SLC25A13 – Citrin deficiency

Citrin deficiency is an autosomal recessive metabolic disease caused by biallelic pathogenic variants in SLC25A13, which encodes the mitochondrial aspartate–glutamate carrier (AGC2). It manifests as neonatal intrahepatic cholestasis (NICCD) in infancy and adult-onset type II citrullinemia (CTLN2) with hepatic encephalopathy and neuropsychiatric disturbances.

The clinical validity of the SLC25A13–Citrin deficiency association is Definitive based on >200 unrelated probands across multiple case series and cohorts, segregation of variants in families, and concordant biochemical and molecular findings (e.g., elevated citrulline and ammonia). Large NICCD cohorts of 51 Chinese children and 6 Korean cases have been molecularly confirmed (PMID:21424115, PMID:17982687). In CTLN2, 102 adult patients were genotyped for seven recurrent mutations (PMID:11153906).

Inheritance is Autosomal recessive with compound heterozygosity or homozygosity for loss-of-function (LoF) variants. Over 80 distinct SLC25A13 variants have been reported, including frameshift, nonsense, splice-site, and missense changes. The recurrent 4 bp deletion c.851_855del (p.Arg284HisfsTer6) exemplifies a founder allele in East Asian populations (PMID:21161389).

Genetic evidence is Strong: biallelic pathogenic variants have been identified in >200 patients from >50 families, with recurrent alleles showing population specificity and familial segregation supporting AR inheritance and achieving the genetic evidence cap.

Functional studies demonstrate a loss-of-function mechanism: Saccharomyces cerevisiae agc1Δ yeast transformed with mutant SLC25A13 alleles (e.g., p.Arg355Gln, p.Val264Ile) show impaired growth, confirming reduced AGC activity (PMID:23053473). Patient lymphocyte analyses reveal aberrant transcripts from splice variants (e.g., c.615+5G>A) and deficient citrin protein in Western blots (PMID:17092749).

Knockout mice lacking Slc25a13 exhibit biochemical deficits in the malate–aspartate shuttle but fail to develop overt CTLN2 phenotypes, suggesting species-specific compensation and incomplete penetrance in some contexts (PMID:14701727).

In summary, genetic and functional data robustly establish SLC25A13 as the causal gene for Citrin deficiency, enabling molecular diagnosis, family counseling, and targeted dietary management. Key take-home: AR SLC25A13 mutations cause Citrin deficiency, for which early genetic testing and dietary intervention are clinically actionable.

References

• International journal of molecular medicine • 2007 • Six cases of citrin deficiency in Korea PMID:17982687
• International journal of molecular medicine • 2011 • Genotypic and phenotypic features of citrin deficiency: five-year experience in a Chinese pediatric center PMID:21424115
• Human genetics • 2000 • Identification of two novel mutations in the SLC25A13 gene and detection of seven mutations in 102 patients with adult-onset type II citrullinemia PMID:11153906
• PloS one • 2014 • Clinical, molecular and functional investigation on an infant with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) PMID:24586645
• Journal of inherited metabolic disease • 2010 • Neonatal intrahepatic cholestasis associated with citrin deficiency (NICCD): a case series of 11 Malaysian patients PMID:21161389
• Journal of inherited metabolic disease • 2013 • Prediction of the functional effect of novel SLC25A13 variants using a S. cerevisiae model of AGC2 deficiency PMID:23053473

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