title: The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane.
abstract: Genetic defects in myelin formation and maintenance cause leukodystrophies, a group of white matter diseases whose mechanistic underpinnings are poorly understood. Hypomyelination and congenital cataract (HCC), one of these disorders, is caused by mutations in FAM126A, a gene of unknown function. We show that FAM126A, also known as hyccin, regulates the synthesis of phosphatidylinositol 4-phosphate (PtdIns(4)P), a determinant of plasma membrane identity. HCC patient fibroblasts exhibit reduced PtdIns(4)P levels. FAM126A is an intrinsic component of the plasma membrane phosphatidylinositol 4-kinase complex that comprises PI4KIIIα and its adaptors TTC7 and EFR3 (refs 5,7). A FAM126A-TTC7 co-crystal structure reveals an all-α-helical heterodimer with a large protein-protein interface and a conserved surface that may mediate binding to PI4KIIIα. Absence of FAM126A, the predominant FAM126 isoform in oligodendrocytes, destabilizes the PI4KIIIα complex in mouse brain and patient fibroblasts. We propose that HCC pathogenesis involves defects in PtdIns(4)P production in oligodendrocytes, whose specialized function requires massive plasma membrane expansion and thus generation of PtdIns(4)P and downstream phosphoinositides. Our results point to a role for FAM126A in supporting myelination, an important process in development and also following acute exacerbations in multiple sclerosis.
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut  06510, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut  06510, USA.|Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut  06510, USA.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Baskin
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut  06510, USA.
authors.forename: Xudong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut  06510, USA.
authors.forename: Romain
authors.initials: R
authors.lastname: Christiano
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut  06510, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut  06510, USA.|Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut  06510, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Oh
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut  06510, USA.
authors.forename: Curtis M
authors.initials: CM
authors.lastname: Schauder
authors.affiliation: Unit of Pediatric Neurology, Giannina Gaslini Institute, 16147 Genova, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Gazzerro
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut  06510, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut  06510, USA.|Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut  06510, USA.
authors.forename: Mirko
authors.initials: M
authors.lastname: Messa
authors.affiliation: Unit of Pediatric Neurology, Giannina Gaslini Institute, 16147 Genova, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Baldassari
authors.affiliation: Unit of Pediatric Neurology, Giannina Gaslini Institute, 16147 Genova, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Assereto
authors.affiliation: Department of Neuroscience, Giannina Gaslini Institute, 16147 Genova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Biancheri
authors.affiliation: Unit of Pediatric Neurology, Giannina Gaslini Institute, 16147 Genova, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Zara
authors.affiliation: Unit of Pediatric Neurology, Giannina Gaslini Institute, 16147 Genova, Italy.|Department of Neuroscience, University of Genova, 16132 Genova, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Minetti
authors.affiliation: San Raffaele Scientific Institute, Experimental Imaging Center, 20132 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Raimondi
authors.affiliation: Max Planck Institute for Experimental Medicine, University of Göttingen, 37075 Göttingen, Germany.|Department of Neurology, University of Göttingen, 37075 Göttingen, Germany.
authors.forename: Mikael
authors.initials: M
authors.lastname: Simons
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut  06510, USA.
authors.forename: Tobias C
authors.initials: TC
authors.lastname: Walther
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut  06510, USA.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Reinisch
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut  06510, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut  06510, USA.|Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut  06510, USA.|Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut  06510, USA.|Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut  06510, USA.
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis* / Q000235:genetics; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000235:genetics / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018129:Phosphatidylinositol Phosphates; C412048:HYCC1 protein, human; C037178:phosphatidylinositol 4-phosphate