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PNLIP – Pancreatic Triacylglycerol Lipase Deficiency

Pancreatic triacylglycerol lipase deficiency is an autosomal recessive disorder characterized by fat malabsorption and steatorrhea. To date, only two siblings have been reported with congenital deficiency carrying a homozygous missense variant c.662C>T (p.Thr221Met) in PNLIP; functional assays in HEK293A and AR42J cells showed that p.Thr221Met PNLIP is retained intracellularly, accumulates in insoluble aggregates, and induces endoplasmic reticulum (ER) stress, explaining the loss of enzyme secretion and clinical phenotype ([PMID:25862608]). A separate study described three novel truncating variants, c.305G>A (p.Trp102Ter) and c.1257G>A (p.Trp419Ter), which also impair secretion and trigger ER stress in transfected cells ([PMID:37926600]). A Pnlip p.Thr221Met knock-in mouse model recapitulated key features of human disease, including progressive pancreatic atrophy, acinar cell loss, fibrosis, fatty change, immune cell infiltration, and elevated ER stress markers, confirming the proteotoxic mechanism in vivo ([PMID:36631248]).

Earlier sequencing of four unrelated children with clinical PNLIP deficiency found no coding or splice mutations, only silent SNPs, suggesting genetic heterogeneity or undiscovered regulatory variants in some cases ([PMID:11393534]). Overall, evidence is currently limited: genetic data derive from a single sib pair and three additional variants without extended segregation, but functional and animal model concordance support a pathogenic LOF mechanism. Key take-home: PNLIP deficiency is a recessive loss-of-function disorder driven by misfolding and ER stress, and genetic testing for known PNLIP variants can guide diagnosis and management.

References

  • Biochimica et Biophysica Acta • 2015 • A novel mutation in PNLIP causes pancreatic triglyceride lipase deficiency through protein misfolding. PMID:25862608
  • Pancreatology • 2023 • Characterization of novel PNLIP variants in congenital pancreatic lipase deficiency. PMID:37926600
  • Gut • 2023 • Preclinical mouse model of a misfolded PNLIP variant develops chronic pancreatitis. PMID:36631248
  • Journal of Human Genetics • 2001 • Polymorphisms in PNLIP, encoding pancreatic lipase, and associations with metabolic traits. PMID:11393534

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Two siblings with homozygous p.Thr221Met variant ([PMID:25862608]); additional truncating variants identified without segregation; functional concordance supports association.

Genetic Evidence

Limited

Homozygous p.Thr221Met in two probands; three truncating variants reported; no extended familial segregation or population‐level pathogenicity data.

Functional Evidence

Moderate

In vitro secretion assays and ER stress induction in cell models ([PMID:25862608], [PMID:37926600]) and recapitulation of pancreatic pathology and ER stress in a p.Thr221Met mouse model ([PMID:36631248]).