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

Jeremy M Baskin1,2,3, Xudong Wu1, Romain Christiano1

  • 1Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut  06510, USA.

Nature Cell Biology
|November 17, 2015
PubMed

Insights

Genetic defects in myelin cause leukodystrophies. Mutations in FAM126A cause Hypomyelination and Congenital Cataract (HCC) by disrupting phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis, crucial for myelin.

Area of Science:

  • Cell Biology
  • Neuroscience
  • Genetics

Background:

  • Leukodystrophies are white matter diseases stemming from genetic defects in myelin formation and maintenance.
  • Hypomyelination and Congenital Cataract (HCC) is a leukodystrophy linked to mutations in the FAM126A gene, whose function was previously unknown.
  • Phosphatidylinositol 4-phosphate (PtdIns(4)P) is vital for plasma membrane identity and function.

Purpose of the Study:

  • To elucidate the function of FAM126A in the context of Hypomyelination and Congenital Cataract (HCC).
  • To investigate the molecular mechanisms underlying FAM126A's role in myelin formation and maintenance.
  • To explore the potential therapeutic targets for HCC and related demyelinating diseases.

Main Methods:

  • Biochemical analysis of FAM126A's role in phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis.
  • Co-crystallography of FAM126A and TTC7 to determine structural interactions.
  • Analysis of FAM126A function in patient fibroblasts and mouse brain models.

Main Results:

  • FAM126A (hyccin) is identified as a key regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis.
  • HCC patient cells show reduced PtdIns(4)P levels, indicating a direct link between FAM126A deficiency and lipid metabolism defects.
  • FAM126A is an integral component of the plasma membrane phosphatidylinositol 4-kinase III alpha (PI4KIIIα) complex, stabilizing it and ensuring proper PtdIns(4)P production in oligodendrocytes.

Conclusions:

  • FAM126A is essential for PtdIns(4)P production in oligodendrocytes, supporting the massive plasma membrane expansion required for myelination.
  • Defects in FAM126A function lead to impaired myelination, explaining the pathogenesis of Hypomyelination and Congenital Cataract (HCC).
  • FAM126A's role highlights its importance in both developmental myelination and myelin repair in conditions like multiple sclerosis.

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