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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.

Original publication

DOI

10.1002/humu.22465

Type

Journal article

Journal

Hum Mutat

Publication Date

01/2014

Volume

35

Pages

58 - 62

Keywords

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