In affected members of a family with X-linked intellectual developmental disorder-106 (XLID106; 300997), Niranjan et al. (2015) identified a hemizygous mutation in the OGT gene, resulting in a leu244-to-phe substitution. The mutation, which was found by X-chromosome exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was filtered through the dbSNP, 1000 Genomes Project, and Exome Variant Server databases, and was compared to a small cohort of unrelated affected males for further enrichment. Although Niranjan et al. (2015) reported the mutation as L244F, Willems et al. (2017) stated that this mutation is a 762G-T transversion (762G-T, NM_181672.2), resulting in a leu254-to-phe (L254F) substitution, and is the same as the mutation reported by Vaidyanathan et al. (2017).
In 3 affected males from a family (K9427) with XLID106, Vaidyanathan et al. (2017) identified a hemizygous c.759G-T transversion in the OGT gene, resulting in a leu254-to-phe (L254F) substitution in the TPR regulatory domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was filtered against the dbSNP, 1000 Genomes Project, and Exome Variant Server databases. Patient cells showed decreased levels of mutant OGT protein, suggesting instability of the mutant protein, but cellular transfection studies showed that the mutant enzyme retained OGT catalytic activity. Patient cells had normal steady-state global O-GlcNAc levels due to a compensatory mechanism, namely a decrease in OGA (604039) protein and mRNA levels. Decreased OGA promoter activity resulted from enrichment of an OGT-containing transcriptional repressor complex containing mSIN3A (607776) and HDAC1 (601241) at the proximal promoter region of OGA. Transcriptome analysis of mutant cells showed differential expression of several genes.
