Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia.

Abstract

Disturbed mitochondrial fusion and fission have been linked to various neurodegenerative disorders. In siblings from two unrelated families who died soon after birth with a profound neurodevelopmental disorder characterized by pontocerebellar hypoplasia and apnoea, we discovered a missense mutation and an exonic deletion in the SLC25A46 gene encoding a mitochondrial protein recently implicated in optic atrophy spectrum disorder. We performed functional studies that confirmed the mitochondrial localization and pro-fission properties of SLC25A46. Knockdown of slc24a46 expression in zebrafish embryos caused brain malformation, spinal motor neuron loss, and poor motility. At the cellular level, we observed abnormally elongated mitochondria, which was rescued by co-injection of the wild-type but not the mutant slc25a46 mRNA. Conversely, overexpression of the wild-type protein led to mitochondrial fragmentation and disruption of the mitochondrial network. In contrast to mutations causing non-lethal optic atrophy, missense mutations causing lethal congenital pontocerebellar hypoplasia markedly destabilize the protein. Indeed, the clinical severity appears inversely correlated with the relative stability of the mutant protein. This genotype-phenotype correlation underscores the importance of SLC25A46 and fine tuning of mitochondrial fission and fusion in pontocerebellar hypoplasia and central neurodevelopment in addition to optic and peripheral neuropathy across the life span.

• Authors: Jijun Wan, Janos Steffen, Michael Yourshaw, Hafsa Mamsa, Erik Andersen, Sabine Rudnik-Schöneborn, Kate Pope, Katherine B Howell, Catriona A McLean, Andrew J Kornberg, Jörg Joseph, Paul J Lockhart, Klaus Zerres, Monique M Ryan, Stanley F Nelson, Carla M Koehler, Joanna C Jen
• Journal: Brain : a journal of neurology (Brain) Vol. 139 Issue 11 Pg. 2877-2890 (11 01 2016) ISSN: 1460-2156 [Electronic] England
• PMID: 27543974 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Amino Acids
• Mitochondrial Proteins
• Phosphate Transport Proteins
• SLC25A46 protein, human

Topics

• Amino Acids (genetics)
• Animals
• Animals, Genetically Modified
• Brain (abnormalities)
• Cell Line, Transformed
• Cells, Cultured
• Cerebellar Diseases (diagnostic imaging, genetics)
• Cohort Studies
• Embryo, Nonmammalian
• Female
• Genetic Predisposition to Disease (genetics)
• Humans
• Infant
• Magnetic Resonance Imaging
• Male
• Mitochondria (metabolism, pathology)
• Mitochondrial Dynamics (genetics)
• Mitochondrial Proteins (genetics)
• Models, Molecular
• Mutation (genetics)
• Phosphate Transport Proteins (genetics)
• Polymorphism, Single Nucleotide (genetics)
• Zebrafish