X-linked alpha-thalassemia/mental retardation syndrome (
ATR-X syndrome, OMIM #301040) is one of the syndromes associated with abnormal epigenetic gene regulation, including ICF(DNMT3B), Rett (MECP2), Rubinstein-Taybi (CBP), Coffin-Lowry (RSK2), and Sotos (NSD1) syndromes. It is a syndromic form of
X-linked mental retardation, which affects males and is characterized by profound
mental retardation, mild HbH disease (
alpha-thalassemia), facial dysmorphism, skeletal abnormalities, and autistic behavior.
ATR-X syndrome is caused by a mutation in the ATRX gene on the X chromosome (Xq13), which encodes
ATRX protein, belonging to the SNF2 family of chromatin-remodeling
proteins. The
protein has two functionally important domains: an ADD (ATRX-DNMT3-DNMT3L) domain at the N-terminus, and chromatin-remodeling domain in the C-terminal half, where the ATRX gene mutations of most ATR-X patients reside. Perturbation in DNA methylation in the
rDNA genes was repored in ATR-X patients, and
ATRX protein is presumed to be involved in the establishment and maintenance of DNA methylation. Based on its various clinical phenotypes, the expressions of many genes, including
alpha globin genes, seem to be abnormally regulated in ATR-X patients. However, the precise mechanism involving
ATRX protein remains to be elucidated. Epigenetics can link environmental and genetic causes of many pathological conditions. The genes, which are abnormally regulated by a perturbed epigenetic mechanism, are, in themselves, structurally normal, and the elucidation of their mechanism may lead to the development of appropriate
therapy.