Home About us Contact
|
Home About us Contact | ||
|
|
||
Homozygous State (homozygous + state)
Selected Abstracts,-thalassaemia masked by , gene defects and a new polyadenylation site mutation on the ,2-globin geneEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2010Cornelis L. Harteveld Abstract We report three examples of chronic anaemia involving complex combinations of ,- and ,-globin gene defects. The first case had a potential Hb H disease caused by the classic SEA/RW deletions masked by Hb E [,26(B8)Glu,Lys] in the homozygous state. The second had an unusual Hb H disease caused by compound heterozygosity for two different ,2 polyadenylation site mutations masked by a ,-thalassaemia heterozygosity. The third had an intermediate ,-thalassaemia with considerable anaemia caused by an as yet unknown polyadenylation site (AATAAA>AATAAC) mutation in combination with a common RW deletion masked by a common Hb C [,6(A3)Glu,Lys] heterozygosity. Diagnostic methods, genotype/phenotype correlations and the chance of overlooking these combinations during risk assessment in a multiethnic society are discussed. [source] Compound heterozygosity of two missense mutations in the NADH-cytochrome b5 reductase gene of a Polish patient with type I recessive congenital methaemoglobinaemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2003Dorota Grabowska Abstract: A case of type I methaemoglobinaemia observed in a Polish subject with compound heterozygosity for two mutations in the reduced nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase (b5R) gene is described. One is a novel mutation 647T,C which leads to substitution of isoleucine by threonine at position 215 (I215T). This maternal mutation was found in several family members. A previously known mutation, 757G,A, leads to the replacement of valine by methionine at position 252 (V252M). The latter mutation was found also in the father and one of the two brothers. The effects of these mutations were analysed on a model of the human b5R protein obtained by homology modelling. Although both amino acid substitutions are located in the NADH-binding domain, the whole protein structure, especially the region between the flavin adenine dinucleotide and NADH-binding domains, is disturbed. The structural changes in the I215T mutant are less prominent than those in the V252M mutant. We presume that the 647T,C mutation is a type I mutation, however, it has not been observed in the homozygous state. [source] PERSPECTIVE: PURGING THE GENETIC LOAD: A REVIEW OF THE EXPERIMENTAL EVIDENCEEVOLUTION, Issue 12 2002Peter Crnokrak Abstract., Inbreeding depression, the reduction in fitness that accompanies inbreeding, is one of the most important topics of research in evolutionary and conservation genetics. In the recent literature, much attention has been paid to the possibility of purging the genetic load. If inbreeding depression is due to deleterious alleles, whose effect on fitness are negative when in a homozygous state, then successive generations of inbreeding may result in a rebound in fitness due to the selective decrease in frequency of deleterious alleles. Here we examine the experimental evidence for purging of the genetic load by collating empirical tests of rebounds in fitness-related traits with inbreeding in animals and plants. We gathered data from 28 studies including five mammal, three insect, one mollusc, and 13 plant species. We tested for purging by examining three measures of fitness-component variation with serial generations of inbreeding: (1) changes in inbreeding depression, (2) changes in fitness components of inbred lines relative to the original outbred line, and (3) purged population (outcrossed inbred lines) trait means as a function of ancestral outbred trait means. Frequent and substantial purging was found using all three measures, but was particularly pronounced when tracking changes in inbreeding depression. Despite this, we found little correspondence between the three measures of purging within individual studies, indicating that the manner in which a researcher chooses to estimate purging will affect interpretation of the results obtained. The discrepancy suggests an alternative hypothesis: rebounds in fitness with inbreeding may have resulted from adaptation to laboratory conditions and not to purging when using outcrossed inbred lines. However, the pronounced reduction in inbreeding depression for a number of studies provides evidence for purging, as the measure is likely less affected by selection for laboratory conditions. Unlike other taxon-specific reviews on this topic, our results provide support for the purging hypothesis, but firm predictions about the situations in which purging is likely or the magnitude of fitness rebound possible when populations are inbred remain difficult. Further research is required to resolve the discrepancy between the results obtained using different experimental approaches. [source] ORIGINAL ARTICLE Laboratory science: Molecular analysis in two Tunisian families with combined factor V and factor VIII deficiencyHAEMOPHILIA, Issue 5 2010H. E. ABDALLAH Summary., Combined factor V (FV) and factor VIII (FVIII) deficiency (F5F8D) is a rare autosomal recessive disorder caused by mutations in LMAN1 or MCFD2 genes which encode proteins that form a complex involved in the transport of FV and FVIII from the endoplasmic reticulum to Golgi apparatus. We report two novel mutations in MCFD2 gene and one recurrent mutation in LMAN1 gene that caused combined FV and FVIII deficiency in two unrelated Tunisian Muslim families. For the first family two patients were homozygous for a new missense mutation Asp81His in exon 3 of MCFD2 and heterozygous for a second new missense mutation Val100Asp in the same exon. Replacement respectively of the hydrophilic Asp residue with hydrophobic positively charged His and of the hydrophobic neutral Val residue with the Asp residue most likely disrupts the MCFD2,LMAN1 interaction, thus leading to the disease phenotype. For the second family a reported Arg202X mutation in exon 5 in the LMAN1 gene was identified in the homozygous state. [source] Mutation spectrum of human SLC39A4 in a panel of patients with acrodermatitis enteropathica,,HUMAN MUTATION, Issue 4 2003Sébastien Küry Abstract Acrodermatitis enteropathica is rare autosomal recessive disorder characterized by a severe nutritional zinc deficiency. We and others have recently identified the human gene encoding an intestinal zinc transporter of the ZIP family, SLC39A4, as the mutated gene in acrodermatitis enteropathica (AE). A first mutation screening in 8 AE families (15 patients out of 36 individuals) revealed the presence of six different mutations described elsewhere. Based on these results, we have evaluated the involvement of SLC39A4 in 14 patients of 12 additional AE pedigees coming either from France, Tunisia, Austria or Lithuania. A total of 7 SLC39A4 mutations were identified (1 deletion, 2 nonsense, 2 missense, and 2 modifications of splice site), of which 4 are novel: a homozygous nonsense mutation in 3 consanguineous Tunisian families [c.143T>G (p.Leu48X)], a heterozygous nonsense mutation (c.1203G>A (p.Trp401X)) in a compound heterozygote from Austria also exhibiting an already known missense mutation, and distinct homozygous mutations in families from France or Tunisia [c.475-2A>G and c.184T>C (p.Cys62Arg)]. Furthermore, two other potential mutations [c.850G>A (p.Glu284Lys) and c.193-113T>C] were also observed at homozygous state in a French family formerly described. This study brings to 21 the number of reported SLC39A4 mutations in AE families. © 2003 Wiley-Liss, Inc. [source] One gene, two phenotypes: ROR2 mutations in autosomal recessive Robinow syndrome and autosomal dominant brachydactyly type B,HUMAN MUTATION, Issue 1 2003Ali R. Afzal Abstract Autosomal recessive Robinow syndrome (RRS) is a severe skeletal dysplasia with short stature, generalized limb shortening, segmental defects of the spine, brachydactyly, and a dysmorphic facial appearance. The gene encoding receptor orphan receptor tyrosine kinase 2 (ROR2) is located on chromosome 9q22 and homozygous loss-of-function mutations in this gene are responsible for RRS. Moreover, knocking out the mouse Ror2 gene causes mesomelic dwarfism in the homozygous state, with almost identical features to recessive Robinow syndrome. The protein product of this gene is a cell membrane receptor, containing distinct motifs including an immunoglobulin-like (Ig) domain, a Frizzled-like cysteine-rich domain (FRZ or CRD), and a kringle domain (KD) in the extracellular region; and an intracellular region with tyrosine kinase (TK), serine/threonine-rich, and proline-rich structures. The extracellular motifs of the ROR2 protein are known to be involved in protein,protein interactions. The tyrosine kinase domain is involved in an as yet uncharacterized signaling pathway. Interestingly, heterozygous mutations in ROR2 have recently been shown to give rise to autosomal dominant brachydactyly type B1 (BDB1). This condition is characterized by terminal deficiency of fingers and toes. A variety of mutations have been reported in ROR2. Here, these genetic defects are compiled and possible genotype,phenotype correlations are discussed. Hum Mutat 22:1,11, 2003. © 2003 Wiley-Liss, Inc. [source] Isolated sulfite oxidase deficiency: identification of 12 novel SUOX mutations in 10 patientsHUMAN MUTATION, Issue 1 2002Jean L. Johnson Abstract We report twelve novel mutations in patients with isolated sulfite oxidase deficiency. The mutations are in SUOX, the gene that encodes the molybdohemoprotein sulfite oxidase. These include two frameshift mutations, a four-basepair deletion (562del4) and a single-basepair insertion (113insC), both resulting in premature termination. Nonsense mutations predicting Y343X and Q364X substitutions were identified in a homozygous state in three patients, the latter in two sibs. The remaining eight are missense mutations generating single amino acid substitutions. From the position of the substituted residues, seven of these mutations are considered to be causative of the enzyme deficiency: I201L, R211Q, G305S, R309H, K322R, Q339R, and W393R. The eighth, a C>T transition, predicts an R319C substitution, which could affect the binding of the molybdenum cofactor and thus severely reduce sulfite oxidase activity. This mutation, however, is downstream of a frameshift mutation and is therefore not the causative mutation in this individual. © 2002 Wiley-Liss, Inc. [source] A RYR1 mutation associated with recessive congenital myopathy and dominant malignant hyperthermia in Asian familiesMUSCLE AND NERVE, Issue 4 2009Danielle Carpenter PhD Abstract In this study we present 3 families with malignant hyperthermia (MH), all of Indian subcontinent descent. One individual from each of these families was fully sequenced for RYR1 and presented with the non-synonymous change c.11315G>A/p.R3772Q. When present in the homozygous state c.11315*A is associated with myopathic symptoms. Muscle Nerve, 2009 [source] Isolated sulfite oxidase deficiency: mutation analysis and DNA-based prenatal diagnosisPRENATAL DIAGNOSIS, Issue 5 2002J. L. Johnson Abstract Isolated sulfite oxidase deficiency is an autosomal recessive, neurological disorder resulting from a defect in SUOX, the gene encoding the enzyme that catalyzes the terminal reaction in the sulfur amino acid degradation pathway. In its classical, severe form, sulfite oxidase deficiency leads to intractable seizures, severe and progressive brain pathology and death at an early age. We report here on clinical features and mutational analysis of the genetic defect in a newborn with sulfite oxidase deficiency. Cultured fibroblasts from this patient exhibited no detectable sulfite oxidase activity, and a unique four base pair deletion was present in the cDNA isolated from the same source. Identification of the same genetic defect in a heterozygous state in each of the parents and the monitoring of subsequent pregnancies in this family by DNA-based prenatal diagnosis are also described. The deletion mutation was identified in a homozygous state in uncultured chorionic villus tissue from the second pregnancy that was subsequently terminated. In the third pregnancy, the presence of sulfite oxidase activity and identification of the mutation in a heterozygous state suggested that the fetus was not affected. This pregnancy resulted in the birth of a normal child. Copyright © 2002 John Wiley & Sons, Ltd. [source] Analysis of recessive lethality on swine chromosome 6 in a Göttingen miniature resource familyANIMAL GENETICS, Issue 5 2005S. Mikawa Summary Previously, we reported recessive gene(s) that terminate fetal development on swine chromosome (SSC) 6 between SW855 and SW122. The affected alleles originated from a Göttingen miniature pig used for construction of a Göttingen miniature pig × Meishan resource population. However, it is not known when the gene(s) are activated during fetal development, which is one of the important factors in selecting candidate genes responsible for fetal death. In the present study, a second swine population consisting of 159 progeny was produced by mating pigs carrying the deleterious allele(s). This population allowed us to narrow the genetic region harbouring the affected gene(s) and to demonstrate that the region was confined between RYR1 and SW782 (5.7 cM on the National Institute of Animal Industry (NIAI) map and 100 cR on the INRA/University of Minnesota porcine radiation hybrid panel map). In order to determine when the affected gene(s) are activated and in turn terminate fetal development, embryos produced in the second population were collected at several development stages and genotyped for markers in the region. Genes in the homozygous state affected embryo development between 9 and 11 days post-coitus. [source] Double Heterozygosity with Mutations Involving both the GJB2 and GJB6 Genes is a Possible, but very Rare, Cause of Congenital Deafness in the Czech PopulationANNALS OF HUMAN GENETICS, Issue 1 2005P. Seeman Summary Mutations in the GJB2 gene are the most common cause of prelingual, autosomal recessive, sensorineural hearing loss worldwide. Nevertheless, 10% to 50% of patients with prelingual nonsyndromic deafness only carry one mutation in the GJB2 gene. Recently a large 342 kb deletion named ,(GJB6-D13S1830) involving the GJB6 gene was reported in Spanish and French deafness patients, either in a homozygous state or in combination with a monoallelic GJB2 mutation. No data have been reported about the frequency of this mutation in central Europe. Thirteen Czech patients with prelingual nonsyndromic sensorineural deafness carrying only one pathogenic mutation in the GJB2 gene were tested for the presence of the ,(GJB6-D13S1830) mutation. One patient with a GJB2 mutation (313del14) also carried the ,(GJB6-D13S1830). This is the first reported Czech case, and probably also the first central European case, of prelingual deafness due to mutations involving both the GJB2 and GJB6 genes. In addition, the ,(GJB6-D13S1830) was not detected in 600 control chromosomes from Czech individuals with normal hearing. We show that in the Czech Republic the ,(GJB6-D13S1830) is not the second most common causal factor in deafness patients heterozygous for a single GJB2 mutation, and that ,(GJB6-D13S1830) is very rare in central Europe compared to reports from Spain, France and Israel. [source] Novel haplotypes in 17q21 are associated with progressive supranuclear palsyANNALS OF NEUROLOGY, Issue 2 2004Pau Pastor MD Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are sporadic neurodegenerative diseases presenting as atypical parkinsonian disorders, characterized by the presence of tau-positive neurofibrillary tangles. Recently, an extended haplotype (H1E) of 787.6kb that comprises several genes including MAPT showed increased association with PSP. The objective of this study was to determine the size of the H1E haplotype associated with PSP and CBD in different populations and to identify specific subhaplotypes in the background of H1E haplotype. Nineteen single nucleotide polymorphisms (SNPs) in the 17q21 region were genotyped in two case,control samples. The SNPs that were associated with higher risk for the disease in the homozygous state delimit a region of more that 1Mb. Haplotype analyses in the Spanish sample showed that the most frequent haplotype found among the patients (H1E,), which extends 1.04Mb and contains several genes such as MAPT, CRHR1, IMP5, Saitohin, WTN3, and NSF. A specific subhaplotype (H1E,A) was present in 16% of PSP patients but was not observed in the controls. Furthermore, the H2E,A haplotype, was rarely present in the disease group suggesting that it plays a protective role. The identification of these specific subhaplotypes that modify risk for PSP/CBD supports the hypothesis that a pathogenic allele exists in a subgroup of PSP patients. Ann Neurol 2004;56:249,258 [source] Haplotypes of the interleukin-4 receptor , chain gene associate with susceptibility to and severity of atopic asthmaCLINICAL & EXPERIMENTAL ALLERGY, Issue 10 2004A.-M. Hytönen Summary Background Development of asthma is likely to depend on a complex interaction between environmental and genetic factors. Several groups have suggested the gene of the IL-4 receptor , chain (IL4R) as a candidate gene for the development of asthma, although association with single polymorphisms has shown contradicting results. Objective We chose to analyse IL4R gene haplotypes and assess their possible relevance in susceptibility to asthma and to certain clinical phenotypes. Methods IL4R gene haplotypes were analysed, based on the three markers C-3223T, Q551R and I50V, using the expectation,maximization algorithm, in 170 atopic asthma patients and 350 controls, all adult Swedish Caucasians. Results Our data showed significantly higher levels of soluble IL-4R (sIL-4R) in asthma patients compared with controls (P<0.0001). Furthermore, we showed a significant association between the IL4R haplotype containing the alleles T-3223, V50 and R551 (TVR) of the IL4R gene, and susceptibility to atopic asthma, with a frequency of 6.5% in the patients compared with 1% in the controls (P<0.0005). A subgroup of patients with heterozygous or homozygous state for the T-3223, V50 and R551 alleles, also had lower levels of sIL-4R in their circulation compared with patients with homozygous state in the C-3223, I50 and Q551 alleles (P<0.05) and showed less severe asthma according to lung function test (P<0.05). Analysis of single markers showed the T-3223 IL4R allele to associate with lower serum levels of sIL-4 receptor (P<0.0001) and patients carrying the T allele also had more symptoms of active asthma (wheezing, P<0.01; coughing, P<0.05 and breathing difficulties, P<0.01). Conclusion Our data suggest that asthmatic patients with low levels of sIL-4 receptor may represent a genetically distinct subgroup of atopic asthma. TVR haplotype analyses confirm the importance of IL4R as a candidate gene for susceptibility to asthma. This finding may have implications for the understanding of the pathogenesis of asthma and possibly for the development of more specific therapies. [source] ATM germline mutations in Spanish early-onset breast cancer patients negative for BRCA1/BRCA2 mutationsCLINICAL GENETICS, Issue 5 2008J Brunet Heterozygous carriers of ATM (ataxia telangiectasia mutated gene) mutations have increased risk of breast cancer (BC). We have estimated the prevalence of mutations in the ATM gene among Spanish patients with early-onset BC. Forty-three patients diagnosed with BC before the age of 46 years, and negative for BRCA1 and BRCA2 mutations, were analysed for the presence of ATM mutations. A total of 34 ATM sequence variants were detected: 1 deleterious mutation, 10 unclassified variants and 23 polymorphisms. One patient (2.3%) carried the ATM deleterious mutation (3802delG that causes ataxia telangiectasia in the homozygous state) and 13 patients carried the 10 ATM unclassified variants. The truncating mutation 3802delG and eight of the rare variants were not detected in a control group of 150 individuals. Different bioinformatic sequence analysis tools were used to evaluate the effects of the unclassified ATM changes on RNA splicing and function protein. This in silico analysis predicted that the missense variants 7653 T>C and 8156 G>A could alter the splicing by disrupting an exonic splicing enhancer motif and the 3763 T>G, 6314 G>C, and 8156 G>A variants would affect the ATM protein function. These are the initial results concerning the prevalence of germline mutations in the ATM gene among BC cases in a Spanish population, and they suggest that ATM mutations can confer increased susceptibility to early-onset BC. [source] | |||||||||||||