Alpha-thalassemia/mental retardation syndrome, X-Linked (ATR-X, MIM #301040, ATR-X/XNP/XH2 gene MIM #300032)

Villard, Laurent; Fontés, Michel

doi:10.1038/sj.ejhg.5200800

Cited by 30 publications

(14 citation statements)

References 10 publications

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“…Subsequently the human ATRX gene was cloned by Gibbons et al (16). The mutation is carried by the mother, as with other X–linked syndromes, and is thought to be involved in the X‐inactivation exhibited by carriers (17, 18).…”

Section: α‐Thalassemia/mental Retardation Syndrome X‐linkedmentioning

confidence: 99%

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Syndromes of disordered chromatin remodeling

Ausió¹,

Levin

Amorim

et al. 2003

Clinical Genetics

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Syndromes of disordered 'chromatin remodeling' are unique in medicine because they arise from a general deregulation of DNA transcription caused by mutations in genes encoding enzymes which mediate changes in chromatin structure. Chromatin is the packaged form of DNA in the eukaryotic cell. It consists almost entirely of repeating units, called nucleosomes, in which short segments of DNA are wrapped tightly around a disk-like structure comprising two subunits of each of the histone proteins H2A, H2B, H3 and H4. Histone proteins are covalently modified by a number of different adducts (i.e. acetylation and phosphorylation) that regulate the tightness of the DNA-histone interactions. Mutations in genes encoding enzymes that mediate chromatin structure can result in a loss of proper regulation of chromatin structure, which in turn can result in deregulation of gene transcription and inappropriate protein expression. In this review we present examples of representative genetic diseases that arise as a consequence of disordered chromatin remodeling. These include: alpha-thalassemia/mental retardation syndrome, X-linked (ATR-X); Rett syndrome (RS); immunodeficiency-centromeric instability-facial anomalies syndrome (ICF); Rubinstein-Taybi syndrome (RSTS); and Coffin-Lowry syndrome (CLS).

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Section: α‐Thalassemia/mental Retardation Syndrome X‐linkedmentioning

confidence: 99%

“…The establishment of ATR‐X as a chromatin‐remodeling syndrome, however, hinges on the discovery of a plant homeodomain (PHD)/zinc‐finger domain in the ATRX protein (18). ATRX is a nuclear protein (19), and a member of the SWI/SNF2 family of proteins, which includes helicases.…”

Section: α‐Thalassemia/mental Retardation Syndrome X‐linkedmentioning

confidence: 99%

Syndromes of disordered chromatin remodeling

Ausió¹,

Levin

Amorim

et al. 2003

Clinical Genetics

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“…Mutations in the X‐linked ATRX gene have been shown to underlie these conditions (7) and more than 60 mutations have been reported so far (8) (Fig. 1).…”

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confidence: 99%

Mutations in PHD‐like domain of the ATRX gene correlate with severe psychomotor impairment and severe urogenital abnormalities in patients with ATRX syndrome

et al. 2006

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Mutations in ATRX are associated with a wide and clinically heterogeneous spectrum of X-linked mental retardation syndromes. The ATRX protein, involved in chromatin remodelling, belongs to the family of SWI/SNF DNA helicases and contains a plant homeodomain (PHD)-like domain. To date, more than 60 different mutations have been reported in ATRX. One of them is recurrent and accounts for 20% of all the reported mutations, whereas all others are private. Most mutations are clustered in the two major functional domains, the helicase and the PHD-like domain. So far, no clear genotype-phenotype correlation has been established, with exception to the rare truncating mutations located at the C-terminal part of the protein, which are consistently associated with severe urogenital defects. In this study, we report the molecular analysis performed in 16 families positive for ATRX. Our findings indicate that, in addition to the previously described mutation 'hotspot' in the PHD-like domain, two other protein sections emerge as minor 'hotspots' in the helicase region encoded by exons 18-20 and 26-29, respectively, gathering 33% of all described mutations. Additionally, based on the clinical data collected for 22 patients from the 16 families, we observe that mutations in the PHD-like domain produce severe and permanent psychomotor deficiency, usually preventing patients from walking, as well as constant urogenital abnormalities, while mutations in the helicase domain lead to delayed but correct psychomotor acquisitions together with mild or absent urogenital abnormalities. In summary, mutations in the helicase domain are associated with milder phenotypes than mutations in the PHD-like domain.

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“…In the developing ovary, DMRT1 is present in the germ cells and then later seen in the granulosa cells and germ cells of the adult ovary [16]. The gonadal phenotype of ATR-X and DMRT1 patients is strikingly overlapping, with initial Sertoli cell development followed by gonadal dysgenesis [16,23-25]. Dmrt1 regulates germ cell proliferation in a cell autonomous and dosage dependent manner in mice, and its loss results in an increased incidence of teratomas [26,27].…”

Section: Discussionmentioning

confidence: 99%

“…In addition Dmrt1 is required to maintain Sertoli cell proliferation and viability [27]. Furthermore, haploinsufficiency of both ATRX and DMRT1 is compatible with normal ovarian development [5,21,25]. The strikingly similar protein distribution of ARTX and DMRT1 and the overlapping gonadal phenotypes (outlined in Table 1) between ATR-X and distal chromosome 9p deletion (including DMRT1) patients suggests a potential interaction between these two genes in the sexual development pathway.…”

Section: Discussionmentioning

confidence: 99%

ATRX has a critical and conserved role in mammalian sexual differentiation

et al. 2011

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BackgroundX-linked alpha thalassemia, mental retardation syndrome in humans is a rare recessive disorder caused by mutations in the ATRX gene. The disease is characterised by severe mental retardation, mild alpha-thalassemia, microcephaly, short stature, facial, skeletal, genital and gonadal abnormalities.ResultsWe examined the expression of ATRX and ATRY during early development and gonadogenesis in two distantly related mammals: the tammar wallaby (a marsupial) and the mouse (a eutherian). This is the first examination of ATRX and ATRY in the developing mammalian gonad and fetus. ATRX and ATRY were strongly expressed in the developing male and female gonad respectively, of both species. In testes, ATRY expression was detected in the Sertoli cells, germ cells and some interstitial cells. In the developing ovaries, ATRX was initially restricted to the germ cells, but was present in the granulosa cells of mature ovaries from the primary follicle stage onwards and in the corpus luteum. ATRX mRNA expression was also examined outside the gonad in both mouse and tammar wallaby whole embryos. ATRX was detected in the developing limbs, craniofacial elements, neural tissues, tail and phallus. These sites correspond with developmental deficiencies displayed by ATR-X patients.ConclusionsThere is a complex expression pattern throughout development in both mammals, consistent with many of the observed ATR-X syndrome phenotypes in humans. The distribution of ATRX mRNA and protein in the gonads was highly conserved between the tammar and the mouse. The expression profile within the germ cells and somatic cells strikingly overlaps with that of DMRT1, suggesting a possible link between these two genes in gonadal development. Taken together, these data suggest that ATRX has a critical and conserved role in normal development of the testis and ovary in both the somatic and germ cells, and that its broad roles in early mammalian development and gonadal function have remained unchanged for over 148 million years of mammalian evolution.

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Alpha-thalassemia/mental retardation syndrome, X-Linked (ATR-X, MIM #301040, ATR-X/XNP/XH2 gene MIM #300032)

Cited by 30 publications

References 10 publications

Syndromes of disordered chromatin remodeling

Syndromes of disordered chromatin remodeling

Mutations in PHD‐like domain of the ATRX gene correlate with severe psychomotor impairment and severe urogenital abnormalities in patients with ATRX syndrome

ATRX has a critical and conserved role in mammalian sexual differentiation

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