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)

We describe a pedigree presenting X-linked severe mental retardation associated with multiple congenital abnormalities and 46,XY gonadal dysgenesis, leading in one family member to female gender assignment. Female carriers are unaffected. The dysmorphic features are similar to those described in the alpha-thalassemia and mental retardation (ATR-X) syndrome, although there is no clinical evidence of alpha-thalassemia in this family. In addition, the family had other clinical features not previously observed in the ATR-X syndrome, including partial optic-nerve atrophy and partial ocular albinism. Mutations in a putative DNA helicase, termed XH2, have been reported to give rise to the ATR-X syndrome. We screened the XH2 gene for mutations in affected members of the family and identified a 4-bp deletion at an intron/exon boundary that removes an invariant 3' splice-acceptor site. The mutation cosegregates with the syndrome. The genomic deletion causes missplicing of the pre-mRNA, which results in the loss of 8 bp of coding sequence, thereby generating a frameshift and a downstream premature stop codon. Our finding increases the range of clinical features associated with mutations in the XH2 gene.
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PMID:A novel mutation in the putative DNA helicase XH2 is responsible for male-to-female sex reversal associated with an atypical form of the ATR-X syndrome. 865 Dec 95

It was shown recently that mutations of the ATRX gene give rise to a severe, X-linked form of syndromal mental retardation associated with alpha thalassaemia (ATR-X syndrome). In this study, we have characterised the full-length cDNA and predicted structure of the ATRX protein. Comparative analysis shows that it is an entirely new member of the SNF2 subgroup of a superfamily of proteins with similar ATPase and helicase domains. ATRX probably acts as a regulator of gene expression. Definition of its genomic structure enabled us to identify four novel splicing defects by screening 52 affected individuals. Correlation between these and previously identified mutations with variations in the ATR-X phenotype provides insights into the pathophysiology of this disease and the normal role of the ATRX protein in vivo.
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PMID:ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome. 896 41

We have previously reported the isolation of a gene from Xq13, coding for a putative regulator of transcription (XNP). It is a member of the helicase family, and has now been shown to be the gene involved in the X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome. ATR-X mutations were only found in the 3'-part of the coding sequence, which includes the helicase domains. However, no ATR-X mutation has yet been found in one of the seven conserved helicase domains. In this paper, we report a mutation in XNP, segregating in a family presenting an "ATR-X' phenotype without alpha-thalassemia, that causes a proline to serine transition in the helicase II domain.
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PMID:A point mutation in the XNP gene, associated with an ATR-X phenotype without alpha-thalassemia. 904 63

A syndrome with distinctive facies, poor muscle tone, absent deep tendon reflexes, tapered fingers, excessive fingerprint arches, genu valgum and mild-moderate mental retardation has occurred in four males in two generations of a white family of European ancestry. The facies are characterised by square configuration, tented upper lip, and thickening of the helices, upper eyelids, and alae nasi. At birth and at maturity, growth (head circumference, height, weight) of affected males is comparable to or greater than unaffected male sibs. Moderate impairment of cognitive function was documented (IQ scores between 40-51). Carriers show no heterozygote manifestations. This X linked condition appears to be different from other syndromes with mental retardation, although there are certain similarities with the alpha thalassaemia-mental retardation syndrome (ATR-X). Linkage analysis found tight linkage to DXS1166 and DXS995 in Xq13 and Xq21 respectively.
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PMID:Arch fingerprints, hypotonia, and areflexia associated with X linked mental retardation. 919 65

A search of the Human Genome Sciences database of expressed sequence-tagged DNA fragments, for sequences containing homology to known yeast DNA recombination and repair genes, yielded a cDNA fragment with high homology to RAD54. Here we describe the complete cDNA sequence and the characterization of the genomic locus coding for the human homologue of the yeast RAD54 gene (hRAD54). The yeast RAD54 belongs to the RAD52 epistasis group and appears to be involved in both DNA recombination and repair. The hRAD54 gene maps to chromosome 1p32 in a region of frequent loss of heterozygosity in breast tumors and encodes a protein of M(r) 93,000 that displays 52% identity to the yeast RAD54 protein. The hRAD54 protein sequence additionally contains all seven of the consensus segments of a superfamily of proteins with presumed or proven DNA helicase activity. Mutations in genes with consensus helicase homology have been found in cancer-prone syndromes such as xeroderma pigmentosum and Bloom syndrome as well as Werner's syndrome, in which patients age prematurely, and the X-linked mental retardation with alpha-thalassemia syndrome, ATR-X. We have examined the hRAD54 gene in several breast tumors and breast tumor cell lines and, although the gene region appears to be deleted in several tumors, at present we have found no coding sequence mutations.
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PMID:Characterization of the human homologue of RAD54: a gene located on chromosome 1p32 at a region of high loss of heterozygosity in breast tumors. 919 13

Six known or predicted helicases that are mutated in human syndromes are now recognized. These syndromes include xeroderma pigmentosum, Cockayne's syndrome, trichothiodystrophy, Bloom's syndrome, Werner's syndrome, and alpha-thalassemia mental retardation on the X chromosome. The clinical abnormalities in these syndromes cover a broad spectrum, pointing to different cellular processes of DNA manipulation that are defective in these syndromes.
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PMID:DNA helicases in inherited human disorders. 922 11

The XNP/ATR-X gene is involved in several X-linked mental retardation phenotypes: the ATR-X syndrome, the Juberg-Marsidi syndrome, and some severe mental retardation phenotypes without alpha-thalassemia. Using a vectorette strategy, we have identified and sequenced the intron/exon boundaries of this gene. The gene is composed of 35 exons. It encodes a potential protein of 2492 amino acids. A search of the databases identified three zinc finger motifs within the 5' end of the gene. Expression analysis in different tissues indicated that an alternative splicing event that involves exon 6 is occurring. One of these alternatively spliced transcripts is predominantly expressed in embryonic tissues. These data led us to search for mutations in the 5' region in ATRX patients without other mutations in the 3' region. In one patient a mutation was found in which part of exon 7 was removed from the XNP transcript, as a result of a mutation creating a novel splice site that is substituted for the natural splice site. This new splicing event removed one zinc finger motif. This is the first example of a mutation in XNP within the 5' coding region. It suggests that mutations will be predominantly found in the helicase region as well as in the zinc finger regions and leads us to propose a large screening of additional patients.
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PMID:Determination of the genomic structure of the XNP/ATRX gene encoding a potential zinc finger helicase. 924 31

Two brothers are presented who were previously diagnosed to have atypical Smith-Lemli-Opitz syndrome. On repeated examinations, however, the facial anomalies of the patients suggested that they would have rather alpha-thalassaemia/mental retardation syndrome. The presence of hemoglobin H inclusions in the peripheral red blood cell supported the clinical suspicion. The search for hemoglobin H inclusions should be considered as a screening test when evaluating mentally retarded boys.
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PMID:[Alpha thalassemia/metal retardation syndrome--a new X-chromosome linked recessive genetically inherited symptom complex]. 967 15

GDP-dissociation inhibitors (GDIs) play a primary role in modulating the activity of GTPases. We recently reported the identification of a new GDI for the Rho-related GTPases named RhoGDIgamma. This gene is now designated ARHGDIG by HUGO. Here, in a detailed analysis of tissue expression of ARHGDIG, we observe high levels in the entire brain, with regional variations. The mRNA is also present at high levels in kidney and pancreas and at moderate levels in spinal cord, stomach, and pituitary gland. In other tissues examined, the mRNA levels are very low (lung, trachea, small intestine, colon, placenta) or undetectable. RT-PCR analysis of total RNA isolated from exocrine pancreas and islets shows that the gene is expressed in both tissues. We also report the genomic structure of ARHGDIG. The gene spans over 4 kb and is organized into six exons and five introns. The upstream region lacks a canonical TATA box and contains several putative binding sites for ubiquitous and tissue-specific factors active in central nervous system development. Using FISH, we have mapped the gene to chromosome band 16p13.3. This band is rich in deletion mutants of genes involved in several human diseases, notably polycystic kidney disease, alpha-thalassemia, tuberous sclerosis, mental retardation, and cancer. The promoter structure and the chromosomal location of RhoGDIgamma suggest its importance and underscore the need for further investigation into its biology.
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PMID:Human ARHGDIG, a GDP-dissociation inhibitor for Rho proteins: genomic structure, sequence, expression analysis, and mapping to chromosome 16p13.3. 978 82

We describe a three-generation family in which X-linked mental retardation (XLMR) is associated with minor facial anomalies and brachydactyly. Two brothers and four nephews have "coarse" facial appearance, brachydactyly with widening of the distal phalanges, short stature, and moderate mental retardation. The three obligate carrier women have normal intelligence and normal physical findings. The results of linkage analysis carried out in 1988 using restriction fragment length polymorphisms (RFLPs) were suggestive of linkage to DXYS1 and DXS101 in proximal Xq (Zmax = 1.63 at straight thetamax = 0.0) [Carpenter et al., 1988: Am J Med Genet 43:A139]. The family was restudied with 16 microsatellite loci from Xp11.4 through Xq24. Linkage analysis demonstrated significant linkage to DXS1003, ALAS2, AR, DXS986, DXS990, DXS454, DXS1106, DXS1105, and DXS1220 from Xp11.3 to Xq23 (Zmax = 2.53 at straight thetamax = 0.0). Recombinations detected between MAOB and DXS1055 and between DXS1220 and DXS1001 place the disease locus between Xp11.3 and Xq23. Among the genes known to map to this region is the XNP gene for the alpha-thalassemia/mental retardation syndrome (ATR-X). This fact, along with the phenotypic similarity between our patients and ATR-X males, led us to consider XNP as a candidate gene for this family. X-inactivation studies provided further evidence for the involvement of XNP by showing completely skewed X-inactivation patterns in the three obligate carrier females, a pattern characteristic of carriers of XNP mutations.
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PMID:X-linked mental retardation syndrome with characteristic "coarse" facial appearance, brachydactyly, and short stature maps to proximal Xq. 1039 34


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