			Home About us Contact

Mutated Alleles (mutated + allele)

Distribution by Scientific Domains

Medical Sciences	58%
Life Sciences	41%

Distribution within Medical Sciences

Pharmacology & Pharmaceutical Medicine	39%
Neurology	18%

Selected Abstracts

Caucasian patients with type 2 diabetes mellitus have elevated levels of monocyte chemoattractant protein-1 that are not influenced by the ,2518 A,G promoter polymorphism

DIABETES OBESITY & METABOLISM, Issue 5 2005
B. Zietz
Aim:, To investigate the association of serum levels and the ,2518 A,G promoter polymorphism of the gene for chemokine monocyte chemoattractant protein-1 (MCP-1), a major chemoattractant of monocytes and activated lymphocytes, with metabolic parameters as well as insulin, leptin and the cytokines tumour necrosis factor-, (TNF-,) and interleukin-6 (IL-6) in 534 Caucasian patients with type 2 diabetes mellitus. Methods:, MCP-1 concentrations were measured by enzyme-linked immunosorbent assay. MCP-1 genotyping was performed by RFLP analysis in a subset of 426 patients. Results:, Two hundred and thirty-one (54.2%) patients were homozygous for the wildtype allele (AA), 156 (36.6%) were heterozygous (AG) and 39 (9.2%) were homozygous for the mutated allele (GG). Allelic frequency was similar to non-diabetic populations (wildtype allele A: 0.73; mutated allele G: 0.27). MCP-1 mean concentrations and percentiles were substantially higher in non-diabetic populations but were not influenced by the genotype (AA: 662.0 ± 323.0 pg/ml; AG: 730.6 ± 491.4 pg/ml; GG: 641.2 ± 323.8 pg/ml). MCP-1 serum levels and genotypes were only marginally related to hormones (insulin and leptin) and cytokines (TNF-, and IL-6). Conclusions:, This is the first study providing MCP-1 levels, percentiles and genotype frequency in a large and representative cohort of patients with type 2 diabetes mellitus. Compared to the literature, MCP-1 levels were found to be substantially higher in patients with type 2 diabetes mellitus. In contrast, genotype frequencies were similar compared to those in non-diabetic patients and were not related to MCP-1 levels. The mechanisms behind these elevated MCP-1 serum levels in type 2 diabetes are not to be explained by simple associations with hormones, cytokines or genotypes. [source]

Allelic imbalance of expression and epigenetic regulation within the alpha-synuclein wild-type and p.Ala53Thr alleles in Parkinson disease,

HUMAN MUTATION, Issue 6 2010
Gerassimos E. Voutsinas
Abstract Genetic alterations in the alpha-synuclein (SNCA) gene have been implicated in Parkinson Disease (PD), including point mutations, gene multiplications, and sequence variations within the promoter. Such alterations may be involved in pathology through structural changes or overexpression of the protein leading to protein aggregation, as well as through impaired gene expression. It is, therefore, of importance to specify the parameters that regulate SNCA expression in its normal and mutated state. We studied the expression of SNCA alleles in a lymphoblastoid cell line and in the blood cells of a patient heterozygous for p.Ala53Thr, the first mutation to be implicated in PD pathogenesis. Here, we provide evidence that: (1) SNCA shows monoallelic expression in this patient, (2) epigenetic silencing of the mutated allele involves histone modifications but not DNA methylation, and (3) steady-state mRNA levels deriving from the normal SNCA allele in this patient exceed those of the two normal SNCA alleles combined, in matching, control individuals. An imbalanced SNCA expression in this patient is thus documented, with silencing of the p.Ala53Thr allele and upregulation of the wild-type-allele. This phenomenon is demonstrated for a first time in the SNCA gene, and may have important implications for PD pathogenesis. Hum Mutat 31:1,7, 2010. © 2010 Wiley-Liss, Inc. [source]

Gs, Mutations in Fibrous Dysplasia and McCune-Albright Syndrome,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue S2 2006
Lee S Weinstein
Abstract Fibrous dysplasia (FD) is a focal bone lesion composed of immature mesenchymal osteoblastic precursor cells. Some FD patients also have hyperpigmented skin lesions (café-au-lait spots), gonadotropin-independent sexual precocity, and/or other endocrine and nonendocrine manifestations (McCune-Albright syndrome [MAS]). MAS results from somatic mutations occurring during early development, resulting in a widespread mosaic of normal and mutant-bearing cells, which predicts that the clinical presentation of each patient is determined by the extent and distribution of abnormal cells. These mutations encode constitutively active forms of Gs,, the ubiquitously expressed G protein ,-subunit that couples hormone receptors to intracellular cAMP generation. These mutations lead to substitution of amino acid residues that are critical for the intrinsic GTPase activity that is normally required to deactivate the G protein. This leads to prolonged activation of Gs, and its downstream effectors even with minimal receptor activation. This explains why MAS patients have stimulation of multiple peripheral endocrine glands in the absence of circulating stimulatory pituitary hormones and increased skin pigment, which is normally induced by melanocyte-stimulating hormone through Gs,/cAMP. Similar mutations are also present in 40% of pituitary tumors in acromegaly patients and less commonly in other endocrine tumors. FD results from increased cAMP in bone marrow stromal cells, leading to increased proliferation and abnormal differentiation. Parental origin of the mutated allele may also affect the clinical presentation, because Gs, is imprinted and expressed only from the maternal allele in some tissues (e.g., pituitary somatotrophs). [source]

Metabolism of Desipramine in Japanese Psychiatric Patients: The Impact of CYP2D6 Genotype on the Hydroxylation of Desipramine

BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2000
Kazutaka Shimoda
We investigated the impact of the genotype of CYP2D6 on the hydroxylation of desipramine in eighteen patients who were administered desipramine hydrochloride per os. Significantly higher plasma concentration of desipramine/daily dose of desipramine/body weight was observed in the subjects with two mutated alleles than in the subjects with either no mutated alleles or one mutated allele (two mutated alleles versus no mutated alleles=530.4±215.2 versus 118.1±63.9 ng/ml/mg/kg, t=5.68, P<0.001; two mutated alleles versus one mutated allele=530.4±215.2 versus 176.2±62.3 ng/ml/mg/kg, P<0.001; One-way analysis of variance followed by Bonferroni's multiple comparison test, respectively). Significantly higher ratio of desipramine/2-hydroxy-desipramine was observed in the subjects with two mutated alleles compared to subjects with no mutated alleles or the subjects with one mutated allele (two mutated alleles versus one mutated allele=4.39±0.36 versus 2.00±0.64, t=5.12, P<0.001; two mutated alleles versus no mutated alleles=4.39±0.36 versus 2.02±0.59, t=4.42, P<0.01). The genotyping of CYP2D6 only grossly predicts the steady state concentration of desipramine, mainly predicts the risk of getting very high plasma levels. Within each genotype there is marked interindividual variability. [source]

Expression of the muscle glycogen phosphorylase gene in patients with McArdle disease: the role of nonsense-mediated mRNA decay,

HUMAN MUTATION, Issue 2 2008
Gisela Nogales-Gadea
Abstract Nearly 35% of all mutations identified in the muscle glycogen phosphorylase gene (PYGM) in patients with McArdle disease result in premature termination codons (PTCs), particularly the p.R50X mutation. The latter accounts for more than 50% of the mutated alleles in most Caucasian patient populations. Mutations resulting in PTC could trigger the degradation of mRNA through a mechanism known as nonsense mediated decay (NMD). To investigate if NMD affects the levels of transcripts containing PYGM mutations, 28 Spanish patients with McArdle disease, harboring 17 different mutations with PTCs in 77% of their alleles, were studied. Transcripts levels of PYGM were measured and sequenced. We assessed that 92% of patients showed NMD. The most frequent mutation (p.R50X) elicited decay in all the genotypes tested. Other PTC producing mutations resulting in NMD were: p.L5VfsX22, p.Q73HfsX7, p.E125X, p.N134KfsX161, p.W388SfsX34, p.R491AfsX7, and p.D534VfsX5. Located in the last exon, the mutation p.E797VfsX19 was not affected by NMD. Missense mutations did not appear to be affected by NMD. In the cDNA sequences they appeared as homozygous, despite being heterozygous in the genomic DNA sequences. Exceptions to the rules governing NMD were found in the mutations p.A704,V and p.K754NfsX49. Hum Mutat 29(2), 277,283, 2008. © 2007 Wiley-Liss, Inc. [source]

USH2A Mutation analysis in 70 Dutch families with Usher syndrome type II,,

HUMAN MUTATION, Issue 2 2004
Ronald J.E. Pennings
Abstract Usher syndrome type II (USH2) is characterised by moderate to severe high-frequency hearing impairment, progressive visual loss due to retinitis pigmentosa and intact vestibular responses. Three loci are known for USH2, however, only the gene for USH2a (USH2A) has been identified. Mutation analysis of USH2A was performed in 70 Dutch USH2 families. Ten mutations in USH2A were detected, of which three are novel, c.949C>A, c.2242C>T (p.Gln748X) and c.4405C>T (p.Gln1468X). Including 9 previously published Dutch USH2a families, estimates of the prevalence of USH2a in the Dutch USH2 population were made. Mutations were identified in 62% of the families. In 28% both mutated alleles were identified, whereas in 34% the mutation in only one allele was found. It is estimated that about 28% of the Dutch USH2 families have a different causative gene. Analysis of deduced haplotypes suggests that c.1256G>T (p.Cys419Phe) is a Dutch ancestral mutation, occurring in 16% of the alleles. © 2004 Wiley-Liss, Inc. [source]

Parkinsonism and essential tremor in a family with pseudo-dominant inheritance of PARK2: An FP-CIT SPECT study

MOVEMENT DISORDERS, Issue 4 2007
Maria Teresa Pellecchia MD
Abstract We report a family with 5 affected individuals manifesting either essential tremor (ET), Parkinsonism, or both, consistent with pseudo-dominant inheritance of PARK2. Two homozygotes presented postural and kinetic tremor several years before the onset of Parkinsonism. Postural and kinetic tremor mimicking ET was the only feature in 1 homozygous and 2 heterozygous carriers of the mutation. Striatal dopamine transporter density was reduced in accordance with phenotype and number of mutated alleles. In 3 homozygotes and 1 heterozygote, a 2-year follow-up single photon emission computed tomography suggested no progression of nigrostriatal deficit. © 2006 Movement Disorder Society [source]

Phenotypic variability in myotonia congenita

MUSCLE AND NERVE, Issue 1 2005
Eskild Colding-Jørgensen MDArticle first published online: 22 MAR 200
Abstract Myotonia congenita is a hereditary chloride channel disorder characterized by delayed relaxation of skeletal muscle (myotonia). It is caused by mutations in the skeletal muscle chloride channel gene CLCN1 on chromosome 7. The phenotypic spectrum of myotonia congenita ranges from mild myotonia disclosed only by clinical examination to severe and disabling myotonia with transient weakness and myopathy. The most severe phenotypes are seen in patients with two mutated alleles. Heterozygotes are often asymptomatic but for some mutations heterozygosity is sufficient to cause pronounced myotonia, although without weakness and myopathy. Thus, the phenotype depends on the mutation type to some extent, but this does not explain the fact that severity varies greatly between heterozygous family members and may even vary with time in the individual patient. In this review, existing knowledge about phenotypic variability is summarized, and the possible contributing factors are discussed. Muscle Nerve, 2005 [source]

Hypophosphatasia: molecular testing of 19 prenatal cases and discussion about genetic counseling,

PRENATAL DIAGNOSIS, Issue 11 2008
Brigitte Simon-Bouy
Abstract Objective We studied hypophosphatasia (HP) mutations in 19 cases prenatally detected by ultrasonography without familial history of HP. We correlated the mutations with the reported ultrasound signs, and discussed genetic counseling with regard to the particular dominantly inherited prenatal benign form of HP. Method The coding sequence of the tissue nonspecific alkaline phosphatase (TNSALP) gene was analyzed by DNA sequencing, and 3D modeling was used to locate the mutated amino acids with regard to the functional domains of TNSALP. Results Although reported ultrasound signs were heterogeneous, two mutated alleles were found in 18 of the 19 cases studied, indicating recessive transmission of the disease. Functional domains of TNSALP were affected by 74% of missense mutations. In all the cases, including one with only a heterozygous mutation, molecular, biological, and familial data do not corroborate the hypothesis of prenatal benign HP. The mutation c.1133A > T observed in the prenatal benign form of HP and common in USA was not found in this series. Conclusion The results point out the prenatally detectable allelic heterogeneity of HP. The nature of the detected mutations and the evidence of recessive inheritance do not support these cases being affected with prenatal benign HP. Copyright © 2008 John Wiley & Sons, Ltd. [source]

Tyrosine kinase mutations in gastrointestinal stromal tumors in a nation-wide study in Iceland

APMIS, Issue 9 2010
GEIR TRYGGVASON
Tryggvason G, Hilmarsdottir B, Gunnarsson GH, Jónsson JJ, Jónasson JG, Magnússon MK. Tyrosine kinase mutations in gastrointestinal stromal tumors in a nation-wide study in Iceland. APMIS 2010; 118: 648,56. Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. It is characterized by activating mutations in the tyrosine kinase genes c-kit or PDGFRA. This study examined the mutation rate and type in a population-based material. All gastrointestinal mesenchymal tumors over the years 1990,2004 were evaluated and GIST tumors identified using immunohistochemistry (c-kit) and conventional pathologic parameters. Paraffin sections from all tumors were subjected to mutation analysis on exons 9, 11, 13 and 17 of the c-kit gene and exons 12 and 18 of the PDGFRA gene. To screen for mutations, we used a highly sensitive conformation-sensitive gel electrophoresis (CSGE) and to define the mutated alleles, we employed direct automated DNA sequencing. All c-kit-positive gastrointestinal mesenchymal tumors were entered into the study. Fifty-six tumors from 55 patients were analyzed. Mutations were found in 52 tumors representing a 92.9% mutational rate. Most of the mutations were found in c-kit exon 11 (76.8%), followed by c-kit exon 9 (10.7%). PDGFRA mutations were only found in three tumors. No correlation of mutation type with biologic behavior was found. This population-based study, using a sensitive CSGE method, identifies mutations in the great majority of patients with GIST. [source]

Metabolism of Desipramine in Japanese Psychiatric Patients: The Impact of CYP2D6 Genotype on the Hydroxylation of Desipramine

Geschichte und Evolution der Lactose(in)toleranz.

BIOLOGIE IN UNSERER ZEIT (BIUZ), Issue 6 2009
Das Erbe der frühen Viehzüchter
Abstract Die Fähigkeit, auch im Erwachsenenalter noch Lactose verarbeiten zu können, basiert auf Punktmutationen in einem dem Lactase-(LPH-)Gen vorgelagerten Sequenzbereich, der Bindestellen für Regulatorproteine enthält. Die Ursache für die weltweit sehr uneinheitliche Verteilung der Lactase-Persistenz liegt in der europäischen Menschheitsgeschichte: Im Verlauf des 8. vorchristlichen Jahrtausends entwickelte sich im Nahen Osten innerhalb einer größtenteils lactoseintoleranten Population eine Tradition der Milchviehzucht und des Milchverzehrs. Durch den starken Selektionsdruck auf die Lactosetoleranz verbreiteten sich die mutierten Allele sehr schnell. Während des 7. Jahrtausends v. Chr. begannen etliche dieser Populationen sukzessiv Europa zu besiedeln. Auch im nordöstlichen Afrika und auf der arabischen Halbinsel entstand eine Milchwirtschaft, die jedoch auf anderen Mutationen basiert. The ability to digest lactose in adulthood is baised on point mutations within an upstream region of the lactase-(LPH-)gene. This region contains multiple binding sites for different transcription factors. The heterogenous distribution of the lactase persistence all over the world originates from the European history of humanity: in the course of the eighth millennium BC among a mainly lactose-intolerant population in the Near East evolved a cultural practice of dairy farming and milk consumption. As a result of the strong and positive selection the mutated alleles spread out rapidly. In the course of the seventh millennium BC many of these populations gradually settled Central Europe. The beginning of dairy farming in the north east of the African continent and on the Arabian Peninsula are based upon different point mutations. [source]

Plasma concentrations of haloperidol are related to CYP2D6 genotype at low, but not high doses of haloperidol in Korean schizophrenic patients

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2001
Hyung-Keun Roh
Aims, This study was carried out to evaluate the influence of CYP2D6 genotype on the steady state plasma concentrations of haloperidol and reduced haloperidol in Korean schizophrenic patients. Methods, One hundred and twenty Korean schizophrenic patients treated with various, clinically determined, doses of haloperidol (range 3,60, median 20 mg day,1) during monotherapy were recruited. CYP2D6 genotypes were determined by analysis of the CYP2D6*10 allele using allele-specific PCR and the CYP2D6*5 allele by long-PCR. Steady state plasma concentrations of haloperidol and reduced haloperidol were analysed by h.p.l.c. Results, Twenty-three (19.2%), 60 (50.0%), 1 (0.8%), 33 (27.5%) and 3 patients (2.5%) possessed the CYP2D6 genotypes *1/*1, *1/*10, *1/*5, *10/*10 and *10/*5, respectively. The allele frequencies of CYP2D6*1, *10 and *5 were 44.6%, 53.8% and 1.7%, respectively. Significant relationships between dose and plasma concentrations of haloperidol (linear; r2 = 0.60, P < 0.0001) and reduced haloperidol (quadratic equation; r2 = 0.67) were observed. Overall, the concentrations normalized for dose (C/D) of haloperidol were significantly different between the CYP2D6*1/*1, *1/*10 and*10/*10 genotype groups (one-way anova; P = 0.028). No significant differences between the genotype groups were found with respect to the C/D of reduced haloperidol (P = 0.755). However, in patients with daily doses less than 20 mg, significant differences in the C/D of haloperidol (P = 0.003), but not of reduced haloperidol, were found between the three major genotype groups. In patients with doses higher than 20 mg, no differences were found between the genotype groups for either haloperidol or reduced haloperidol. 68 patients (57%) used benztropine, an antimuscarinic agent. All four patients with a *5 allele (one together with *1 and three with *10) were found to use benztropine. The patients homozygous for the *1 allele seemed to need less benztropine than the patients with one or two mutated alleles (Fisher's exact test; P = 0.036). Conclusions, The dose-corrected steady state plasma concentrations of haloperidol, but not of reduced haloperidol, were significantly different between the CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups when doses lower than 20 mg haloperidol were given. No differences were found at higher doses. These results suggest the involvement of CYP2D6 in the metabolism of haloperidol at low doses of haloperidol (< 20 mg daily), while another enzyme, probably CYP3A4, contributes at higher doses. [source]

Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature

CLINICAL GENETICS, Issue 4 2009
C Nemos
The CDKL5 gene has been implicated in the molecular etiology of early-onset intractable seizures with infantile spasms (IS), severe hypotonia and atypical Rett syndrome (RTT) features. So far, 48 deleterious alleles have been reported in the literature. We screened the CDKL5 gene in a cohort of 177 patients with early-onset seizures, including 30 men and 10 girls with Aicardi syndrome. The screening was negative for all men as well as for women with Aicardi syndrome, excluding the CDKL5 gene as a candidate for this neurodevelopmental disorder. We report 11 additional de novo mutations in CDKL5 in female patients. For the first time, the MLPA approach allowed the identification of a partial deletion encompassing the promoter and the first two exons of CDKL5. The 10-point mutations consist of five missenses (with recurrent amino acid changes at p.Ala40 and p.Arg178), four splicing variants and a 1-base pair duplication. We present a review of all mutated alleles published in the literature. In our study, the overall frequency of mutations in CDKL5 in women with early-onset seizures is around 8.6%, a result comparable with previous reports. Noteworthy, the CDKL5 mutation rate is high (28%) in women with early-onset seizures and IS. [source]

Spectrum of novel mutations in the human PKLR gene in pyruvate kinase-deficient Indian patients with heterogeneous clinical phenotypes

CLINICAL GENETICS, Issue 2 2009
P Kedar
Eighteen unrelated pyruvate kinase (PK)-deficient Indian patients were identified in the past 4 years with varied clinical phenotypes ranging from a mild chronic haemolytic anaemia to a severe transfusion-dependent disorder. We identified 17 different mutations in the PKLR gene among the 36 mutated alleles. Ten novel mutations were identified: 427G>A, 499C>A, 1072G>A, 1180G>T, 1216G>A, 1220A>G, 644delG, IVS5 (+20) C>A, IVS9 (+44) C>T, and IVS9 (+93) A>C. A severe syndrome was commonly associated with some mutations, 992A>G, 1436G>A, 1220A>G, 644delG and IVS9 (+93) A>C, in the PKLR gene. Molecular graphics analysis of human red blood cell PK (RPK), based on the crystal structure of human PK, shows that mutations located near the substrate or fructose 1,6-diphosphate binding site may change the conformation of the active site, resulting in very low PK activity and severe clinical symptoms. The mutations target distinct regions of RPK structure, including domain interfaces and catalytic and allosteric sites. In particular, the 1216G>A and 1219G>A mutations significantly affect the interdomain interaction because they are located near the catalytic site in the A/B interface domains. The most frequent mutations in the Indian population appear to be 1436G>A (19.44%), followed by 1456C>T (16.66%) and 992A>G (16.66%). This is the first study to correlate the clinical profile with the molecular defects causing PK deficiency from India where 10 novel mutations that produce non-spherocytic haemolytic anaemia were identified. [source]

Free sialic acid storage (Salla) disease in Sweden

ACTA PAEDIATRICA, Issue 12 2002
A Erikson
The first 23 patients diagnosed with Salla disease in Sweden are presented. A high incidence of the "Finnish" R39C mutation, together with genealogical data, indicates that a large proportion of the mutations are of Finnish origin. All patients had pathologically high levels of free sialic acid in urine and in fibroblasts. The clinical picture confirms what has already been reported from Finland, with early psychomotor retardation, ataxia and speech problems. One-third of the patients had epilepsy. Conclusions: Salla disease is more common in Sweden than supposed. A large proportion of the mutated alleles seem to be of Finnish origin. The clinical picture is the same as that reported from Finland. [source]