Mental Retardation, X-Linked 106

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-106 (MRX106) is caused by hemizygous mutation in the OGT gene (300255) on chromosome Xq13.

Clinical Features

Willems et al. (2017) reported 2 unrelated boys with X-linked mental retardation. One patient had more notable dysmorphic features including hypertelorism, low-set ears, broad nose, full lips, supernumerary nipple, hypoplastic toe, mild retrognathia, long and thin fingers, clinodactyly, microcephaly, amblyopia, and possible astigmatism. Additional neurologic symptoms were also present, including pyramidal syndrome, mild spastic diplegia, and behavioral conduct disorder. He had a bicuspid aortic valve and periventricular leukomalacia on brain imaging. The second patient had mouth hypotonia with drooling, nystagmus, astigmatism, and hypermetropia. Other features included a small phallus, bitemporal narrowing, and ventricular septal defect.

Vaidyanathan et al. (2017) reported 3 male patients from a family with intellectual disability. The patients were 56.5, 14.7, and 6.7 years of age, and their IQs ranged from 49 to 61. Variable additional minor abnormalities included small head circumference, fifth finger clinodactyly, hair whorls, open mouth, thin upper lip, hypospadias, and small testes.

Inheritance

The transmission pattern of MRX106 in the family reported by Vaidyanathan et al. (2017) was consistent with X-linked recessive inheritance.

Molecular Genetics

In 3 affected males from a family (K9427) with MRX106, Vaidyanathan et al. (2017) identified a hemizygous missense mutation in the OGT gene (L254F; 300255.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed decreased levels of OGT protein, suggesting instability of the mutant protein, but cellular transfection studies showed that 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 (MGEA5; 604039) protein and mRNA levels. Decreased OGA promoter activity was associated with enrichment of an OGT-containing transcriptional repressor complex containing mSin3A (607776) and HDAC1 (601241) that localized to the proximal promoter region of OGA. Transcriptome analysis of mutant cells showed differential expression of several genes. Female mutation carriers showed highly skewed X inactivation.

In 2 unrelated boys with MRX106, Willems et al. (2017) identified hemizygous mutations in the OGT gene (300255.0002 and 300255.0003). The mutations were found by exome sequencing and confirmed by Sanger sequencing; one of the mutations occurred de novo, whereas the other was inherited from the unaffected mother. Patient cells showed slightly reduced levels of OGT protein and reduced levels of OGA protein, but global O-GlcNAc levels were similar to controls. Recombinant studies of 1 of the mutations (R284P; 300255.0002) showed that mutant OGT was prone to unfolding and had reduced glycosylation activity against complex array of glycosylation substrates. Proteolytic processing of HCFC1 (300019) was also decreased. The findings suggested that defects in O-GlcNAc homeostasis and HCFC1 proteolysis may play a role in intellectual disability in patients with OGT mutations.