Evidence map›Paper›PMID 27543974›Full record

ArticleBrain : a journal of neurology2016

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 and 7 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Brain : a journal of neurology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.

0numbers the graph read from it
0cells of the map it votes in
55citing papers in PubMed
4.4field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

55 citing papers in PubMed, 97 citations in OpenAlex.

  1. Review
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  6. Identifying motor resilience proteins associated with motor decline in older adults.The journals of gerontology. Series A, Biological sciences and medical sciences · 2025
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  17. A novel homozygous variant inFrontiers in pediatrics · 2024
    Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors at 7 institutions in 4 countries.

Jijun WanDepartment of Neurology, University of California, Los Angeles, CA, USA.
Janos SteffenDepartment of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA.
Michael YourshawDepartment of Human Genetics, University of California, Los Angeles, CA, USA.
Hafsa MamsaDepartment of Neurology, University of California, Los Angeles, CA, USA.
Erik AndersenRoyal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia.
Sabine Rudnik-SchönebornDivision of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
Kate PopeRoyal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia.
Katherine B HowellRoyal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia.
Catriona A McLeanAnatomical Pathology, The Alfred Hospital; Howard Florey Neuroscience Institute, Melbourne, Victoria, Australia.
Andrew J KornbergRoyal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia.
Jörg JosephDepartment of Neonatology, Bürgerhospital Frankfurt am Main, Germany.
Paul J LockhartBruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
Klaus ZerresInstitut für Humangenetik der RWTH Aachen, Aachen, Germany.
Monique M RyanRoyal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia.
Stanley F NelsonDepartment of Human Genetics, University of California, Los Angeles, CA, USA.
Carla M KoehlerDepartment of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA.
Joanna C JenDepartment of Neurology, University of California, Los Angeles, CA, USA.
University of California, Los Angeles · USRoyal Children's Hospital · AUMurdoch Children's Research Institute · AUBürgerhospital Frankfurt am Main · DEFlorey Institute of Neuroscience and Mental Health · AUInnsbruck Medical University · ATRWTH Aachen University · DE

Funding

UCLA Clinical and Translational Science InstituteUL1TR000124 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI DUBINETT, STEVEN M. · 2012 to 2015
$57.0M
Biogenesis of the mitochondrial inner membrane diversity supplementR01GM061721 · NIGMS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI KOEHLER, CARLA M · 2000 to 2025
$8.1M
Genetics of Familial Episodic AtaxiaR01NS064183 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI JEN, JOANNA C · 2009 to 2010
$965k
NCATS NIH HHS UL1 TR000124NIGMS NIH HHS R01 GM061721NINDS NIH HHS R01 NS064183
6 · The paper itself

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.

Indexed as

Amino AcidsAnimalsAnimals, Genetically ModifiedBrainCell Line, TransformedCells, CulturedCerebellar DiseasesCohort StudiesEmbryo, NonmammalianFemaleGenetic Predisposition to DiseaseHumansInfantMagnetic Resonance ImagingMaleMitochondriaAmino AcidsMitochondrial ProteinsPhosphate Transport ProteinsSLC25A46 protein, humanmitochondriaoptic atrophy spectrum disorderpontocerebellar hypoplasiaSLC25A46

Identifiers

PMID27543974
PMCPMC5840878
OpenAlexW2513713486

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.