Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Telomeres define the ends of chromosomes; they consist of short tandemly repeated DNA sequences loosely conserved in eukaryotes (G1-8(T/A)1-4). Telomerase is a ribonucleoprotein which, in vitro, recognizes a single-stranded G-rich telomere primer and adds multiple telomeric repeats to its 3' end by using a template in the RNA moiety. In conjunction with other components, telomerase may balance the loss of telomeric repeats due to DNA replication. Another role of telomerase may be the de novo formation of telomeres. In eukaryotes like Tetrahymena, this process is an integral part of the formation of macronuclear chromosomes. In other eukaryotes this process stabilizes broken chromosomes. A case of human alpha-thalassaemia is caused by a truncation of chromosome 16 that has been healed by the addition of telomeric repeats (TTAGGG)n. Using an in vitro assay, I show here that human telomerase correctly recognizes the chromosome 16 breakpoint sequence and adds (TTAGGG)n repeats. The DNA sequence requirements are minimal and seem to define two modes of DNA recognition by telomerase.
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PMID:Recognition of a chromosome truncation site associated with alpha-thalassaemia by human telomerase. 189 89

The instability of chromosomes with breaks induced by X-irradiation led to the proposal that the natural ends of chromosomes are capped by a specialized structure, the telomere. Telomeres prevent end-to-end fusions and exonucleolytic degradation, enable the end of the linear DNA molecule to replicate, and function in cell division. Human telomeric DNA comprises approximately 2-20 kilobases (kb) of the tandemly repeated sequence (TTAGGG)n oriented 5'----3' in towards the end of the chromosome, interspersed with variant repeats in the proximal region. Immediately subtelomeric lie families of unrelated repeat motifs (telomere-associated sequences) whose function, if any, is unknown. In lower eukaryotes the formation and maintenance of telomeres may be mediated enzymatically (by telomerase) or by recombination; in man the mechanisms are poorly understood, although telomerase has been identified in HeLa cells. Here we describe an alpha thalassaemia mutation associated with terminal truncation of the short arm of chromosome 16 (within band 16p13-3) to a site 50 kb distal to the alpha globin genes, and show that (TTAGGG)n has been added directly to the site of the break. The mutation is stably inherited, proving that telomeric DNA alone is sufficient to stabilize the broken chromosome end. This mechanism may occur in any genetic disease associated with chromosome truncation.
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PMID:A truncated human chromosome 16 associated with alpha thalassaemia is stabilized by addition of telomeric repeat (TTAGGG)n. 197 28

A constitutional, balanced chromosomal translocation t(11;22)(p15.5;q11.21) was discovered in a tall young man during investigation of a red cell dimorphism. The red cells are predominantly normochromic and normocytic with a small population of hypochromic, microcytic cells. Contained within the regions involved in the translocation are determinants of height (IGF2:11p15.5), red cell haemoglobinization (non-alpha globin gene complex: 11p15.5) and oncogenesis (cHa-Ras-1, Beckwith-Wiedemann syndrome: 11p15.5; BCR, Burkitts lymphoma, Ewings sarcoma: 22q11.21). To map these regions in the patient, somatic cell hybrids were generated and cell lines that segregated the chromosomes 11, 22 and 22q- were obtained. All 11p15.5 sequences investigated, in particular the whole of the non-alpha globin gene complex including its 5' and 3' regulatory sequences, were found to be translocated to 22q-. All chromosome 22 sequences studied were missing from the 22q- cell lines, including the proximal anonymous marker D22S24, and therefore assumed to be translocated to 11p+. These results suggest that the non-alpha globin gene complex has been moved close to the centromeric region of chromosome 22q-. It is postulated that such a positioning subjects the complex to a variegated position-effect bringing about a clonal exclusion of the complex and thus producing a beta-thalassaemia trait mosaic.
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PMID:Red cell dimorphism in a young man with a constitutional chromosomal translocation t(11;22)(p15.5;q11.21). 794 83

Linkage analysis was performed in a three generation family with three males affected by the recently delineated X-linked form of alpha-thalassemia/mental retardation syndrome (ATR-X). Results are in agreement with the linkage study reported by Gibbons et al in 1992 and further confirm that the ATR-X gene is located in proximal Xq. Positive LOD scores were obtained for several markers situated in the pericentromeric region. A maximum LOD score of 2.09 at a recombination fraction of 0 was obtained for DXS453 located at the boundary q12-q13.1. The nearest flanking loci demonstrating recombination with the disease locus were AR at Xq11.2-q12 on the centromeric side and DXS72 at Xq21.1 on the telomeric side. Consequently the authors were able to reduce the previously defined candidate region for the gene location. Their results are compatible with a distal boundary at Xq21.1 instead of q21.31.
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PMID:X-linked alpha-thalassemia/mental retardation syndrome. Linkage analysis in a new family further supports localization in proximal Xq. 816 23

We have previously described a series of patients in whom the deletion of 1-2 megabases (Mb) of DNA from the tip of the short arm of chromosome 16 (band 16p13.3) is associated with alpha-thalassemia/mental retardation syndrome (ATR-16). We now show that one of these patients has a de novo truncation of the terminal 2 Mb of chromosome 16p and that telomeric sequence (TTAGGG)n has been added at the site of breakage. This suggests that the chromosomal break, which is paternal in origin and which probably arose at meiosis, has been stabilized in vivo by the direct addition of the telomeric sequence. Sequence comparisons of this breakpoint with that of a previously described chromosomal truncation (alpha alpha)TI do not reveal extensive sequence homology. However, both breakpoints show minimal complementarity (3-4 bp) to the proposed RNA template of human telomerase at the site at which telomere repeats have been added. Unlike previously characterized individuals with ATR-16, the clinical features of this patient appear to be solely due to monosomy for the terminal portion of 16p13.3. The identification of further patients with "pure" monosomy for the tip of chromosome 16p will be important for defining the loci contributing to the phenotype of this syndrome.
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PMID:De novo truncation of chromosome 16p and healing with (TTAGGG)n in the alpha-thalassemia/mental retardation syndrome (ATR-16). 846 Jun 33

The chromosome-16 and the X-chromosome forms of alpha-thalassemia--ATR-16 and ATR-X--exemplify 2 important causes of syndromal mental retardation. ATR-16 is a contiguous gene syndrome which arises from loss of DNA from the tip of chromosome 16p13.3 by truncation, interstitial deletion, or unbalanced translocation. It provided the first example of a chromosome translocation that could be detected by molecular analysis but not conventional cytogenetics. It also provided the first example of a telomeric truncation giving rise to a complex genetic syndrome. In contrast ATR-X appears to be due to mutations in a trans-acting factor that regulates gene expression. Mutations in transcription factors have recently been identified in a number of genetic diseases (for example, Denys-Drash syndrome, WT1 [19]; pituitary dwarfism, PIT1 [16]; Rubinstein-Taybi syndrome, CBP [20]. Not only is this mechanism proving to be an important cause of complex syndromes but it is providing new perspectives on certain developmental pathways. XH2 may not be a classical transcription factor but it is certainly involved in the regulation of gene expression, exerting its effects on several different genes. It seems likely that other mutations in this class of regulatory proteins will be found in patients with complex disorders including mental retardation. In broader terms the 2 mechanisms described here may prove to be responsible for a significant proportion of mental retardation. However, without a feature such as alpha-thalassemia to pinpoint the area of genome or pathways involved it may prove difficult to identify other, similarly affected genes underlying other forms of mental retardation. As the human genome project and rapid genome analysis evolve this problem should become less of an obstacle. In the meantime, it is very worthwhile to continue looking for unusual clinical associations that may point to critical genes underlying human genetic disorders.
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PMID:The alpha-thalassemia/mental retardation syndromes. 860 26

SOX proteins are transcription factors that are characterized by a common DNA-binding motif known as the HMG domain. We describe the 5. 4-kb human SOX8 gene that codes for a 446-amino-acid protein and that is expressed strongly in brain and less abundantly in other tissues. SOX8 shows an overall identity of 47% to SOX9 and SOX10. The latter two possess a C-terminal transactivation domain, whereas in SOX8, this domain is located in the central part of the protein. We have mapped SOX8 within 700 kb of the telomeric repeats of band 16p13.3. Hemizygosity for 1 Mb from this region causes the ATR-16 syndrome characterized by alpha-thalassemia and mental retardation. We show that SOX8 is deleted in an ATR-16 patient, and from its location, we deduce that it should be deleted in all previously described cases. Thus, SOX8 is a good candidate gene contributing to the mental retardation phenotype seen in ATR-16 patients.
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PMID:The SOX8 gene is located within 700 kb of the tip of chromosome 16p and is deleted in a patient with ATR-16 syndrome. 1066 50

We have sequenced 1949 kb from the terminal Giemsa light band of human chromosome 16p, enabling us to fully annotate the region extending from the telomeric repeats to the previously published tuberous sclerosis disease 2 (TSC2) and polycystic kidney disease 1 (PKD1) genes. This region can be subdivided into two GC-rich, Alu-rich domains and one GC-rich, Alu-poor domain. The entire region is extremely gene rich, containing 100 confirmed genes and 20 predicted genes. Many of the genes encode widely expressed proteins orchestrating basic cellular processes (e.g. DNA recombination, repair, transcription, RNA processing, signal transduction, intracellular signalling and mRNA translation). Others, such as the alpha globin genes (HBA1 and HBA2), PDIP and BAIAP3, are specialized tissue-restricted genes. Some of the genes have been previously implicated in the pathophysiology of important human genetic diseases (e.g. asthma, cataracts and the ATR-16 syndrome). Others are known disease genes for alpha thalassaemia, adult polycystic kidney disease and tuberous sclerosis. There is also linkage evidence for bipolar affective disorder, epilepsy and autism in this region. Sixty-three chromosomal deletions reported here and elsewhere allow us to interpret the results of removing progressively larger numbers of genes from this well defined human telomeric region.
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PMID:Sequence, structure and pathology of the fully annotated terminal 2 Mb of the short arm of human chromosome 16. 1115 97

We have examined the phenotypic effects of 21 independent deletions from the fully sequenced and annotated 356 kb telomeric region of the short arm of chromosome 16 (16p13.3). Fifteen genes contained within this region have been highly conserved throughout evolution and encode proteins involved in important housekeeping functions, synthesis of haemoglobin, signalling pathways and critical developmental pathways. Although a priori many of these genes would be considered candidates for critical haploinsufficient genes, none of the deletions within the 356 kb interval cause any discernible phenotype other than alpha thalassaemia whether inherited via the maternal or paternal line. These findings contrast with previous observations on patients with larger (> 1 Mb) deletions from the 16p telomere and therefore address the mechanisms by which monosomy gives rise to human genetic disease.
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PMID:Monosomy for the most telomeric, gene-rich region of the short arm of human chromosome 16 causes minimal phenotypic effects. 1131 62

The alpha- and beta-globin gene clusters have been extensively studied. Regulation of these genes ensures that proteins derived from both loci are produced in balanced amounts, and that expression is tissue-restricted and specific to developmental stages. Here we compare the subnuclear location of the endogenous alpha- and beta-globin loci in primary human cells in which the genes are either actively expressed or silent. In erythroblasts, the alpha- and beta-globin genes are localized in areas of the nucleus that are discrete from alpha-satellite-rich constitutive heterochromatin. However, in cycling lymphocytes, which do not express globin genes, the distribution of alpha- and beta-globin genes was markedly different. beta-globin loci, in common with several inactive genes studied here (human c-fms and SOX-1) and previously (mouse lambda5, CD4, CD8alpha, RAGs, TdT and Sox-1), were associated with pericentric heterochromatin in a high proportion of cycling lymphocytes. In contrast, alpha-globin genes were not associated with centromeric heterochromatin in the nucleus of normal human lymphocytes, in lymphocytes from patients with alpha-thalassaemia lacking the regulatory HS-40 element or entire upstream region of the alpha-globin locus, or in mouse erythroblasts and lymphocytes derived from human alpha-globin transgenic mice. These data show that the normal regulated expression of alpha- and beta-globin gene clusters occurs in different nuclear environments in primary haemopoietic cells.
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PMID:Expression of alpha- and beta-globin genes occurs within different nuclear domains in haemopoietic cells. 1138 46


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