The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane

Jeremy M. Baskin, Xudong Wu, Romain Christiano, Michael S. Oh, Curtis M. Schauder, Elisabetta Gazzerro, Mirko Messa, Simona Baldassari, Stefania Assereto, Roberta Biancheri, Federico Zara, Carlo Minetti, Andrea Raimondi, Mikael Simons, Tobias C. Walther, Karin M. Reinisch, Pietro De Camilli

Research output: Contribution to journalArticle

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,). 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.
Original languageEnglish
Pages (from-to)132 - 138
Number of pages7
JournalNature Cell Biology
Volume18
Issue number1
DOIs
Publication statusPublished - Jan 1 2016

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Cell Membrane
Oligodendroglia
Proteins
Fibroblasts
Leukoencephalopathies
1-Phosphatidylinositol 4-Kinase
Myelin Sheath
Phosphatidylinositols
Multiple Sclerosis
Protein Isoforms
Maintenance
Mutation
phosphatidylinositol 4-phosphate
Brain
Genes
Leukodystrophy, Hypomyelinating, 5

ASJC Scopus subject areas

  • Cell Biology

Cite this

Baskin, J. M., Wu, X., Christiano, R., Oh, M. S., Schauder, C. M., Gazzerro, E., ... De Camilli, P. (2016). The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane. Nature Cell Biology, 18(1), 132 - 138. https://doi.org/10.1038/ncb3271

The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane. / Baskin, Jeremy M.; Wu, Xudong; Christiano, Romain; Oh, Michael S.; Schauder, Curtis M.; Gazzerro, Elisabetta; Messa, Mirko; Baldassari, Simona; Assereto, Stefania; Biancheri, Roberta; Zara, Federico; Minetti, Carlo; Raimondi, Andrea; Simons, Mikael; Walther, Tobias C.; Reinisch, Karin M.; De Camilli, Pietro.

In: Nature Cell Biology, Vol. 18, No. 1, 01.01.2016, p. 132 - 138.

Research output: Contribution to journalArticle

Baskin, JM, Wu, X, Christiano, R, Oh, MS, Schauder, CM, Gazzerro, E, Messa, M, Baldassari, S, Assereto, S, Biancheri, R, Zara, F, Minetti, C, Raimondi, A, Simons, M, Walther, TC, Reinisch, KM & De Camilli, P 2016, 'The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane', Nature Cell Biology, vol. 18, no. 1, pp. 132 - 138. https://doi.org/10.1038/ncb3271
Baskin JM, Wu X, Christiano R, Oh MS, Schauder CM, Gazzerro E et al. The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane. Nature Cell Biology. 2016 Jan 1;18(1):132 - 138. https://doi.org/10.1038/ncb3271
Baskin, Jeremy M. ; Wu, Xudong ; Christiano, Romain ; Oh, Michael S. ; Schauder, Curtis M. ; Gazzerro, Elisabetta ; Messa, Mirko ; Baldassari, Simona ; Assereto, Stefania ; Biancheri, Roberta ; Zara, Federico ; Minetti, Carlo ; Raimondi, Andrea ; Simons, Mikael ; Walther, Tobias C. ; Reinisch, Karin M. ; De Camilli, Pietro. / The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane. In: Nature Cell Biology. 2016 ; Vol. 18, No. 1. pp. 132 - 138.
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