An inherited disease of myelin marked by slow, progressive neurological impairment is caused by mutations of a gene that controls lipid metabolism, a finding that may shed insight into mechanisms to control the course of multiple sclerosis (MS), a Yale team has found.
Mutations in a single gene, called FAM126A, causes a panoply of pathologies, such as developmental delay, intellectual disability, peripheral neuropathy, and muscle wasting, in addition to congenital cataracts. Until now the precise function of the gene was unknown.
The labs of Yale cell biologists Pietro De Camilli and Karin Reinisch found that the protein encoded by the gene, called hyccin, helps produce a lipid crucial to formation of the myelin sheaths that surround and protect the axons of neurons throughout the nervous system.
Their labs, working with other groups in the United States, Italy, and Germany, analyzed cells from patients suffering from the disease known as Hypomyelination and Congenital Cataract and found that FAM126A mutations results in the destabilization of an enzyme complex crucial to production of myelin.
In MS, the course of the disease is critically dependent upon the reformation of myelin sheaths after immune system attacks then destroys them, eventually leading to the death of the neurons. The researchers hypothesize that the lipid that hyccin helps generate may play a key role in creation of myelin sheaths in normal development as well as in recovering MS patients.
Postdoc Jeremy Baskin (now at Cornell) and graduate student Xudong Wu (now at Harvard) led the study in the De Camilli and Reinisch labs, respectively.
Source: Bill Hathaway – Yale
Image Source: The image is adapted from the Yale press release
Original Research: Abstract for “The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane” by 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 and Pietro De Camilli in Nature Cell Biology. Published online November 16 2015 doi:10.1038/ncb3271
Abstract
The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane
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. 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
“The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane” by 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 and Pietro De Camilli in Nature Cell Biology. Published online November 16 2015 doi:10.1038/ncb3271
