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Pathogenic variants of the mitochondrial aspartate/glutamate carrier causing citrin deficiency.

Published version
Peer-reviewed

Type

Article

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Authors

Thangaratnarajah, Chancievan 
Kunji, Edmund RS 

Abstract

Citrin deficiency is a pan-ethnic and highly prevalent mitochondrial disease with three different stages: neonatal intrahepatic cholestasis (NICCD), a relatively mild adaptation stage, and type II citrullinemia in adulthood (CTLN2). The cause is the absence or dysfunction of the calcium-regulated mitochondrial aspartate/glutamate carrier 2 (AGC2/SLC25A13), also called citrin, which imports glutamate into the mitochondrial matrix and exports aspartate to the cytosol. In citrin deficiency, these missing transport steps lead to impairment of the malate-aspartate shuttle, gluconeogenesis, amino acid homeostasis, and the urea cycle. In this review, we describe the geological spread and occurrence of citrin deficiency, the metabolic consequences and use our current knowledge of the structure to predict the impact of the known pathogenic mutations on the calcium-regulatory and transport mechanism of citrin.

Description

Keywords

SLC25A12, SLC25A13, calcium regulation, mitochondrial carrier family, transport, urea cycle disorders, Adult, Aspartic Acid, Calcium, Citrullinemia, Glutamates, Humans, Infant, Newborn, Mitochondrial Membrane Transport Proteins, Mutation

Journal Title

Trends Endocrinol Metab

Conference Name

Journal ISSN

1043-2760
1879-3061

Volume Title

Publisher

Elsevier BV
Sponsorship
Citrin Foundation (Unknown)
SNSF (via University Of Bern) (REF-18-285)
Medical Research Council (MC_UU_00015/1)
Medical Research Council (MC_UU_00015/7)
MRC (MC_UU_00028/2)