ATP6AP2-Related Disease Caused by Splicing Defects: Abnormal Glycosylation and the First Affected Female

Area of Science:

• Genetics
• Biochemistry
• Neuroscience

Background:

• ATP6AP2 gene variants are linked to distinct neurological and hepatic disorders.
• Splicing variants cause X-linked intellectual disability (XPDS) and parkinsonism (MRXSH), while missense variants cause N-/O-glycosylation defects (ATP6AP2-CDG).
• The relationship between neurological and hepatic manifestations of ATP6AP2-related diseases remains unclear.

Purpose of the Study:

• To investigate glycosylation biomarkers in patients with ATP6AP2 splicing variants and neurological symptoms.
• To determine if glycosylation abnormalities are a common feature in ATP6AP2-related neurological disorders.
• To explore the role of glycosylation in the pathogenesis of ATP6AP2 splicing variant-associated diseases.

Main Methods:

• Identified patients with ATP6AP2 splicing variants and neurological conditions.
• Analyzed RNA-Seq data from patient-derived fibroblasts to confirm defective splicing.
• Assessed ATP6AP2 protein levels and glycosylation status in patient fibroblasts.

Main Results:

• Four patients (three males, one female) with ATP6AP2 splicing variants presented with intellectual disability, epilepsy, hypotonia, neuropathy, and microcephaly.
• RNA-Seq confirmed defective splicing and reduced ATP6AP2 protein levels in patient fibroblasts.
• Abnormal glycosylation biomarkers were detected in patients with ATP6AP2 splicing variants.
• The heterozygous female exhibited a milder phenotype, suggesting gene dosage sensitivity.

Conclusions:

• Defective glycosylation is associated with ATP6AP2 splicing variants, linking XPDS/MRXSH and ATP6AP2-CDG phenotypes.
• Abnormal glycosylation may be a consistent pathological mechanism in ATP6AP2-related diseases caused by splicing defects.
• Neurodevelopment is highly sensitive to ATP6AP2 gene dosage, explaining isolated neurological phenotypes.