An international consortium led by University of Miami researchers finds a novel disease gene causing neurodegenerative conditions.
Researchers at the University of Miami (UM) have discovered and characterized a previously unknown disease gene linked to the degeneration of optic and peripheral nerve fibers. The study titled “Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder” is published in the journal Nature Genetics.
Patients with mutations in this gene present symptoms similar to optic atrophy and Charcot-Marie-Tooth Type 2 (CMT2), including vision loss and weakening of the lower leg and foot muscles beginning in the first decade of life.
The novel variants occur in a gene called SLC25A46 that functions in mitochondria, organelles inside animal cells known as the “cellular engines.” They transform food into fuel that allow cells to carry out energy-demanding functions.
“Mitochondria play a large role in human health,” said Alexander Abrams, Ph.D. student in Neuroscience at the UM Miller School of Medicine and first author of the study. “Although we study rare diseases such as CMT2 and optic atrophy, the implications encompass all forms of neurodegeneration including Lou Gehrig’s and Parkinson’s Diseases.”
Mitochondria constantly undergo fusion and fission to respond to cellular energy demands. By changing their size and connectivity through fusion and fission, mitochondria can travel to regions in cells where they are needed.
“Our study reveals that disrupting SLC25A46 causes mitochondria to become both more highly interconnected and improperly localized in cells,” said Julia E. Dallman, assistant professor of Biology in the UM College of Arts and Sciences and a senior author of the study. “These data support a critical role for SLC25A46 and mitochondrial dynamics in the establishment and maintenance of neuronal processes.”
SLC25A46 encodes an atypical protein in the SLC25 family. SLC25 family members act like a channel, transporting molecules across the bilayer membranes inside mitochondria. But unlike the majority of human SLC25 family members (there are 53) that transport molecules across the inner mitochondrial membrane, SLC25A46 settles on the outer mitochondrial membrane where it regulates mitochondrial dynamics.
Mutations in the genes associated with mitochondria dynamics OPA1 and MFN2 are linked to similar mitochondrial disorders. Homologous genes in baker’s yeast, work in combination with a gene called UGO1, which has ancestral similarities to SLC25A46. The new findings suggest that the SLC25A46 and Ugo1 proteins may play similar roles.
Given the similarities between the diseases caused by mutations in OPA1, MFN2 and SLC25A46, these genes could be involved in common pathological mechanisms of neurodegeneration, the study says.
“This finding builds on our discovery of MFN2 as a major disease gene in this area over 10 years ago,” said Dr. Stephan Züchner, professor and chair of the Dr. John T. Macdonald Foundation Department of Human Genetics, at UM’s Miller School of Medicine, and a senior author of the study. “Only through the new genome sequencing methods and active global data exchange were we able to solve this puzzle.”
The study is a collaborative effort with investigators from nine universities and research institutions in the United States, Italy and the U.K. Co-authors from the Dr. John T. Macdonald Department of Human Genetics and the John P. Hussman Institute for Human Genomics at the UM Miller School of Medicine are Adriana Rebelo, Ph.D. and Alleene V. Strickland, Ph.D., postdoctoral fellows; Michael A. Gonzalez, Ph. D., graduate; Feifei Tao, Ph.D. student; Fiorella Speziani, former research project manager; Lisa Abreu, clinical research coordinator; Rebecca Schüle, M.D., Ph.D., visiting Marie-Curie Fellow. From the UM Miller School of Medicine co-authors are Antonio Barrientos, Ph.D. in the Department of Neurology; Flavia Fontanesi, Ph.D., research assistant professor in the Department of Biochemistry and Molecular Biology.
Source: Megan Ondrizek – University of Miami
Image Credit: Image is credited to Abrams et al 2015/Nature Genetics
Original Research: Abstract for “Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder” by Alexander J Abrams, Robert B Hufnagel, Adriana Rebelo, Claudia Zanna, Neville Patel, Michael A Gonzalez, Ion J Campeanu, Laurie B Griffin, Saskia Groenewald, Alleene V Strickland, Feifei Tao, Fiorella Speziani, Lisa Abreu, Rebecca Schüle, Leonardo Caporali, Chiara La Morgia, Alessandra Maresca, Rocco Liguori, Raffaele Lodi, Zubair M Ahmed, Kristen L Sund, Xinjian Wang, Laura A Krueger, Yanyan Peng, Carlos E Prada, Cynthia A Prows, Elizabeth K Schorry, Anthony Antonellis, Holly H Zimmerman, Omar A Abdul-Rahman, Yaping Yang, Susan M Downes, Jeffery Prince, Flavia Fontanesi, Antonio Barrientos, Andrea H Németh, Valerio Carelli, Taosheng Huang, Stephan Zuchner and Julia E Dallman in Nature Genetics. Published online July 13 2015 doi:10.1038/ng.3354
Abstract
Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder
Dominant optic atrophy (DOA)1, 2 and axonal peripheral neuropathy (Charcot-Marie-Tooth type 2, or CMT2)3 are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes OPA1 and MFN2, respectively4. In yeast, homologs of OPA1 (Mgm1) and MFN2 (Fzo1)5, 6 work in concert with Ugo1, for which no human equivalent has been identified thus far7. By whole-exome sequencing of patients with optic atrophy and CMT2, we identified four families with recessive mutations in SLC25A46. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein mitofilin (Fcj1). Loss of function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of SLC25A46 strengthens the genetic overlap between optic atrophy and CMT2 while exemplifying a new class of modified solute transporters linked to mitochondrial dynamics.
“Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder” by Alexander J Abrams, Robert B Hufnagel, Adriana Rebelo, Claudia Zanna, Neville Patel, Michael A Gonzalez, Ion J Campeanu, Laurie B Griffin, Saskia Groenewald, Alleene V Strickland, Feifei Tao, Fiorella Speziani, Lisa Abreu, Rebecca Schüle, Leonardo Caporali, Chiara La Morgia, Alessandra Maresca, Rocco Liguori, Raffaele Lodi, Zubair M Ahmed, Kristen L Sund, Xinjian Wang, Laura A Krueger, Yanyan Peng, Carlos E Prada, Cynthia A Prows, Elizabeth K Schorry, Anthony Antonellis, Holly H Zimmerman, Omar A Abdul-Rahman, Yaping Yang, Susan M Downes, Jeffery Prince, Flavia Fontanesi, Antonio Barrientos, Andrea H Németh, Valerio Carelli, Taosheng Huang, Stephan Zuchner and Julia E Dallman in Nature Genetics. Published online July 13 2015 doi:10.1038/ng.3354
