Mutations in a putative global transcriptional regulator cause X-linked mental retardation with α-thalassemia (ATR-X syndrome)

@article{Gibbons1995MutationsIA,
  title={Mutations in a putative global transcriptional regulator cause X-linked mental retardation with $\alpha$-thalassemia (ATR-X syndrome)},
  author={Richard J. Gibbons and David J. Picketts and Laurent Villard and Douglas R. Higgs},
  journal={Cell},
  year={1995},
  volume={80},
  pages={837-845}
}

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The alpha-thalassemia/mental retardation syndromes.

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Evidence for a new X-linked mental retardation gene in Xp21-Xp22: clinical and molecular data in one family.

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ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome.

The full-length cDNA and predicted structure of the ATRX protein is characterised and 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.
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References

SHOWING 1-10 OF 63 REFERENCES

X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome: localization to Xq12-q21.31 by X inactivation and linkage analysis.

It is shown that intellectually normal female carriers of this syndrome may be identified by the presence of rare cells containing HbH inclusions in their peripheral blood and by an extremely skewed pattern of X inactivation seen in cells from a variety of tissues.

X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome: a new kindred with severe genital anomalies and mild hematologic expression.

More widespread use of brilliant cresyl blue staining for HbH inclusions in individuals with the facial phenotype of ATR-X and/or ambiguous genitalia may lead to the identification of more affected patients and improved understanding of the clinical spectrum of ATr-X.

Cloning and expression of the murine homologue of a putative human X-linked nuclear protein gene closely linked to PGK1 in Xq13.3.

The cloning and characterization of the murine homologue of the XNP suggests that this gene might be involved in neuronal differentiation, and among the different morbid phenotypes assigned to the region, X-linked mental retardation would be the best candidate to be associated with this gene.

Clinical and hematologic aspects of the X-linked α-thalassemia/mental retardation syndrome (ATR-X)

The consistency of the main characteristics of this syndrome is demonstrated and the developmental changes in phenotype, in particular the coarsening of the facial appearance, are illustrated and the hematologic findings are shown to vary widely.

Clinical features and molecular analysis of the alpha thalassemia/mental retardation syndromes. II. Cases without detectable abnormality of the alpha globin complex.

It is speculated that the locus of this underlying mutation is not closely linked to the alpha globin complex and may encode a trans-acting factor involved in the normal regulation ofalpha globin expression.

Hemoglobin H disease and mental retardation: a new syndrome or a remarkable coincidence?

Each of three families of northern European origin contains a mentally retarded son with hemoglobin H (Hb H) disease, suggesting that this form of Hb H disease results from the interaction between an inherited defect of alpha-chain production and one member of the pair in chromosome 16 and a new mutation on the other.

Cloning and characterization of a new human Xq13 gene, encoding a putative helicase.

Cl cloning and characterization of a new human Xq13 gene (XH2) is described, extending over a 220 kb genomic stretch between MNK and DXS56, which contains a 4 kb open reading frame and encodes a putative NTP-binding nuclear protein homologous to several members of the helicase II superfamily.

Delineation of the dystonia-parkinsonism syndrome locus in Xq13.

Assignment of DYT3 to a region in Xq13, flanked by loci 4548-7 and DXS159, is further supported by highly significant allelic association between DyT3 and a total of four DNTR loci--PY2-31, PY5-10, 45 48-1, and 4548 -7--located in a region defined by PGK1 andDXS56.

Mutations in the xeroderma pigmentosum group D DNA repair/transcription gene in patients with trichothiodystrophy

This work has identified causative mutations in XPD in four TTD patients and suggested relationships between different domains in the gene and its roles in excision repair and transcription.

A deletion of the human beta-globin locus activation region causes a major alteration in chromatin structure and replication across the entire beta-globin locus.

The results suggest that the LAR is required for both the erythroid-specific chromatin structure and timing of DNA replication over a large physical distance.
...