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

Abstract

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.

Neuroradiologic Features in X-linked α-Thalassemia/Mental Retardation Syndrome

“…These results would indicate that mutations in the ADD domain produce more severe and permanent psychomotor deficiencies than those in chromatin-remodeling domains, though the clear phenotype-genotype correlation remains to be established. 11 However, conclusion may be too hasty because we have studied fewer cases with ATRX mutations in the chromatin-remodeling domains. A number of intellectual disorders have been identified whose gene products regulate chromatin and chromosome architecture, and ATR-X syndrome is a disease of chromatin remodeling, as well as Rett syndrome (MeCP2) and Cornelia de Lange syndrome (SMC1A, SMC3, and NIPBL).…”

SPOC1: a novel PHD-containing protein modulating chromatin structure and mitotic chromosome condensation

“…As a consequence of their chromatin regulatory functions, disruptive aberrations to PHD-fingercontaining proteins can have severe genomic consequences, and therefore have been found to be involved in various human pathological conditions, ranging from mental retardation to malignancy (Badens et al, 2006;Barrett et al, 2007;Bronner et al, 2007;Campos et al, 2004;Chen et al, 2008;Coles and Jones, 2009;Ythier et al, 2008). The PHF23 protein is the most closely related protein to SPOC1, containing a predicted N-terminal domain, two predicted PEST motifs, a NLS and a PHD domain with strong sequence homologies (supplementary material Fig.…”

Mutant ATRX: uncovering a new therapeutic target for glioma

“…Most ATRX mutations in the ATRX syndrome are located in the ADD and the ATPase/helicase domains and the mutated domain is related with the severity of the condition [28]. Interestingly, some of the mutations appearing in ATRX syndrome may be partially rescued by the synthesis of alternative splicing products that exclude the mutated exon.…”