ATP6AP2 ‐Related Disease Caused by Splicing Defects: Abnormal Glycosylation and the First Affected Female
Year: 2025
Type: article
Study design: Case Report
Abstract: ATP6AP2 splicing variants cause syndromic X-linked intellectual disability Hedera type (XPDS; OMIM#300423) and X-linked parkinsonism with spasticity (MRXSH; OMIM#300911). Alternatively, ATP6AP2 missense variants lead to hepatopathy, immunological abnormalities, cutis laxa and only mild intellectual disability with N-/O-glycosylation defects (ATP6AP2-CDG; OMIM#301045). The disparity between neurological and hepatic ATP6AP2-related disease entities is an ongoing puzzle. We aimed to investigate whether patients with an isolated neurological presentation of ATP6AP2-related disease, consistent with XPDS/MRXSH, also have abnormal glycosylation biomarkers, potentially implicating this as part of the pathological mechanism. We identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. We describe defective glycosylation alongside ATP6AP2 splicing variants in four patients, including the first female with ATP6AP2-related disease. This connects more closely the phenotypes of XPDS/MRXSH and ATP6AP2-CDG and indicates that abnormal glycosylation markers may be a consistent feature of splicing variants, and potentially part of the pathological mechanism underlying ATP6AP2-related disease caused by abnormal splicing. We also provide additional evidence that neurodevelopment is uniquely sensitive to the gene dosage of ATP6AP2, linked to the isolated neurological phenotype found in patients with splice variants and the attenuated, but still severe, phenotype of the female in our study. Glycosylation defects can be found in "splicing" forms of ATP6AP2-related diseases, bridging the gap between XPDS, MRXSH and ATP6AP2-CDG.
DOI: 10.1002/jimd.70109
Authors: Alexandre Raynor, Jean‐Madeleine de Sainte‐Agathe, Merel A. Post, Magalie Barth, Fokje Zijlstra, Karin Huijben, Ioanna Kouri, Alexis Couasnard, Paola Bellenda, Thierry Dupré, Erika Souche, Elodie Lebredonchel, Sophie Cholet, Isabelle Cantaloube, Ameetha Ratier, Elise Jacquin, Katell Peoc'h, François Fenaille, Gert Matthijs, Jaak Jaeken, Anabela Bandeira, Dulce Quelhas, Dirk J. Lefeber, Arnaud Bruneel, Matthew P. Wilson
Institutions: Université Paris Cité, Assistance Publique – Hôpitaux de Paris, Hôpital Bichat-Claude-Bernard, Sorbonne Université, Radboud University Nijmegen, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Centre Hospitalier Universitaire d'Angers, Université d'Angers, Inserm, Université Paris-Saclay, KU Leuven, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, CEA Paris-Saclay, MetaboHUB, Médicaments et Technologies pour la Santé, Universidade do Porto, Instituto de Ciências Biomédicas Albel Salazar
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4415493199