The biallelic expression pattern of X-linked genes in Klinefelter syndrome by pyrosequencing.
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Alleles↗
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Colorectal cancer risk in individuals with biallelic or monoallelic mutations of MYH.
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Adult↗
Biallelic IgH rearrangements in patients with indolent lymphoproliferative disorders: molecular and practical implications.
We report a group of patients (pts) with indolent lymphoproliferative disorder who had both alleles for the immunoglobulin heavy chain genes rearranged (biIgH). This group of 17 pts consisted of 9 small lymphocytic lymphomas (SLL) and 8 chronic lymphocytic leukemia (CLL). The polymerase chain reaction (PCR) amplification of clonal immunoglobulin heavy (IgH) rearrangement using the complementarity determining region III (CDRIII) constantly retrieved two distinct bands in all PCR informative samples of those pts. To rule out biclonality, we evaluated samples by fluorescein activated cell sorting (FACS) analysis and sequenced the PCR products. We were able to obtain both IgH sequences from 12 patients. FACS suggested biclonality in one case, which also correlated with sequencing results as both IgH rearrangements were in-frame. Recently, we reported a patient who sustained transformation into an aggressive disease after biIgH was detected in the setting of monoclonal disease (Cerny et al., 2003b, Haematologica 88(05):ECR15 B.). We decided to compare clinical characteristics and prognosis of 17 pts with biIgH and 37 pts with monoIgH rearrangements. Although we found some minor differences in disease characteristics between both groups, these did not translate into a significantly different overall survival. Our findings suggest that true biclonal cases of CLL are rare.
Adult↗
A new biallelic polymorphism in intron 1 of the CHRNA4 gene may cause erroneous genotyping of a closely linked CA repeat marker.
A new polymorphism in intron 1 of the neuronal nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4) was identified. It consists of a G to T substitution located in the downstream flanking region of a previously reported CA repeat marker. This polymorphism whose frequency is about six percent in a control population occurs near the 3' end of the reverse primer generally used to type the CA repeat marker. Data are presented showing that the newly identified polymorphism causes erroneous genotyping of the CA repeat marker which can alter the results of linkage analysis for CHRNA4. The use of a different reverse primer located 34 nt downstream of the published sequence overcame errors in genotyping and identified two novel alleles of the CA repeat marker. Re-typing of the marker with the new proposed primer pair in a Caucasian control population of 107 unrelated individuals was also performed
Alleles↗
Biallelic heavy chain immunoglobulin gene rearrangement in acute nonlymphocytic leukemia.
Acute nonlymphocytic leukemia (ANLL) was diagnosed in 18 patients based on morphological, cytochemical and immunological criteria. Leukemic cells of these cases were subjected to Southern blot analysis and subsequent hybridization to heavy chain immunoglobulin and T-cell-receptor gene probes. A rearrangement within the immunoglobulin joining region was detected in 2 cases, while the T-cell-receptor beta-chain gene was in germline configuration in all samples investigated. These data confirm recent reports indicating that immunoglobulin heavy chain gene rearrangements are not restricted to B-lineage neoplasms.
Adult↗
The biallelic a mating type locus of Ustilago maydis: remnants of an additional pheromone gene indicate evolution from a multiallelic ancestor.
The a mating type locus of Ustilago maydis contains the structural genes for a pheromone-based cell recognition system that governs fusion of haploid cells. The locus exists in two alleles, termed a1 and a2. We have completed the analysis of the nucleotide sequences unique to a1 and a2. Within these dissimilar regions we find two short patches of DNA sequence similarity. Interestingly, one of these segments corresponds to the transcribed region of the a1 pheromone precursor. As a result of multiple nucleotide exchanges this sequence does not code for a functional product. The existence of a second pheromone gene in the a2 allele suggests that the present locus had a multiallelic ancestor. In addition, we describe the presence of two additional genes in the a2 allele. We have investigated the role of these genes during mating and pathogenic development and speculate that they might affect mitochondrial inheritance.
Alleles↗
Sequence of a 42-kb mouse region containing the imprinted H19 locus: identification of a novel muscle-specific transcription unit showing biallelic expression.
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Alleles↗
HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability.
Individuals with hemizygous germline fumarate hydratase (FH) mutations are predisposed to renal cancer. These tumors predominantly exhibit functional inactivation of the remaining wild-type allele, implicating FH inactivation as a tumor-promoting event. Hypoxia-inducible factors are expressed in many cancers and are increased in clear cell renal carcinomas. Under normoxia, the HIFs are labile due to VHL-dependent proteasomal degradation, but stabilization occurs under hypoxia due to inactivation of HIF prolyl hydroxylase (HPH), which prevents HIF hydroxylation and VHL recognition. We demonstrate that FH inhibition, together with elevated intracellular fumarate, coincides with HIF upregulation. Further, we show that fumarate acts as a competitive inhibitor of HPH. These data delineate a novel fumarate-dependent pathway for regulating HPH activity and HIF protein levels.
Adult↗
Biallelic ATP8B3 variants cause male infertility and fertilization failure in humans.
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Letter↗
Biallelic rescue of CTG18.1 in two Fuchs endothelial corneal dystrophy-derived iPSC lines (SCTCi047-A-2, SCTCi046-A-2) following a two-step gene editing strategy.
Fuchs endothelial corneal dystrophy (FECD) is an age-related condition distinguished by the degeneration of the corneal endothelium. An intronic CTG18.1 repeat in the transcription factor 4 (TCF4) gene has been associated with a 78-fold increased risk of developing the disease when at least one copy of the CTG18.1 expands above 50 repeats. Employing patient-derived material, we applied a dual CRISPR/Cas9-mediated editing approach to rescue the expansion. Combining non-homologous end-joining (NHEJ) and homologous direct repair (HDR) events, we generated two FECD-derived +/+(CTG)8 induced pluripotent stem cell (iPSC) lines, which were then successfully characterized, providing relevant isogenic controls for disease-modelling purposes.
Humans↗
Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors.
Germline mutations in the fumarate hydratase (FH) gene at 1q43 predispose to dominantly inherited cutaneous and uterine leiomyomas, uterine leiomyosarcoma, and papillary renal cell cancer (HLRCC syndrome). To evaluate the role of FH inactivation in sporadic tumorigenesis, we analyzed a series of 299 malignant tumors representing 10 different malignant tumor types for FH mutations. Additionally, 153 uterine leiomyomas from 46 unselected individuals were subjected to and informative in loss of heterozygosity analysis at the FH locus, and the five (3.3%) tumors displaying loss of heterozygosity were subjected to FH mutation analysis. Although mutation search in the 299 malignant tumors was negative, somatic FH mutations were found in two nonsyndromic leiomyomas; a splice site change IVS4 + 3A>G, leading to deletion of exon four, and a missense mutation Ala196Thr. The occurrence of somatic mutations strongly suggests that FH is a true target of the 1q43 deletions. Although uterine leiomyomas are the most common tumors of women, specific inactivating somatic mutations contributing to the formation of nonsyndromic leiomyomas have not been reported previously. Taking into account the apparent risk of uterine leiomyosarcoma associated with FH germline mutations, the finding raises the possibility that also some nonsyndromic leiomyomas may have a genetic profile that is more prone to malignant degeneration. Our data also indicate that somatic FH mutations appear to be limited to tumor types observed in hereditary leiomyomatosis and renal cell cancer.
Base Sequence↗
Lack of association between a biallelic polymorphism in the adducin gene and blood pressure in whites and African Americans.
Population-based candidate gene association analyses are becoming increasingly popular as a result of a greater number of genes and gene polymorphisms having been identified for which some functional information is available. Because many biochemical and physiologic systems impact blood pressure regulation and hypertension susceptibility, many of these identified genes and polymorphisms are candidates for population-level association studies involving blood pressure levels or hypertension status. Recent studies have suggested that the alpha-adducin gene may harbor polymorphisms that influence blood pressure level. Therefore, we embarked on a study to test one such polymorphism in two large US samples: one from an urban African American population (Maywood, IL) and another from a rural white population (Tecumseh, MI). We used both family-based association tests and tests that consider the impact of additional measured factors beyond adducin gene variation on blood pressure levels. We found no evidence for a significant effect of the chosen adducin polymorphism on blood pressure variation in either sample. We also found no association between Adducin genotypes and antihypertensive use. These facts, together with similar findings in companion studies, suggest that the alpha-adducin gene polymorphism does not have a pronounced effect on blood pressure variation in the populations studied. This does not suggest, however, that the alpha-adducin gene does not have a role in blood pressure regulation and hypertension susceptibility.
Adult↗
Biallelic transcription of Igf2 and H19 in individual cells suggests a post-transcriptional contribution to genomic imprinting.
The H19 and insulin-like growth factor 2 (Igf2) genes in the mouse are models for genomic imprinting during development. The genes are located only 90 kb apart in the same transcriptional orientation [1], but are reciprocally imprinted: Igf2 is paternally expressed while H19 is maternally expressed. It has been suggested that expression of H19 and repression of Igf2 (or the converse) on a given chromosome are mechanistically linked and that the parental imprint operates at the level of transcription [2]. Although expression of Igf2 and H19 is thought to be monoallelic, the data have so far been obtained exclusively by looking at steady-state RNA levels using techniques that reflect the average activity of the genes in a cell population [3] [4]. Here, we have adapted a fluorescent in situ hybridisation (FISH) method to detect nascent RNA molecules of Igf2 and H19 at the initial transcription sites in the nuclei of wild-type mouse embryonic liver cells. Nine different transcription patterns were observed, reflecting a high heterogeneity of transcription at the single-cell level. Our observations suggest that regulation of Igf2 and H19 by parental imprinting is much more complex than previously proposed and acts at both transcriptional and post-transcriptional levels.
Alleles↗
Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2.
The gene for spinocerebellar ataxia type 2 (SCA2) has been mapped to 12q24.1. A 1.1-megabase contig in the candidate region was assembled in P1 artificial chromosome and bacterial artificial chromosome clones. Using this contig, we identified a CAG trinucleotide repeat with CAA interruptions that was expanded in patients with SCA2. In contrast to other unstable trinucleotide repeats, this CAG repeat was not highly polymorphic in normal individuals. In SCA2 patients, the repeat was perfect and expanded to 36-52 repeats. The most common disease allele contained (CAG)37, one of the shortest expansions seen in a CAG expansion syndrome. The repeat occurs in the 5'-coding region of SCA2 which is a member of a novel gene family.
Amino Acid Sequence↗
Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B.
Mosaic variegated aneuploidy is a rare recessive condition characterized by growth retardation, microcephaly, childhood cancer and constitutional mosaicism for chromosomal gains and losses. In five families with mosaic variegated aneuploidy, including two with embryonal rhabdomyosarcoma, we identified truncating and missense mutations of BUB1B, which encodes BUBR1, a key protein in the mitotic spindle checkpoint. These data are the first to relate germline mutations in a spindle checkpoint gene with a human disorder and strongly support a causal link between aneuploidy and cancer development.
Abnormalities, Multiple↗
Biallelic mutations in the ATM gene in T-prolymphocytic leukemia.
Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, oculocutaneous telangiectasia, immune deficiency, genome instability and predisposition to malignancies, particularly T-cell neoplasms. The responsible gene, designated ataxia-telangiectasia mutated (ATM), was recently identified by positional cloning in the chromosomal region 11q22.3-23.1 (ref. 4, 5) ATM is 150 kb in length, consists of 66 exons and encodes a nuclear phosphoprotein of approximately 350 kDa (ref. 4-9). Although ATM is considered to be a tumorigenic factor in several human cancers, it has not yet been found mutated in tumors of non-AT patients. Given the marked predisposition of AT patients to develop neoplasms of the T-cell lineage, we analyzed a series of T-cell leukemias (T-prolymphocytic leukemia, or T-PLL) in non-AT patients in search of genomic changes associated with the development of this disease. Among the recurrent aberrations identified, deletion of the chromosome arm 11q was very frequent. Subsequent molecular cytogenetic analyses allowed us to define a small commonly deleted segment at 11q22.3-23.1 in 15 of 24 T-PLLs studied. Since this critical region contained ATM, we further analyzed the remaining copy of the gene in six cases showing deletions affecting one ATM allele. In all six cases, mutations of the second ATM allele were identified, leading to the absence, premature truncation or alteration of the ATM gene product. Thus, our study demonstrates disruption of both ATM alleles by deletion or point mutation in T-PLL, suggesting that ATM functions as a tumor-suppressor gene in tumors of non-AT individuals.
Alleles↗
Biallelic inactivation of the RIZ1 gene in human gastric cancer.
The distal short arm of chromosome 1 is commonly deleted in a variety of human neoplasms including gastrointestinal cancer. Genetic alterations of the retinoblastoma protein-interacting zing-finger gene (RIZ)1 including loss of heterozygosity (LOH) at 1p36, frameshift mutations, and promoter hypermethylation were reported previously in several cancers. In this study, we evaluated RIZ1 in 30 primary gastric cancers and found frameshift mutations in two cases (6.7%). Moreover, using real-time quantitative methylation-specific PCR, methylation of the RIZ1 promoter was detected in 11 (37%) cases. In all 11 cases with methylation, inactivation of the second allele occurred through frameshift mutation, LOH or promoter methylation. Our results suggest that RIZ1 is a specific target of inactivation in human gastric cancer.
Adult↗
Biallelic mutations in the CEBPA gene and low CEBPA expression levels as prognostic markers in intermediate-risk AML.
The CCAAT/enhancer binding protein alpha is an essential transcription factor for granulocytic differentiation. Recent studies reported N- and C-terminal CEBPA mutations in approximately 7% of acute myeloid leukaemia (AML) patients. C-terminal mutations are usually in-frame and occur in the basic-leucine zipper (bZIP) domain, resulting in deficient DNA binding. Using a rapid PCR approach, we screened for bZIP mutations and determined the prognostic value of these mutations in a cohort of 277 de novo AMLs. In addition, we set out to quantify CEBPA mRNA levels by 'real-time' PCR using TaqMan technology. In-frame insertions were observed in 12 (4.3%) cases. All cases with mutations carried an intermediate-risk karyotype and all but one belonged to M1 or M2 FAB class. Further sequence analysis revealed that CEBPA C-terminal mutations are associated with frameshift mutations in the N-terminus of CEBPA. These two mutations were always found in different alleles. Event-free survival (EFS) and overall survival (OS) of patients with CEBPA mutations were significantly increased (P=0.02 and 0.03, respectively) in comparison to the patients lacking these mutations. Mutations were associated with a significantly reduced hazard ratio for death (OS: HR=0.35, P=0.04) and failure (EFS: no CR, death in CR or relapse, HR=0.37, P=0.03). This favourable hazard ratio was maintained after adjustment for cytogenetic risk, FLT3-ITD and CEBPA expression levels in multivariable analysis. In contrast, low CEBPA expression in AML with intermediate-risk karyotype (n=6) seemed to be associated with poor prognosis (not significant). By including this newly developed PCR assay, we define a subgroup of good-risk patients within the heterogeneous intermediate-risk group of AML.
Acute Disease↗