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Homozygosity
Terms modified by Homozygosity Selected AbstractsH63D homozygotes with hyperferritinaemia: is this genotype, the primary cause of iron overload?EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2007Carles De Diego Abstract Objectives:,Hereditary haemochromatosis is a disease that affects iron metabolism and leads to iron overload. Homozygosity for the H63D mutation is associated with increased transferrin saturation (TS) and ferritin levels. Our objective was to find out if the homozygosity of H63D mutation was the primary cause of iron overload. Patients and methods:,We studied 45 H63D homozygotes (31 males and 14 females) with biochemical iron overload and/or clinical features of haemochromatosis. The simultaneous detection of 18 known HFE, TFR2 and FPN1 mutations and sequencing of the HAMP gene were performed to rule out the possible existence of genetic modifier factors related with iron overload. Results:,Values of biochemical iron overload, measured as percentage TS and serum ferritin concentration (SF), in our H63D homozygotes were significantly higher in patients than in controls: TS 55 ± 15% vs. 35 ± 15% and SF 764 (645,883) ,g/L vs. 115 (108,123) ,g/L for patients and controls, respectively. These H63D homozygotes presented extreme hyperferritinaemia and no additional mutations in HFE, TFR2, FPN1 and HAMP genes were detected. Conclusions:,The lack of additional mutations in our H63D homozygotes suggests that this genotype could be the primary cause of iron overload in these patients. Despite our results, we cannot entirely discount the possibility that one or more genetic modifier factor exists, simply because we were unable to find it, although there was a precedent in the HFE gene. Genetic modifier factors have been described for C282Y mutations in the HFE gene, but at the present time they have never been reported in H63D homozygotes. [source] Juvenile Paget's Disease: The Second Reported, Oldest Patient Is Homozygous for the TNFRSF11B "Balkan" Mutation (966_969delTGACinsCTT), Which Elevates Circulating Immunoreactive Osteoprotegerin Levels,,§¶JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2007Michael P Whyte MD Abstract The oldest person (60 yr) with juvenile Paget's disease is homozygous for the TNFRSF11B mutation 966_969delTGACinsCTT. Elevated circulating levels of immunoreactive OPG and soluble RANKL accompany this genetic defect that truncates the OPG monomer, preventing formation of OPG homodimers. Introduction: Juvenile Paget's disease (JPD), a rare autosomal recessive disorder, features skeletal pain, fracture, and deformity from extremely rapid bone turnover. Deafness and sometimes retinopathy also occur. Most patients have diminished osteoprotegerin (OPG) inhibition of osteoclastogenesis caused by homozygous loss-of-function defects in TNFRSF11B, the gene that encodes OPG. Circulating immunoreactive OPG (iOPG) is undetectable with complete deletion of TNFRSF11B but normal with a 3-bp in-frame deletion. Materials and Methods: We summarize the clinical course of a 60-yr-old Greek man who is the second reported, oldest JPD patient, including his response to two decades of bisphosphonate therapy. Mutation analysis involved sequencing all exons and adjacent mRNA splice sites of TNFRSF11B. Over the past 4 yr, we used ELISAs to quantitate his serum iOPG and soluble RANKL (sRANKL) levels. Results: Our patient suffered progressive deafness and became legally blind, although elevated markers of bone turnover have been normal for 6 yr. He carries the same homozygous mutation in TNFRSF11B (966_969delTGACinsCTT) reported in a seemingly unrelated Greek boy and Croatian man who also have relatively mild JPD. This frame-shift deletes 79 carboxyterminal amino acids from the OPG monomer, including a cysteine residue necessary for homodimerization. Nevertheless, serum iOPG and sRANKL levels are persistently elevated. Conclusions: Homozygosity for the TNFRSF11B "Balkan" mutation (966_969delTGACinsCTT) causes JPD in the second reported, oldest patient. Elevated circulating iOPG and sRANKL levels complement evidence that this deletion/insertion omits a cysteine residue at the carboxyterminus needed for OPG homodimerization. [source] Localization of the Gene Causing the Osteopetrotic Phenotype in the Incisors Absent (Ia) Rat on Chromosome 10q32.1,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2004Liesbeth van Wesenbeeck Abstract The incisors absent rat is an osteopetrotic animal model. Segregation analysis in 37 affected animals from an outcross enabled us to assign the disease causing gene to a 4.7-cM interval on rat chromosome 10q32.1. Further analysis of the genes mapped in this region will provide more insight into the underlying pathogenesis. Introduction: Many of the insights into the factors that regulate the differentiation and activation of osteoclasts are gained from different spontaneous and genetically induced osteopetrotic animal models. The osteopetrotic incisors absent (ia) rat exhibits a generalized skeletal sclerosis and a delay of tooth eruption. Although the ia rat has well been studied phenotypically, the genetic defect still remains unknown. Material and Methods: To map the ia locus, we outcrossed the inbred ia strain with the inbred strain Brown Norway. Intercrossing F1 animals produced the F2 generation. Thirty-one mutant F2 animals and six mutant F4 animals were available for segregation analysis. Results: Segregation analysis enabled us to assign the disease causing gene to rat chromosome 10q32.1. Homozygosity for the ia allele was obtained for two of the markers analyzed (D10Rat18 and D10Rat84). Key recombinations delineate a candidate region of 4.7 cM flanked by the markers D10Rat99 and D10Rat17. Conclusion: We have delineated a 4.7-cM region on rat chromosome 10q32.1 in which the gene responsible for the osteopetrotic phenotype of the ia rat is located. Although the sequence of this chromosomal region is not complete, over 140 known or putative genes have already been assigned to this region. Among these, several candidate genes with a putative role in osteoclast functioning can be identified. However, at this point, it cannot be excluded that one of the genes with a currently unknown function is involved in the pathogenesis of the ia rat. Further analysis of the genes mapped in this region will provide us more insight into the pathogenesis of this osteopetrotic animal model. [source] Homozygous Defects In Lmna, Encoding Lamin A/C Nuclear-Envelope Proteins, Cause Autosomal Recessive Axonal Neuropathy In Human (Charcot-Marie-Tooth Disorder Type 2) And MouseJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 3 2002A De Sandre-Giovannoli The Charcot-Marie-Tooth (CMT) disorders comprise a group of clinically and genetically heterogeneous hereditary motor and sensory neuropathies, which are mainly characterized by muscle weakness and wasting, foot deformities, and electrophysiological, as well as histological, changes. A subtype, CMT2, is defined by a slight or absent reduction of nerve-conduction velocities together with the loss of large myelinated fibers and axonal degeneration. CMT2 phenotypes are also characterized by a large genetic heterogeneity, although only two genes-NF-L and KIF1Bbeta-have been identified to date. Homozygosity mapping in inbred Algerian families with autosomal recessive CMT2 (AR-CMT2) provided evidence of linkage to chromosome 1q21.2-q21.3 in two families (Z(max) = 4.14). All patients shared a common homozygous ancestral haplotype that was suggestive of a founder mutation as the cause of the phenotype. A unique homozygous mutation in LMNA (which encodes lamin A/C, a component of the nuclear envelope) was identified in all affected members and in additional patients with CMT2 from a third, unrelated family. Ultrastructural explor- ation of sciatic nerves of LMNA null (i.e., ,/,) mice was performed and revealed a strong reduction of axon density, axonal enlargement, and the presence of nonmyelinated axons, all of which were highly similar to the phenotypes of human peripheral axonopathies. The finding of site-specific amino acid substitutions in limb-girdle muscular dystrophy type 1B, autosomal dominant Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy type 1A, autosomal dominant partial lipodystrophy, and, now, AR-CMT2 suggests the existence of distinct functional domains in lamin A/C that are essential for the maintenance and integrity of different cell lineages. To our knowledge, this report constitutes the first evidence of the recessive inheritance of a mutation that causes CMT2; additionally, we suggest that mutations in LMNA may also be the cause of the genetically overlapping disorder CMT2B1. [source] Microsatellite variability and its use in the characterization of cultivated clones of Hevea brasiliensisPLANT BREEDING, Issue 1 2005T. Saha Abstract Microsatellite markers were developed and evaluated in Hevea brasiliensis, an important crop species producing natural rubber of commercial utility. Of eight microsatellite markers, four were found to be highly informative, amplifying a total of 19 alleles when evaluated against 27 cultivated Hevea clones/genotypes. Power of discrimination of the microsatellite loci was in the range of 0.62-0.89, with a mean of 0.76 indicating these microsatellites could be valuable genetic markers for diversity characterization. A combination of four microsatellite markers was successfully used to discriminate uniquely all the 27 Hevea clones and some clone-specific allelic profiles were generated. Cross-species amplification of the markers developed in H. brasiliensis had also been demonstrated with two other Hevea species, H. benthamiana and H. spruceana, indicating a high degree of sequence homology at the flanking regions. Sequence analysis of the repeat region at the 3,-UTR of the hydroxymethylglutaryl-coenzyme A reductase gene, containing clusters of AG repeats in 15 clones, revealed the existence of two alleles based on the repeat length polymorphisms. Homozygosity as well as heterozygosity for both the alleles had also been detected among the clones. Frequency of homozygotes for the smaller allele (allele-1) was found to be lower than the larger allele (allele-2) among the primary clones of H. brasiliensis. [source] ORIGINAL ARTICLE: Are Polymorphisms in the ACE and PAI-1 Genes Associated with Recurrent Spontaneous Miscarriages?AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2009Chelsi Goodman Problem, To determine whether the ACE D/D genotype or the combination of PAI-1 4G/4G and ACE D/D genotypes may serve as a risk factor for recurrent pregnancy loss. Method of study, Buccal swabs were obtained from 120 women experiencing recurrent pregnancy loss and from 84 fertile control women. DNA was extracted from the buccal swab samples using the Qiagen DNA Mini Kit (Qiagen), followed by multiplex polymerase chain reaction (PCR). PCR products were analyzed for the ACE gene polymorphism, which consists of the insertion or deletion (I/D) of a 287-bp fragment in intron 16, and the PAI-1 4G/4G genotype. Results, No significant differences in specific ACE gene mutations were observed when patients experiencing recurrent miscarriage were compared with control women. When the frequencies of homozygous mutations for ACE D/D and PAI-I 4G/4G were compared between recurrent aborters and controls, again no significant differences in the prevalence of the combination of these gene mutations were noted. Conclusion, Homozygosity for the D allele of the ACE gene and the combination of the D/D genotype with two 4G alleles of the PAI-1 promoter gene are not associated with a significant increase in the risk of recurrent miscarriage. [source] The homozygous P582S mutation in the oxygen-dependent degradation domain of HIF-1, is associated with increased risk for prostate cancerTHE PROSTATE, Issue 1 2007Avi Orr-Urtreger Abstract BACKGROUND The heterodimeric transcription factor HIF-1 (hypoxia-inducible factor 1), consisting of a critically regulated HIF-1, subunit and a constitutively expressed HIF-1, subunit, is a master regulator of genes involved in adaptation and survival under low-oxygen conditions. Increased levels of HIF-1 activity are associated with increased tumor aggressiveness, therapeutic resistance, and mortality. METHODS We studied 402 prostate cancer patients for the presence of the 1772C,>,T (P582S) and 1790G,>,A (A588T) mutations within the oxygen-dependent domain of HIF-1,. RESULTS Homozygosity for the P582S mutation was fourfold greater among prostate cancer patients compared to controls (OR,=,4.10 [C.I. 95% 1.11,<,OR,<,17.87], P,=,0.018). The existence of this mutation in prostate cancer patients was not associated with any of the clinical or pathological characteristics of the disease. No significant differences were found between the frequencies of A588T mutation in prostate cancer patients and controls. CONCLUSIONS Our data suggest that homozygous HIF1A P582S mutation confers significant susceptibility to prostate cancer. Prostate 67:8,13, 2007. © 2006 Wiley-Liss, Inc. [source] A mutation in NF,B interacting protein 1 causes cardiomyopathy and woolly haircoat syndrome of Poll Hereford cattleANIMAL GENETICS, Issue 1 2009M. A. Simpson Summary Cardiomyopathy and woolly haircoat syndrome (CWH) of Poll Hereford cattle is a lethal, autosomal recessive disorder. Cardiac and haircoat changes are congenital, neonatal ocular keratitis develops in some cases and death usually occurs within the first 12 weeks of life. We undertook a homozygosity mapping approach to identify the chromosomal location of the causative gene. Seven candidate genes were examined for homozygosity in affected animals: desmoplakin and junction plakoglobin (both previously implicated in human cardiocutaneous syndromes), desmocollin 2, desmoglein 2, plakophilin 2, nuclear factor kappa B (NFKB1) and NF,B interacting protein 1 (PPP1R13L, also known as NKIP1). Homozygosity in 13 affected animals was observed at the PPP1R13L locus, located on bovine chromosome 18. Subsequent sequence analysis revealed a 7-bp duplication (c.956_962dup7) in exon 6 of this 13-exon gene. This frameshift variant is predicted to result in the substitution of three amino acids and the introduction of a premature stop codon at position 325 of the protein product (p.Ser322GlnfsX4). PPP1R13L interacts with NF,B, a family of structurally related transcription factors that regulate genes controlling inflammation, immune responses and cell proliferation and survival. CWH represents a large-animal model for cardiocutaneous disorders caused by a mutation in the PPP1R13L gene. The identification of this bovine mutation also indicates that PPP1R13L and other genes affecting NF,B activity may be candidate genes in the study of human cardiovascular disease. [source] No Association of the ACTN3 Gene R577X Polymorphism with Endurance Performance in Ironman TriathlonsANNALS OF HUMAN GENETICS, Issue 6 2007C. J. Saunders Summary Alpha-actinins are major structural components of the Z-discs in skeletal muscle. Alpha-actinin 3 is encoded by the ACTN3 gene and is expressed only in type II muscle fibres. Homozygosity for the nonsense mutation, 577X, within ACTN3 results in deficiency of ,-actinin-3 but does not result in an abnormal muscular phenotype. Previous research has found an association of the 577R allele with sprinting and/or power performance. It has also been suggested that the 577X allele may confer an advantage during endurance events. Four hundred and fifty seven Caucasian male triathletes who completed either the 2000 and/or 2001 226 km South African Ironman Triathlons, and 143 Caucasian controls, were genotyped for the R577X mutation within the ACTN3 gene. There were no significant differences in either the genotype (P = 0.486) or allele (P = 0.375) frequencies within the fastest, middle of the field or slowest Caucasian male finishers and the control population. In conclusion, the R577X polymorphism within the ACTN3 gene was not associated with ultra-endurance performance in the 2000 and 2001 South African Ironman Triathlons. [source] Homozygosis for (12) CA repeats in the first intron of the human IFN- , gene is significantly associated with the risk of aplastic anaemia in Caucasian populationBRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2004Carlo Dufour Summary Interferon- , (IFN- ,) mediates the final damage of the stem cell compartment in Aplastic Anaemia (AA). Normal subjects homozygous for 12 (CA) repeats of polymorphism variable number of dinucleotide (CA) repeat (VNDR) in position 1349 of the IFN- , gene (IFNG) were shown to overproduce IFN- ,in vitro. We studied the distribution of polymorphism VNDR 1349 of IFNG in 67 Caucasian AA patients and in normal controls. Genotype (CA)12-12, (homozygosis for allele 2) and the single allele 12 were significantly more frequent (P = 0·005 and 0·004 respectively) in patients versus controls. The polymorphism was equally distributed in AA patients regardless of their response to immunosuppression. Homozygosity for 12 (CA) repeats of polymorphism VNDR 1349 of IFNG is strongly associated with the risk of AA in Caucasian subjects. [source] The occurrence of dominant spinocerebellar ataxias among 251 Finnish ataxia patients and the role of predisposing large normal alleles in a genetically isolated populationACTA NEUROLOGICA SCANDINAVICA, Issue 3 2005V. Juvonen Objectives,,, Frequency and distribution of dominant ataxias caused by dynamic mutations may vary in different populations, which has been explained on the basis of relative frequency of predisposing normal alleles. The aim of the study was to evaluate the occurrence of spinocerebellar ataxias (SCAs) and dentatorubral-pallidoluysian atrophy (DRPLA) in Finland, and to investigate the role of predisposing normal alleles in a genetically homogenous population. Material and methods,,, Mutation analyses for SCA1, 2, 3, 6, 7, 8, 10, 12, 17, and DRPLA and frataxin genes were performed for 251 unrelated Finnish patients who presented with progressive ataxia disorder. Results,,, Expansions of SCA1, SCA2, SCA6, SCA7, SCA8, and SCA17 genes were detected in 2, 1, 1, 7, 22, and 1 patients, respectively. Altogether, 39 and 7% of dominant and sporadic SCA patients, respectively, harboured expansions at some of the investigated loci. Normal variation, collected from 477 to 502 chromosomes at each disease loci, revealed that Finns were different from the Japanese but largely similar to other Caucasians. Conclusions,,, Lack of SCA3 and excess of SCA8 are characteristic to the Finnish population. Homozygosity for the SCA8 expansion increases penetrance. Frequencies of large normal alleles at the SCA loci predict poorly prevalence of the respective diseases in Finland. Prioritization in DNA testing, based on ethnic origin and geographical location, is recommendable in Finland, and analogous approach may be applied to other countries as well. [source] Mutations in sarcomeric protein genes not only lead to cardiomyopathy but also to congenital cardiovascular malformationsCLINICAL GENETICS, Issue 1 2008Marja W. Wessels Noncompaction of the ventricular myocardium is associated with de novo mutation in the beta-myosin heavy chain gene Budde et al. (2007) PLoS ONE 2: e1362 Homozygosity for a novel splice site mutation in the cardiac myosin-binding protein C gene causes severe neonatal hypertrophic cardiomyopathy Xin et al. (2007) Am J Med Genet 143: 2662,2667 Alpha-cardiac actin mutations produce atrial septal defects Matsson et al. (2008) Hum Mol Genet 17: 256,265 [source] Cognition genes on autosomes: the paradoxCLINICAL GENETICS, Issue 1 2007PJ Willems Homozygosity mapping in consanguineous families reveals extreme heterogeneity of non-syndromic autosomal recessive mental retardation and identifies eight novel gene loci Najmabadi H et al. (2007) Human Genetics 12: 43,48 A new locus for autosomal recessive non-syndromic mental retardation maps to 1p21.1,p13.3 Uyguner O et al. (2007) Clinical Genetics 71: 212,219 [source] Determination of HLA-A, -B and -DRB1 haplotypes based on allelic homozygosity data in selected bone marrow donors of the Taiwanese marrow donor registryINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 5 2007K. L. Yang Summary From 120 unrelated Taiwanese marrow stem cell donors with allelic homozygosities at human leucocyte antigen (HLA)-A, -B and -DRB1 loci, we determined 85 distinguishable haplotypes. Using the predetermined haplotype data, we deduced 418 haplotypes from 1903 unrelated individual stem cell donors selected for HLA confirmatory test. Eighteen of the 20 (90%) most frequently observed haplotypes determined in Asian Americans using computer prediction were found in this study. In comparison with haplotypes determined by maximum likelihood algorithm in Korean population, 18 of the 29 (62.07%) Korean haplotypes with a frequency over 0.5% were also among the haplotypes determined in this investigation. Randomized family studies confirmed that over 50% of the haplotypes observed in the families were among the haplotypes deduced based on allelic homozygosity, suggesting that proportionally additional haplotypes can be determined as the number of donors being studied is increased. Haplotypes carrying low incidence allele characteristics of Taiwanese were also observed in this study. This established haplotype information will be beneficial for patients searching for stem cell donors in our registry domestically and internationally. [source] Homozygous thermolabile variant of the methylenetetrahy-drofolate reductase gene: a potential risk factor for hyperhomo-cysteinaemia, CVD, and stroke in childhoodDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 4 2001Mara Prengler In this study of 118 children (median age 5.1 years; range 6 months to 17 years) with ischaemic stroke or transient ischaemic attack (TIA), 22 children (19%) were homozygous for the thermolabile variant of the methylenetetrahydrofolate reductase allele (t-MTHFR), compared with nine of 78 (12%) of a reference population (p=0.18, OR 1.76, 95% CI 0.76 to 4.04). Of those with cerebrovascular disease (CVD), 17 of 84 were homozygous for the t-MTHFR allele (p=0.13 compared with the reference population (OR 1.95, 95% CI 0.81 to 4.65). There was a significant (p<0.025) increment of plasma total homocysteine concentration in homozygotes for the t-MTHFR allele compared with heterozygotes, negatives for the t-MTHFR allele, and control children with no history of stroke. In four of 12 homozygotes for the t-MTHFR allele, plasma homocysteine levels were raised, compared with three of 38 of those who were negative or heterozygous (p=0.047; OR 5.8, 95% CI 1.1 to 31.2). Homozygotes for the t-MTHFR allele were significantly more likely to have a recurrent event than those who were negative or heterozygous (Cox regression p=0.031, hazard ratio 2.18, 95% CI 1.08 to 4.42). These data suggest that homozygosity for the t-MTHFR allele is associated with raised homocysteine levels in children and is a risk factor for primary and secondary stroke and TIA. [source] Examining the relationships between the Pro12Ala variant in PPARG and Type 2 diabetes-related traits in UK samplesDIABETIC MEDICINE, Issue 12 2005E. Zeggini Abstract Aims The Pro12Ala polymorphism in the PPARG gene alters amino acid sequence and has shown consistent association with susceptibility to Type 2 diabetes in several populations. The present study makes use of large, well-characterized case-control resources to enhance understanding of this susceptibility effect by examining related traits, such as body mass index (BMI), waist,hip ratio and age at diagnosis. Methods The Pro12Ala variant was genotyped in two UK case samples, ascertained for positive family history and/or early onset of Type 2 diabetes (combined n = 971); and in 1257 ethnically matched control subjects. Results There were significant associations of the Pro12Ala single nucleotide polymorphism (SNP) genotypes with diabetes in both case-control comparisons (P = 0.025 and P = 0.039). Comparing individuals homozygous for the Pro allele, with those carrying an Ala allele, the combined odds ratio for diabetes was 1.40 (95% CIs, 1.12,1.76, P = 0.0031). There was no association between the variant and either waist,hip ratio or age at diagnosis. Proline homozygosity was associated with increased BMI in one patient group (P = 0.013) and decreased BMI in the other (P = 0.038). Conclusions This study confirms that variation within PPARG influences susceptibility to Type 2 diabetes in UK samples. However, the relationship between PPARG variation and BMI is more complex, and studies in much larger sample sets will be required to more precisely characterize the effect of this variant on adiposity. [source] New insights on attention-deficit/hyperactivity disorder pharmacogenomicsDRUG DEVELOPMENT RESEARCH, Issue 3 2004Luis Augusto Rohde Abstract Although there is an impressive literature documenting both a strong participation of genetics in the etiology of attention-deficit/hyperactivity disorder (ADHD) and a high rate of response to stimulants and atomoxetine, surprisingly few studies on the pharmacogenomics of ADHD were conducted. This review aims to present a critical discussion of findings from recent investigations on this emerging new area of research. We performed a systematic computer review of the literature on ADHD pharmacogenomics. In addition, we contacted some research centers involved in research on ADHD genetics, asking for any kind of nonpublished data relevant for the topic of this revision. This review strategy identified only seven papers presenting nonduplicated research findings on ADHD pharmacogenomics. Contact with other investigators resulted in five more studies presented in medical meetings or still nonpublished. The majority of investigations are on dopaminergic genes, especially on polymorphisms at the dopamine transporter gene (DAT1). Although there were some instigating preliminary results suggesting the association between the homozygosity for the 10-repeat allele at DAT1 gene and response to methylphenidate, recent studies were not able to replicate these previous findings. Very few investigations addressed the role of nondopaminergic genes, or gene-to-gene interactions in ADHD pharmacogenomics. Pharmacogenomic studies of ADHD are in their infancy. We presented a discussion on the limitations and possible future directions of the research in the field. Drug Dev. Res. 62:172,179, 2004. © 2004 Wiley-Liss, Inc. [source] Low clinical penetrance of homozygosity for HFE C282Y: implications for genetic testing?EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 9 2003M. Födinger No abstract is available for this article. [source] Evaluation of the genetic basis of phenotypic heterogeneity in north Indian patients with Thalassemia majorEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2010Nidhi Sharma Abstract Objectives: To assess the molecular basis of phenotypic heterogeneity in north Indian patients with thalassemia major (TM). Methods: To determine the clinical severity, 130 patients of TM were studied for the age of first presentation and frequency of blood transfusion. The type of beta mutations, Xmn,1G, polymorphism and G6PD Mediterranean mutation was characterized. Analysis of the phenotypic presentation and the genotype was performed. Results: Majority (83.8%) presented before 1 year of age (mean 8.8 months). The caste distribution showed 41.6% were Aroras and 32.3% were migrants from Pakistan. IVS1-5(G,C) was commonest (32.7%) and the common five Indian mutations comprised of 88.4% of alleles. The mean age of presentation with IVS1-5(G,C), Fr 8/9, (+G) 619-bp del and IVS1-1(G,T) homozygosity was 4.3, 6, 3.4 and 9.1 months respectively. Xmn,1G, status showed ,/, in 66.9%, +/, in 26.1% and +/+ in 6.9% patients. Xmn,1G,,/, presented before 1 year of age. The mean age of presentation with +/+ was 18.3 months. Six hemizygous boys and one heterozygous girl with G6PD Mediterranean were found (prevalence 5.3%). Eight patients could be reclassified as thalassemia intermedia on follow up. Conclusions: This study showed that majority of TM in north India present before 1 year of age and homozygous 619-bp deletion presents the earliest. The presence of Xmn-1G, polymorphism delays the presentation, is associated with the IVS 1-1 (G,T) and shows variable improvement with hydroxyurea therapy. Based on the results of genotyping, reevaluation of patients can improve the outcome in a few patients. [source] H63D homozygotes with hyperferritinaemia: is this genotype, the primary cause of iron overload?EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2007Carles De Diego Abstract Objectives:,Hereditary haemochromatosis is a disease that affects iron metabolism and leads to iron overload. Homozygosity for the H63D mutation is associated with increased transferrin saturation (TS) and ferritin levels. Our objective was to find out if the homozygosity of H63D mutation was the primary cause of iron overload. Patients and methods:,We studied 45 H63D homozygotes (31 males and 14 females) with biochemical iron overload and/or clinical features of haemochromatosis. The simultaneous detection of 18 known HFE, TFR2 and FPN1 mutations and sequencing of the HAMP gene were performed to rule out the possible existence of genetic modifier factors related with iron overload. Results:,Values of biochemical iron overload, measured as percentage TS and serum ferritin concentration (SF), in our H63D homozygotes were significantly higher in patients than in controls: TS 55 ± 15% vs. 35 ± 15% and SF 764 (645,883) ,g/L vs. 115 (108,123) ,g/L for patients and controls, respectively. These H63D homozygotes presented extreme hyperferritinaemia and no additional mutations in HFE, TFR2, FPN1 and HAMP genes were detected. Conclusions:,The lack of additional mutations in our H63D homozygotes suggests that this genotype could be the primary cause of iron overload in these patients. Despite our results, we cannot entirely discount the possibility that one or more genetic modifier factor exists, simply because we were unable to find it, although there was a precedent in the HFE gene. Genetic modifier factors have been described for C282Y mutations in the HFE gene, but at the present time they have never been reported in H63D homozygotes. [source] HOW ARE DELETERIOUS MUTATIONS PURGED?EVOLUTION, Issue 12 2003DRIFT VERSUS NONRANDOM MATING Abstract Accumulation of deleterious mutations has important consequences for the evolution of mating systems and the persistence of small populations. It is well established that consanguineous mating can purge a part of the mutation load and that lethal mutations can also be purged in small populations. However, the efficiency of purging in natural populations, due to either consanguineous mating or to reduced population size, has been questioned. Consequences of consanguineous mating systems and small population size are often equated under "inbreeding" because both increase homozygosity, and selection is though to be more efficient against homozygous deleterious alleles. I show that two processes of purging that I call "purging by drift" and "purging by nonrandom mating" have to be distinguished. Conditions under which the two ways of purging are effective are derived. Nonrandom mating can purge deleterious mutations regardless of their dominance level, whereas only highly recessive mutations can be purged by drift. Both types of purging are limited by population size, and sharp thresholds separate domains where purging is either effective or not. The limitations derived here on the efficiency of purging are compatible with some experimental studies. Implications of these results for conservation and evolution of mating systems are discussed. [source] In Candida albicans, resistance to flucytosine and terbinafine is linked to MAT locus homozygosity and multilocus sequence typing clade 1FEMS YEAST RESEARCH, Issue 7 2009Frank C. Odds Abstract A panel of 637 isolates of Candida albicans that had been typed by multilocus sequence typing (MLST) and tested for susceptibility to amphotericin B, caspofungin, fluconazole, flucytosine, itraconazole, ketoconazole, miconazole, terbinafine and voriconazole was the material for a statistical analysis of possible associations between antifungal susceptibility and other properties. For terbinafine and flucytosine, the greatest proportion of low-susceptibility isolates, judged by two resistance breakpoints, was found in MLST clade 1 and among isolates homozygous at the MAT locus, although only three isolates showed cross-resistance to the two agents. Most instances of low susceptibility to azoles, flucytosine and terbinafine were among oropharyngeal isolates from HIV-positive individuals. Statistically significant correlations were found between terbinafine and azole minimal inhibitory concentrations (MICs), while correlations between flucytosine MICs and azole MICs were less strong. It is concluded that a common regulatory mechanism may operate to generate resistance to the two classes of agent that inhibit ergosterol biosynthesis, terbinafine and the azoles, but that flucytosine resistance, although still commonly associated with MAT homozygosity, is differently regulated. [source] Novel regions of acquired uniparental disomy discovered in acute myeloid leukemiaGENES, CHROMOSOMES AND CANCER, Issue 9 2008Manu Gupta The acquisition of uniparental disomy (aUPD) in acute myeloid leukemia (AML) results in homozygosity for known gene mutations. Uncovering novel regions of aUPD has the potential to identify previously unknown mutational targets. We therefore aimed to develop a map of the regions of aUPD in AML. Here, we have analyzed a large set of diagnostic AML samples (n = 454) from young adults (age: 15,55 years) using genotype arrays. Acquired UPD was found in 17% of the samples with a nonrandom distribution particularly affecting chromosome arms 13q, 11p, and 11q. Novel recurrent regions of aUPD were uncovered at 2p, 17p, 2q, 17q, 1p, and Xq. Overall, aUPDs were observed across all cytogenetic risk groups, although samples with aUPD13q (5.4% of samples) belonged exclusively to the intermediate-risk group as defined by cytogenetics. All cases with a high FLT3 -ITD level, measured previously, had aUPD13q covering the FLT3 gene. Significantly, none of the samples with FLT3 -ITD - /FLT3 -TKD+ mutation exhibited aUPD13q. Of the 119 aUPDs observed, the majority (87%) were due to mitotic recombination while only 13% were due to nondisjunction. This study demonstrates aUPD is a frequent and significant finding in AML and pinpoints regions that may contain novel mutational targets. © 2008 Wiley-Liss, Inc. [source] Linkage mapping methods applied to the COGA data set: Presentation Group 4 of Genetic Analysis Workshop 14GENETIC EPIDEMIOLOGY, Issue S1 2005E. Warwick Daw Abstract Presentation Group 4 participants analyzed the Collaborative Study on the Genetics of Alcoholism data provided for Genetic Analysis Workshop 14. This group examined various aspects of linkage analysis and related issues. Seven papers included linkage analyses, while the eighth calculated identity-by-descent (IBD) probabilities. Six papers analyzed linkage to an alcoholism phenotype: ALDX1 (four papers), ALDX2 (one paper), or a combination both (one paper). Methods used included Bayesian variable selection coupled with Haseman-Elston regression, recursive partitioning to identify phenotype and covariate groupings that interact with evidence for linkage, nonparametric linkage regression modeling, affected sib-pair linkage analysis with discordant sib-pair controls, simulation-based homozygosity mapping in a single pedigree, and application of a propensity score to collapse covariates in a general conditional logistic model. Alcoholism linkage was found with ,2 of these approaches on chromosomes 2, 4, 6, 7, 9, 14, and 21. The remaining linkage paper compared the utility of several single-nucleotide polymorphism (SNP) and microsatellite marker maps for Monte Carlo Markov chain combined oligogenic segregation and linkage analysis, and analyzed one of the electrophysiological endophenotypes, ttth1, on chromosome 7. Linkage was found with all marker sets. The last paper compared the multipoint IBD information content of several SNP sets and the microsatellite set, and found that while all SNP sets examined contained more information than the microsatellite set, most of the information contained in the SNP sets was captured by a subset of the SNP markers with ,1-cM marker spacing. From these papers, we highlight three points: a 1-cM SNP map seems to capture most of the linkage information, so denser maps do not appear necessary; careful and appropriate use of covariates can aid linkage analysis; and sources of increased gene-sharing between relatives should be accounted for in analyses. Genet. Epidemiol. 29(Suppl. 1):S29,S34, 2005. © 2005 Wiley-Liss, Inc. [source] Potential role for Interleukin-28B genotype in treatment decision-making in recent hepatitis C virus infection,HEPATOLOGY, Issue 4 2010Jason Grebely Polymorphisms in the IL28B (interleukin-28B) gene region are important in predicting outcome following therapy for chronic hepatitis C virus (HCV) infection. We evaluated the role of IL28B in spontaneous and treatment-induced clearance following recent HCV infection. The Australian Trial in Acute Hepatitis C (ATAHC) was a study of the natural history and treatment of recent HCV, as defined by positive anti-HCV antibody, preceded by either acute clinical HCV infection within the prior 12 months or seroconversion within the prior 24 months. Factors associated with spontaneous and treatment-induced HCV clearance, including variations in IL28B, were assessed. Among 163 participants, 132 were untreated (n = 52) or had persistent infection (infection duration ,26 weeks) at treatment initiation (n = 80). Spontaneous clearance was observed in 23% (30 of 132 participants). In Cox proportional hazards analysis (without IL28B), HCV seroconversion illness with jaundice was the only factor predicting spontaneous clearance (adjusted hazards ratio = 2.86; 95% confidence interval = 1.24, 6.59; P = 0.014). Among participants with IL28B genotyping (n = 102 of 163 overall and 79 of 132 for the spontaneous clearance population), rs8099917 TT homozygosity (versus GT/GG) was the only factor independently predicting time to spontaneous clearance (adjusted hazard ratio = 3.78; 95% confidence interval = 1.04, 13.76; P = 0.044). Participants with seroconversion illness with jaundice were more frequently rs8099917 TT homozygotes than other (GG/GT) genotypes (32% versus 5%, P = 0.047). Among participants adherent to treatment and who had IL28B genotyping (n = 54), sustained virologic response was similar among TT homozygotes (18 of 29 participants, 62%) and those with GG/GT genotype (16 of 25, 64%, P = 0.884). Conclusion: During recent HCV infection, genetic variations in IL28B region were associated with spontaneous but not treatment-induced clearance. Early therapeutic intervention could be recommended for individuals with unfavorable IL28B genotypes. (HEPATOLOGY 2010;) [source] Quantitative isolation of ,1AT mutant Z protein polymers from human and mouse livers and the effect of heat,HEPATOLOGY, Issue 1 2005Jae-Koo An Alpha-1-antitrypsin (,1AT) deficiency in its most common form is caused by homozygosity for the ,1AT mutant Z gene. This gene encodes a mutant Z secretory protein, primarily synthesized in the liver, that assumes an abnormal conformation and accumulates within hepatocytes causing liver cell injury. Studies have shown that mutant ,1ATZ protein molecules form unique protein polymers. These Z protein polymers have been hypothesized to play a critical role in the pathophysiology of liver injury in this disease, although a lack of quantitative methods to isolate the polymers from whole liver has hampered further analysis. In this study, we demonstrate a quantitative ,1ATZ polymer isolation technique from whole liver and show that the hepatocellular periodic acid-Schiff,positive globular inclusions that are the histopathological hallmark of this disease are composed almost entirely of the polymerized ,1ATZ protein. Furthermore, we examine the previously proposed but untested hypothesis that induction of ,1ATZ polymerization by the heat of physiological fever is part of the mechanism of hepatic ,1ATZ protein accumulation. The results, however, show that fever-range temperature elevations have no detectable effect on steady-state levels of intrahepatic Z protein polymer in a model in vivo system. In conclusion, methods to separate insoluble protein aggregates from liver can be used for quantitative isolation of ,1ATZ protein polymers, and the effect of heat from physiological fever may be different in vivo compared with in vitro systems. (HEPATOLOGY 2005;41:160,167.) [source] Effects of structural variations of APOBEC3A and APOBEC3B genes in chronic hepatitis B virus infectionHEPATOLOGY RESEARCH, Issue 12 2009Hiromi Abe Aim:, Human APOBEC3 deaminases induce G to A hypermutation in nascent DNA strand of hepatitis B virus (HBV) genomes and seem to operate as part of the innate antiviral immune system. We analyzed the importance of APOBEC3A (A3A) and APOBEC3B (A3B) proteins, which are potent inhibitors of adeno-associated-virus and long terminal repeat (LTR)-retrotransposons, in chronic HBV infection. Methods:, We focused on the common deletion polymorphism that spans from the 3, part of A3A gene to the 3, portion of A3B gene. An association study was carried out in 724 HBV carriers and 469 healthy control subjects. We also analyzed hypermutated genomes detected in deletion and insertion (non-deletion) homozygous patients to determine the effect of APOBEC3 gene deletion. Further, we performed functional analysis of A3A gene by transient transfection experiments. Results:, The association study showed no significant association between deletion polymorphism and chronic HBV carrier state. Context analysis also showed a negligible effect for the deletion. Rather, mild liver fibrosis was associated with APOBEC gene deletion homozygosity, suggesting that A3B deletion is not responsible for chronic HBV infection. Functional analysis of A3A showed that overexpression of A3A induced hypermutation in HBV genome, although the levels of hypermutants were less than those introduced by A3G. However, overexpression of A3A did not decrease replicative intermediates of HBV. Conclusion:, These results suggest that A3A and A3B play little role in HBV elimination through anti-viral defense mechanisms. The significance of hypermutation induced by A3A should be investigated further. [source] OBSL1 mutations in 3-M syndrome are associated with a modulation of IGFBP2 and IGFBP5 expression levels,HUMAN MUTATION, Issue 1 2010Celine Huber Abstract 3-M syndrome is an autosomal recessive disorder characterized by severe pre- and postnatal growth retardation and minor skeletal changes. We have previously identified CUL7 as a disease-causing gene but we have also provided evidence of genetic heterogeneity in the 3-M syndrome. By homozygosity mapping in two inbred families, we found a second disease locus on chromosome 2q35,36.1 in a 5.2-Mb interval that encompasses 60 genes. To select candidate genes, we performed microarray analysis of cultured skin fibroblast RNA from one patient, looking for genes with altered expression; we found decreased expression of IGFBP2 and increased expression of IGFBP5. However, direct sequencing of these two genes failed to detect any anomaly. We then considered other candidate genes by their function/location and found nine distinct mutations in the OBSL1 gene in 13 families including eight nonsense and one missense mutations. To further understand the links between OBSL1, CUL7, and insulin-like growth factor binding proteins (IGFBPs), we performed real-time quantitative PCR (RT-PCR) analysis for OBSL1, CUL7, IGFBP2, and IGFBP5, using cultured fibroblast RNAs from two patients with distinct OBSL1 mutations (p.F697G; p.H814RfsX15). We found normal CUL7 mRNA levels but abnormal IGFBP2 and IGFBP5 mRNA levels in the two patients, suggesting that OBSL1 modulates the expression of IGFBP proteins. Hum Mutat 30:1,7, 2009. © 2009 Wiley-Liss, Inc. [source] Mutation analysis in nephronophthisis using a combined approach of homozygosity mapping, CEL I endonuclease cleavage, and direct sequencing,HUMAN MUTATION, Issue 3 2008Edgar A. Otto Abstract Nephronophthisis (NPHP), an autosomal recessive kidney disease, is the most frequent genetic cause of chronic renal failure in the first three decades of life. Mutations in eight genes (NPHP1,8) have been identified. We here describe a combined approach for mutation screening of NPHP1, NPHP2, NPHP3, NPHP4, and NPHP5 in a worldwide cohort of 470 unrelated patients with NPHP. First, homozygous NPHP1 deletions were detected in 97 patients (21%) by multiplex PCR. Second, 25 patients with infantile NPHP were screened for mutations in inversin (NPHP2/INVS). We detected a novel compound heterozygous frameshift mutation (p.[Q485fs]+[R687fs]), and a homozygous nonsense mutation (p.R899X). Third, 37 patients presenting with NPHP and retinitis pigmentosa (Senior-Lřken syndrome [SLS]) were screened for NPHP5/IQCB1 mutations by direct sequencing. We discovered five different (three novel) homozygous premature termination codon (PTC) mutations (p.F142fsX; p.R461X; p.R489X; p.W444X; and c.488,1G>A). The remaining 366 patients were further investigated for mutations in NPHP1, NPHP3, and NPHP4. We applied a "homozygosity only" strategy and typed three highly polymorphic microsatellite markers at the respective loci. A total of 32, eight, and 14 patients showed homozygosity, and were screened by heteroduplex crude celery extract (CEL I) endonuclease digests. The sensitivity of CEL I was established as 92%, as it detected 73 out of 79 different known mutations simply on agarose gels. A total of 10 novel PTC mutations were found in NPHP1 (p.P186fs, p.R347X, p.V492fs, p.Y509X, and c.1884+1G>A), in NPHP3 (c.3812+2T>C and p.R1259X), and in NPHP4 (p.R59X, p.T1004fs, and p.V1091fs). The combined homozygosity mapping and CEL I endonuclease mutation analysis approach allowed us to identify rare mutations in a large cohort of patients at low cost. Hum Mutat 29(3), 418,426, 2008. © 2007 Wiley-Liss, Inc. [source] Susceptibility to refractory ulcerative colitis is associated with polymorphism in the hMLH1 mismatch repair geneINFLAMMATORY BOWEL DISEASES, Issue 6 2004Siro Bagnoli MD Abstract The hMLH1 gene lies in the linkage susceptibility region to inflammatory bowel disease (IBD) on 3p21. A single nucleotide polymorphism, 655A>G, in exon 8 of the gene causes an I219V change in the MLH1 protein. To test whether hMLH1 may confer susceptibility to ulcerative colitis (UC), we investigated an association between the 655A>G polymorphism and the disease. DNA-based technologies were used to analyze the 655A>G polymorphism in 201 UC patients and 126 healthy ethnically matched controls. The comparison of the allelic frequencies of the 655A>G polymorphism in UC patients and healthy controls did not show significant differences. However, genotype frequencies at the hMLH1 655 position were found to be significantly different when patients with and without refractory UC were compared. This was mainly attributable to a higher level of homozygosity for the G allele in refractory UC patients. Almost 5 times as many (4.9 times) refractory UC patients carried the GG genotype compared with nonrefractory patients (P < 0.0001). The present study provides evidence that the hMLH1 gene is involved in genetic susceptibility to refractory UC. If confirmed by other studies, the GG genotype at position 655 of the hMLH1 gene may represent a useful predictive factor for the clinical management of UC patients. [source] | ||||||||||||||||||||||||||||||||||