{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T01:01:57Z","timestamp":1784682117359,"version":"3.55.0"},"reference-count":49,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:italic>ATP6AP2<\/jats:italic>\n                    splicing variants cause syndromic X\u2010linked intellectual disability Hedera type (XPDS; OMIM#300423) and X\u2010linked parkinsonism with spasticity (MRXSH; OMIM#300911). Alternatively,\n                    <jats:italic>ATP6AP2<\/jats:italic>\n                    missense variants lead to hepatopathy, immunological abnormalities, cutis laxa and only mild intellectual disability with N\u2010\/O\u2010glycosylation defects (ATP6AP2\u2010CDG; OMIM#301045). The disparity between neurological and hepatic ATP6AP2\u2010related disease entities is an ongoing puzzle. We aimed to investigate whether patients with an isolated neurological presentation of ATP6AP2\u2010related 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\n                    <jats:italic>ATP6AP2<\/jats:italic>\n                    splicing variants and ID\/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA\u2010Seq in patient\u2010derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. We describe defective glycosylation alongside\n                    <jats:italic>ATP6AP2<\/jats:italic>\n                    splicing variants in four patients, including the first female with\n                    <jats:italic>ATP6AP2<\/jats:italic>\n                    \u2010related disease. This connects more closely the phenotypes of XPDS\/MRXSH and ATP6AP2\u2010CDG and indicates that abnormal glycosylation markers may be a consistent feature of splicing variants, and potentially part of the pathological mechanism underlying ATP6AP2\u2010related 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 \u201csplicing\u201d forms of ATP6AP2\u2010related diseases, bridging the gap between XPDS, MRXSH and ATP6AP2\u2010CDG.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70109","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T04:01:34Z","timestamp":1761278494000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>ATP6AP2<\/scp>\n                    \u2010Related Disease Caused by Splicing Defects: Abnormal Glycosylation and the First Affected Female"],"prefix":"10.1002","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2651-650X","authenticated-orcid":false,"given":"Alexandre","family":"Raynor","sequence":"first","affiliation":[{"name":"AP\u2010HP, Biochimie m\u00e9tabolique et Cellulaire H\u00f4pital Bichat  Paris France"},{"name":"Paris Cit\u00e9 University Xavier Bichat Medicine Department  Paris 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