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Several cutis laxa syndromes are inborn errors of metabolism and lead to severe neurological symptoms. In a patient with cutis laxa, a choreoathetoid movement disorder, dysmorphic features and intellectual disability we performed exome sequencing to elucidate the underlying genetic defect. We identified the amino acid substitution R275W in phosphatidylinositol 4\u2010kinase type II\u03b1, caused by a homozygous missense mutation in the <jats:italic>PI4K2A<\/jats:italic> gene. We used lipidomics, complexome profiling and functional studies to measure phosphatidylinositol 4\u2010phosphate synthesis in the patient and evaluated PI4K2A deficient mice to define a novel metabolic disorder. The R275W residue, located on the surface of the protein, is involved in forming electrostatic interactions with the membrane. The catalytic activity of PI4K2A in patient fibroblasts was severely reduced and lipid mass spectrometry showed that particular acyl\u2010chain pools of PI4P and PI(4,5)P<jats:sub>2<\/jats:sub> were decreased. Phosphoinositide lipids play a major role in intracellular signalling and trafficking and regulate the balance between proliferation and apoptosis. Phosphatidylinositol 4\u2010kinases such as PI4K2A mediate the first step in the main metabolic pathway that generates PI4P, PI(4,5)P<jats:sub>2<\/jats:sub> and PI(3,4,5)P<jats:sub>3<\/jats:sub>. Although neurologic involvement is common, cutis laxa has not been reported previously in metabolic defects affecting signalling. Here we describe a patient with a complex neurological phenotype, premature ageing and a mutation in <jats:italic>PI4K2A<\/jats:italic>, illustrating the importance of this enzyme in the generation of inositol lipids with particular acylation characteristics.<\/jats:p>","DOI":"10.1002\/jimd.12255","type":"journal-article","created":{"date-parts":[[2020,5,17]],"date-time":"2020-05-17T07:08:57Z","timestamp":1589699337000},"page":"1382-1391","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Novel defect in phosphatidylinositol 4\u2010kinase type 2\u2010alpha (<scp><i>PI4K2A<\/i><\/scp>) at the membrane\u2010enzyme interface is associated with metabolic cutis laxa"],"prefix":"10.1002","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1636-1292","authenticated-orcid":false,"given":"Miski","family":"Mohamed","sequence":"first","affiliation":[{"name":"Department of Paediatrics Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thatjana","family":"Gardeitchik","sequence":"additional","affiliation":[{"name":"Department of Paediatrics Radboud University Medical Center  Nijmegen The Netherlands"},{"name":"Department of Genetics Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shanti","family":"Balasubramaniam","sequence":"additional","affiliation":[{"name":"Clinical Genetic Department Hospital Kuala Lumpur, Jalan Pahang  Kuala Lumpur Malaysia"},{"name":"Discipline of Genetic Medicine, Sydney Medical School University of Sydney  Sydney New South Wales Australia"},{"name":"Western Sydney Genetics Program The Children's Hospital at Westmead  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergio","family":"Guerrero\u2010Castillo","sequence":"additional","affiliation":[{"name":"Radboud Center for Mitochondrial Medicine Radboud University Medical Center  Nijmegen The Netherlands"},{"name":"Translational Metabolic Laboratory, Department of Laboratory Medicine Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisy","family":"Dalloyaux","sequence":"additional","affiliation":[{"name":"Department of Paediatrics Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanne","family":"van Kraaij","sequence":"additional","affiliation":[{"name":"Translational Metabolic Laboratory, Department of Laboratory Medicine Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanka","family":"Venselaar","sequence":"additional","affiliation":[{"name":"Center of Molecular and Biomolecular Informatics Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Hoischen","sequence":"additional","affiliation":[{"name":"Department of Genetics Radboud University Medical Center  Nijmegen The Netherlands"},{"name":"Department of Internal Medicine Radboud University Medical Center  Nijmegen The Netherlands"},{"name":"Radboud Institute for Molecular Life Sciences Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zsolt","family":"Urban","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Graduate School of Public Health University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich","family":"Brandt","sequence":"additional","affiliation":[{"name":"Radboud Center for Mitochondrial Medicine Radboud University Medical Center  Nijmegen The Netherlands"},{"name":"Translational Metabolic Laboratory, Department of Laboratory Medicine Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raya","family":"Al\u2010Shawi","sequence":"additional","affiliation":[{"name":"Wolfson Drug Discovery Unit, Division of Medicine, Royal Free Campus University College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Paul","family":"Simons","sequence":"additional","affiliation":[{"name":"Wolfson Drug Discovery Unit, Division of Medicine, Royal Free Campus University College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele","family":"Frison","sequence":"additional","affiliation":[{"name":"Wolfson Drug Discovery Unit, Division of Medicine, Royal Free Campus University College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lock\u2010Hock","family":"Ngu","sequence":"additional","affiliation":[{"name":"Clinical Genetic Department Hospital Kuala Lumpur, Jalan Pahang  Kuala Lumpur Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bert","family":"Callewaert","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Ghent University Hospital  Ghent Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans","family":"Spelbrink","sequence":"additional","affiliation":[{"name":"Department of Paediatrics Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wouter W.","family":"Kallemeijn","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Leiden Institute of Chemistry Leiden University  Leiden The Netherlands"},{"name":"Department of Chemistry Imperial College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes M. 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