Molecular genetic study of X-linked mental retardation・αthalassemia syndrome (ATR-X)

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X-linked mental retardation・αthalassemia syndrome (ATR-X) is one of syndromic X-linked mental retardation, which is caused by mutations of the ATRX gene. We have investigated 27 Japanese ATR-X patients from 24 families, and identified mutations of ATRX in 24 patients from 21 families. Most mutations (14 patients from 12 families) were located in the ADD domain, while the second prevalent mutations (4 patients from 3 families) were located in helicase domain. Other minor mutations were also identified. We subsequently studied 8 mothers and identified the same mutations in 6 mothers, indicating 6/8 (75%) mothers were mutation carriers. We could examine X inactivation status using peripheral leukocytes in 4 female carries, and 3 females demonstrated skewed X inactivation pattern while one showed random pattern. The female who showed random X inactivation was associated with mild mental retardation. These findings may imply that ATRX can cause female mental retardation unless X inactivation properly inactivates the mutated X chromosome.