Variant ATRX syndrome with dysfunction of ATRX and MAGT1 genes

Hum Mutat. 2014 Jan;35(1):58-62. doi: 10.1002/humu.22465.


A 0.8 kb intronic duplication in MAGT1 and a single base pair deletion in the last exon of ATRX were identified using a chromosome X-specific microarray and exome sequencing in a family with five males demonstrating intellectual disability (ID) and unusual skin findings (e.g., generalized pruritus). MAGT1 is an Mg²⁺ transporter previously associated with primary immunodeficiency and ID, whereas mutations in ATRX cause ATRX-ID syndrome. In patient cells, the function of ATRX was demonstrated to be abnormal based on altered RNA/protein expression, hypomethylation of rDNA, and abnormal cytokinesis. Dysfunction of MAGT1 was reflected in reduced RNA/protein expression and Mg²⁺ influx. The mutation in ATRX most likely explains the ID, whereas MAGT1 disruption could be linked to abnormal skin findings, as normal magnesium homeostasis is necessary for skin health. This work supports observations that multiple mutations collectively contribute to the phenotypic variability of syndromic ID, and emphasizes the importance of correlating clinical phenotype with genomic and cell function analyses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cation Transport Proteins / genetics*
  • Cation Transport Proteins / metabolism*
  • Chromosomes, Human, X
  • Cytokinesis
  • DNA Helicases / genetics*
  • DNA Helicases / metabolism*
  • DNA Methylation
  • DNA, Ribosomal / metabolism
  • Exome
  • Female
  • Genes, Duplicate
  • Humans
  • Introns
  • Magnesium / metabolism
  • Male
  • Mental Retardation, X-Linked / genetics*
  • Mental Retardation, X-Linked / metabolism
  • Mental Retardation, X-Linked / pathology
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Pedigree
  • Phenotype
  • Point Mutation
  • Pruritus / genetics*
  • Pruritus / pathology
  • Sequence Analysis, DNA
  • Syndrome
  • X-linked Nuclear Protein


  • Cation Transport Proteins
  • DNA, Ribosomal
  • MagT1 protein, human
  • Nuclear Proteins
  • DNA Helicases
  • ATRX protein, human
  • X-linked Nuclear Protein
  • Magnesium