Journal
NATURE CELL BIOLOGY
Volume 18, Issue 1, Pages 132-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3271
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Funding
- National Institutes of Health [R37N5036251, R01DK082700, P30DK45735, P30DA018343, R01GM080616, R01GM095982, K99GM110121]
- Simons Foundation
- Telethon [GP2007250]
- Mariani Foundation
- San Paolo Foundation
- European Leukodystrophy Association Foundation
- Jane Coffin Childs Memorial Fund fellowship
- National Science Foundation [DGE-1122492]
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Genetic defects in myelin formation and maintenance cause leukodystrophies, a group of white matter diseases whose mechanistic underpinnings are poorly understood(1,2). Hypomyelination and congenital cataract (HCC), one of these disorders, is caused by mutations in FAM126A, a gene of unknown function(3). We show that FAM126A, also known as hyccin, regulates the synthesis of phosphatidylinositol 4-phosphate (PtdIns(4)P), a determinant of plasma membrane identity(4-6). HCC patient fibroblasts exhibit reduced PtdIns(4)P levels. FAM126A is an intrinsic component of the plasma membrane phosphatidylinositol 4-kinase complex that comprises PI4KIII alpha and its adaptors TTC7 and EFR3 (refs 5,7). A FAM126A TTC7 alpha-crystal structure reveals an all-alpha-helical heterodimer with a large protein protein interface and a conserved surface that may mediate binding to PI4KIII alpha. Absence of FAM126A, the predominant FAM126 isoform in oligodendrocytes, destabilizes the PI4KIII alpha 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(8-11). Our results point to a role for FAM126A in supporting myelination, an important process in development and also following acute exacerbations in multiple sclerosis(12-14).
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