CPT2

Chr 1ADAR

carnitine palmitoyltransferase 2

Also known as: CPT1, CPTASE, IIAE4

NCBI Gene: 1376 ENSG00000157184 UniProt: P23786 OMIM: 600650

The protein is transported to the mitochondrial inner membrane where it works with carnitine palmitoyltransferase I to oxidize long-chain fatty acids. Mutations cause CPT II deficiency with autosomal recessive inheritance, presenting as lethal neonatal, infantile, or myopathic stress-induced forms, as well as susceptibility to acute infection-induced encephalopathy with autosomal dominant inheritance. The pathogenic mechanism involves impaired mitochondrial long-chain fatty acid oxidation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a nuclear protein which is transported to the mitochondrial inner membrane. Together with carnitine palmitoyltransferase I, the encoded protein oxidizes long-chain fatty acids in the mitochondria. Defects in this gene are associated with mitochondrial long-chain fatty-acid (LCFA) oxidation disorders. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 1.174 OMIM phenotypes

Clinical Summary— CPT2

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Gene-Disease Validity (ClinGen)

carnitine palmitoyltransferase II deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.17LOEUF

pLI 0.000

Z-score 0.95

OE 0.78 (0.53–1.17)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.40Z-score

OE missense 0.94 (0.86–1.03)

337 obs / 358.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.78 (0.53–1.17)

0≤0.351.4

Missense OE?0.94 (0.86–1.03)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 17 / 21.8Missense obs/exp: 337 / 358.1Syn Z: -1.17

This gene — mechanism propensity

0.6163th %ile

GOF

0.4283th %ile

LOF

0.3260th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DN1 literature citation

LOF1 literature citation

Literature Evidence

DNIn vitro studies by Yao et al. (2008) demonstrated that the F352C/V368I variant proteins exerted a dominant-negative effect on the CPT2 homotetramer and had shortened half-lives compared to wildtype, consistent with intracellular instability.1

LOFThe heterozygous knockout of CPT2 resulted in thymus FAO haploinsufficiency and an approximately 30% improvement in survival time, paralleling the antiproliferative signaling observed with MB disruption.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References