In 4 male cousins with the X-linked mental retardation-hypotonic facies syndrome (309580), Guerrini et al. (2000) identified a 109C-T transition in exon 2 of the ATRX gene, resulting in an arg37-to-ter (R37X) substitution. Two patients had moderate to profound mental retardation and the typical facial features of the syndrome, whereas the other 2 patients presented with mild mental retardation and epilepsy, but without the characteristic facial dysmorphism.
Howard et al. (2004) found that human embryonic kidney cells carrying the R37X mutation expressed approximately 20% of a slightly shortened ATRX protein compared to controls. Analysis of the 5-prime end of the ATRX gene revealed a downstream AUG start codon at residue 40, suggesting an alternative initiation event. Howard et al. (2004) suggested that 'phenotypic rescue' due to the expression of a truncated ATRX protein using the alternative downstream initiation site underlies the relatively mild phenotype seen in some patients with the R37X mutation.
Abidi et al. (2005) identified the R37X mutation in 3 affected males originally reported by Chudley et al. (1988) as having Chudley-Lowry syndrome. Western blot and immunocytochemical analyses using a specific monoclonal antibody directed against ATRX showed the protein to be present in lymphoblastoid cells, despite the premature stop codon. Abidi et al. (2005) suggested that the less severe phenotype was due to the presence of some residual ATRX protein. The phenotypic variation between patients with the same mutation suggested that the ATRX gene may influence the expression of several genes in multiple tissues during development.
