mutation-accumulation experiment with replicate lines of the nematode Caenorhabditis elegans maintained by single-progeny descent indicates that recurrent spontaneous mutation causes approximately 0.1% decline in fitness per generation, which is about an order of magnitude less than that suggested by previous studies with Drosophila. Two rather different approaches, Bateman-Mukai and maximum likelihood, suggest that this observation, along with the observed rate of increase in the variance of fitness among lines, is consistent with a genomic deleterious mutation rate for fitness of approximately 0.03 per generation and with an average homozygous effect of approximately 12%. The distribution of mutational effects for fitness appears to have a relatively low coefficient of variation, being no more extreme than expected for a negative exponential, and for one composite fitness measure (total progeny production) approaches constancy of effects. These results are derived from assays in a benign environment. At stressful temperatures, estimates of the genomic deleterious mutation rate (for genes expressed at such temperatures) is sixfold lower, whereas those for the average homozygous effect is approximately eightfold higher. Our results are reasonably compatible with existing estimates for flies, when one considers the differences between these species in the number of germ-line cell divisions per generation and the magnitude of transposable element activity. [source]

ORIGINAL ARTICLE Laboratory science: Spectrum of F8 gene mutations in haemophilia A patients from a region of Italy: identification of 23 new mutations

HAEMOPHILIA, Issue 5 2010
Summary., Haemophilia A (HA) is an X-linked recessive bleeding disorder caused by a lack or decrease of coagulation factor VIII activity. The molecular diagnosis of HA is challenging and a variety of different mutations have been identified throughout the F8 gene. Our aim was to detect the causative mutation in 266 HA patients from Emilia-Romagna region (Italy) and in all suspected carriers. Molecular analysis of F8 in 201 HA patients (152 index cases) was performed with a combination of several indirect and direct molecular approaches, such as long distance polymerase chain reaction, multiplex ligation-dependent probe amplification, denaturing high performance liquid chromatography and direct sequencing. The analysis revealed 78 different mutations, 23 of which were novel, not having been reported in national or international databases. The detection rate was 100%, 86% and 89% in patients with severe, moderate and mild HA, respectively. The information provided by this registry will be helpful for monitoring the treatment of HA patients in Emilia-Romagna and also for reliable genetic counselling of affected families in the future. [source]

Microelectronic DNA chip for hereditary hyperferritinemia cataract syndrome, a model for large-scale analysis of disorders of iron metabolism,

HUMAN MUTATION, Issue 2 2006
Francesca Ferrari
Abstract Hereditary hyperferritinemia cataract syndrome (HHCS) is caused by mutations in the regulatory iron responsive element (IRE) in the 5,UTR of the L-ferritin transcript that reduce binding affinity to the iron regulatory proteins (IRPs) and lead to a constitutive upregulation of the protein in tissue and serum. Twenty-nine mutations have been reported within the L-ferritin (FTL) IRE sequence, 21 of which were available to us. In addition, we included in this study three new mutations. Thus, we analyzed 24 mutations spanning over a DNA stretch of 48 nucleotides, including four deletions 2,29 nucleotides long and 20 substitutions, seven of which were conservative transversions. With this unique experimental model we developed a microchip diagnostic platform for identifying known molecular defects in the L-ferritin IRE structure with a microelectronic array approach, which we optimized after studying the effects of various parameters. The system enables electronic deposition of biotinylated amplicons to selected pads. Under optimized conditions, no cross-hybridization was found, even for mutations that affected the same or adjacent nucleotide positions. The same cartridge could be serially hybridized with all the 24 reporter probe sets, which allowed correct genotyping right up until the end of the analysis. Extensive validation on 200 samples in a blinded fashion gave total concordance of results. This pilot study represents a first step toward developing a diagnostic microchip for large-scale analyses for epidemiological studies and screening of mutations associated with iron disorders. Hum Mutat 27(2), 201,208, 2006. © 2006 Wiley-Liss, Inc. [source]

CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia,

HUMAN MUTATION, Issue 2 2004
Svetlana Pidasheva
Abstract Familial hypocalciuric hypercalcemia (FHH) is caused by heterozygous loss-of-function mutations in the calcium-sensing receptor (CASR), in which the lifelong hypercalcemia is generally asymptomatic. Homozygous loss-of-function CASR mutations manifest as neonatal severe hyperparathyroidism (NSHPT), a rare disorder characterized by extreme hypercalcemia and the bony changes of hyperparathyroidism, which occur in infancy. Activating mutations in the CASR gene have been identified in several families with autosomal dominant hypocalcemia (ADH), autosomal dominant hypoparathyroidism, or hypocalcemic hypercalciuria. Individuals with ADH may have mild hypocalcemia and relatively few symptoms. However, in some cases seizures can occur, especially in younger patients, and these often happen during febrile episodes due to intercurrent infection. Thus far, 112 naturally-occurring mutations in the human CASR gene have been reported, of which 80 are unique and 32 are recurrent. To better understand the mutations causing defects in the CASR gene and to define specific regions relevant for ligand-receptor interaction and other receptor functions, the data on mutations were collected and the information was centralized in the CASRdb (, which is easily and quickly accessible by search engines for retrieval of specific information. The information can be searched by mutation, genotype,phenotype, clinical data, in vitro analyses, and authors of publications describing the mutations. CASRdb is regularly updated for new mutations and it also provides a mutation submission form to ensure up-to-date information. The home page of this database provides links to different web pages that are relevant to the CASR, as well as disease clinical pages, sequence of the CASR gene exons, and position of mutations in the CASR. The CASRdb will help researchers to better understand and analyze the mutations, and aid in structure,function analyses. Hum Mutat 24:107,111, 2004. © 2004 Wiley-Liss, Inc. [source]

Screening of 25 Italian patients with Niemann-Pick a reveals fourteen new mutations, one common and thirteen private, in SMPD1,,

HUMAN MUTATION, Issue 1 2004
V. Ricci
Abstract Niemann-Pick disease (NPD) results from the deficiency of lysosomal acid sphingomyelinase (SMPD1). To date, out of more than 70-disease associated alleles only a few of them have a significant frequency in various ethnic groups. In contrast, the remainder of the mutations are rare or private. In this paper we report the molecular characterization of an Italian series consisting of twenty-five NPD patients with the severe neurodegenerative A phenotype. Mutation detection identified a total of nineteen different mutations, including 14 novel mutations and five previously reported lesions. The known p.P189fs and the novel p.T542fs were the most frequent mutations accounting for 34% and 18% of the alleles, respectively. Screening the alleles for the three common polymorphisms revealed the variant c.1516G>A (exon 6) and the repeat in exon 1, but not the variant c.965C>T (exon 2). In absence of frequent mutations, the prognostic value of genotyping is limited. However, new genotype/phenotype correlations were observed for this disorder that could in the future facilitate genetic counseling and guide selection of patients for therapy. © 2004 Wiley-Liss, Inc. [source]

Peutz,Jeghers syndrome in a 14-year-old boy: case report and review of the literature

Summary., Peutz,Jeghers syndrome (PSJ) is a relatively rare but well-recognized condition, with a prevalence of approximately one in 120 000 births in the USA. It is generally inherited as an autosomal dominant trait, although 35% of cases are new mutations. This disorder is characterized by melanocytic macules on the hands, feet, peri,oral skin and oral mucosa, and multiple gastrointestinal hamartomatous polyps. People with PSJ have an increased risk for developing a variety of malignant tumours. The aim of the present study was to report one case of PSJ in a 14-year-old boy with mucocutaneous pigmentation associated with duodenal hamartomatous polyps. [source]

Simultaneous genotyping to detect myostatin gene polymorphism in beef cattle breeds

M. E. Miranda
Summary The myostatin gene codes for a growth factor involved in muscle development, and polymorphism in this gene can have important economic consequences. Nine mutations affecting the amino-acidic sequence have already been described, six of which are disruptive, inactivating the protein and causing bovine muscular hypertrophy. As the number of known mutations grows, it is necessary to develop a simple, routinely usable technique able to screen individuals in all populations. The oligonucleotide ligation assay (OLA) is proposed here for the rapid genotyping of the nine mutations known affecting the coding sequence in the main breeds of beef cattle. This technique showed its ability to reveal the genotype of individuals being a good tool to determine the frequency of each mutation in a population. The procedure is very flexible as new mutations can be added and removed at any time. Depending on the genotype of each individual, the technique allows breeders to make quick decisions on matings and general selection tendencies. Zusammenfassung Simultane Genotypisierung von Polymorphismen im Myostatin-Gen in Fleischrinderrassen Das Myostatin-Gen kodiert für einen Wachstumsfaktor, der in die Muskelentwicklung eingebunden ist und Polymorphismen in diesem Gen können daher wichtige ökonomische Konsequenzen haben. Bisher wurden neun Mutationen, die Auswirkungen auf die Aminosäuresequenz haben, beschrieben. Sechs davon inaktivieren das Protein und verursachen bovine muskuläre Hypertrophie. Da die Anzahl der bekannten Mutationen in diesem Gen steigt, ist es notwendig, eine einfache, in der Routine einsetzbare Methode zu entwickeln, um Individuen in allen Populationen untersuchen zu können. Zur schnellen Genotypisierung der neun bekannten Mutationen, welche die kodierende Sequenz in den Hauptfleischrinderrassen betreffen, wird hier der Oligo-Ligationsassay (OLA) vorgeschlagen. Durch diese Technik ist es möglich, den Genotyp jedes Individuums und die Frequenz jeder einzelnen Mutation in der Population festzustellen. Die Prozedur ist sehr flexibel, da zu jedem Zeitpunkt neue Mutationen hinzugefügt bzw. weggelassen werden können. Diese Methode erlaubt dem Züchter, in Abhängigkeit vom Genotyp jedes Individiums schnelle Entscheidungen über die Anpaarung und die allgemeine Selektionsrichtung zu treffen. [source]