Variant Synonymizer: Platform to identify mutations defined in different ways is available now!

VarSy

Over 2,000 gene–disease validation summaries are now available—no login required!

Browse Summaries

CREB3L3 – Hypertriglyceridemia

CREB3L3 encodes the liver-enriched transcription factor CREB-H, which is essential for maintaining normal plasma triglyceride levels by regulating lipoprotein lipase (LPL) coactivators and inhibitors (PMID:21666694). Complete loss of CREB-H in mice leads to severe hypertriglyceridemia due to deficient expression of Apoc2, Apoa4 and Apoa5 and concurrent upregulation of Apoc3, demonstrating a clear in vivo requirement for CREB-H in triglyceride clearance.

In humans, multiple rare nonsynonymous and loss-of-function CREB3L3 variants have been identified in individuals with extreme hypertriglyceridemia. Fourteen distinct alleles—including the nonsense variant c.577C>T (p.Gln193Ter)—were found in affected probands, supporting a Mendelian contribution to severe hypertriglyceridemia (PMID:21666694).

Large-scale resequencing in 413 adult-onset hypertriglyceridemia cases versus 324 controls revealed a significant excess of heterozygous rare CREB3L3 variants (47 versus 16 total rare variants; odds ratio=2.3, P=0.005), indicating that even single-allele hypomorphic variants elevate disease risk (PMID:22135386).

Functional studies in Creb3l3-knockout mice recapitulate the human phenotype, confirming that CREB-H haploinsufficiency impairs LPL-mediated triglyceride clearance. There are no reported studies that dispute this gene-disease relationship.

Integration of human genetic findings with concordant mouse models establishes a strong gene-disease association. Genetic evidence is moderate based on multiple probands and significant burden data, and functional evidence is moderate given the robust in vivo model.

Key takeaway: CREB3L3 haploinsufficiency causes hypertriglyceridemia via dysregulation of the LPL pathway, supporting the clinical utility of CREB3L3 genetic testing in patients with elevated triglycerides.

References

  • Nature Medicine • 2011 • The transcription factor cyclic AMP-responsive element-binding protein H regulates triglyceride metabolism. PMID:21666694
  • Circulation: Cardiovascular Genetics • 2012 • Excess of rare variants in non-genome-wide association study candidate genes in patients with hypertriglyceridemia. PMID:22135386

Evidence Based Scoring (AI generated)

Gene–Disease Association

Strong

14 probands with LoF/missense variants causing hypomorphic CREB-H in extreme hypertriglyceridemia; significant enrichment in 413 patients vs 324 controls (OR=2.3; P=0.005); concordant mouse knockout model (PMID:21666694; PMID:22135386)

Genetic Evidence

Moderate

14 rare nonsynonymous variants in CREB3L3 in probands with extreme hypertriglyceridemia; significant enrichment of heterozygous rare variants in 413 cases versus 324 controls (PMID:21666694; PMID:22135386)

Functional Evidence

Moderate

Creb3l3-deficient mice develop hypertriglyceridemia due to reduced expression of LPL coactivators and increased inhibitor expression, recapitulating the human phenotype (PMID:21666694)