Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia

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

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66 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2877-2890
Number of pages14
Issue number11
Publication statusPublished - Nov 2016
Externally publishedYes


  • mitochondria
  • optic atrophy spectrum disorder
  • pontocerebellar hypoplasia
  • SLC25A46

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