Alternative titles; symbols
HGNC Approved Gene Symbol: PNLIP
Cytogenetic location: 10q25.3 Genomic coordinates (GRCh38): 10:116,545,931-116,567,855 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q25.3 | ?Pancreatic lipase deficiency | 614338 | Autosomal recessive | 3 |
Pancreatic lipase (EC 3.1.1.3), a 56-kD protein that hydrolyzes dietary long chain triglycerides to free fatty acids and monoacylglycerols, is essential for the intestinal absorption of fats. The activity of pancreatic lipase is stimulated in the presence of intestinal bile salts by pancreatic colipase (120105) (summary by Lowe et al., 1989).
See 614338 for discussion of pancreatic lipase deficiency.
By screening a pancreatic cDNA expression library with polyclonal antibodies against pancreatic lipase, Lowe et al. (1989) cloned a PNLIP cDNA. The cDNA encodes a predicted 465-amino acid protein, including a 16-amino acid signal peptide, that is 85% and 70% identical to pig and dog pancreatic lipase, respectively. Northern blot analysis detected PNLIP expression only in pancreas.
Sims et al. (1993) determined that the PNLIP gene contains 13 exons spanning more than 20 kb. A PNLIP pseudogene is located less than 10 kb downstream of PNLIP.
Davis et al. (1991) mapped the PNLIP gene to chromosome 10 by study of mouse-human somatic cell hybrids and regionalized the assignment to 10q26.1 by in situ hybridization.
In 2 Arab Muslim brothers with pancreatic lipase deficiency, Behar et al. (2014) identified homozygosity for a missense mutation in the PNLIP gene (T221M; 246600.0001) that segregated with disease in the family and was not found in ethnically matched controls or in public variant databases.
In 2 Arab Muslim brothers from central Israel with pancreatic lipase deficiency (PNLIPD; 614338), Behar et al. (2014) identified homozygosity for a c.662C-T transition in exon 6 of the PNLIP gene, resulting in a thr221-to-met (T221M) substitution at a highly conserved residue located near the catalytic triad. The unaffected parents were heterozygous for the mutation, which was not found in 2 unaffected brothers, in 150 Arab Muslim controls from central Israel, or in public variant databases.
Szabo et al. (2015) performed functional analysis of the T221M mutant in HEK293A cells and in AR42J rat acinar cells. In both models, the T221M mutant showed no lipase activity and was not secreted, but it was present in cell lysates where it accumulated in the insoluble fraction. In addition, intracellular retention of the mutant resulted in endoplasmic reticulum stress as measured by elevated XBP1 (194355) splicing and increased levels of ER chaperones. Szabo et al. (2015) concluded that the T221M mutation causes misfolding and aggregation of the T221M mutant inside the cell, with consequent loss of enzyme secretion.
Behar, D. M., Basel-Vanagaite, L., Glaser, F., Kaplan, M., Tzur, S., Magal, N., Eidlitz-Markus, T., Haimi-Cohen, Y., Sarig, G., Bormans, C., Shohat, M., Zeharia, A. Identification of a novel mutation in the PNLIP gene in two brothers with congenital pancreatic lipase deficiency. J. Lipid Res. 55: 307-312, 2014. [PubMed: 24262094] [Full Text: https://doi.org/10.1194/jlr.P041103]
Davis, R. C., Diep, A., Hunziker, W., Klisak, I., Mohandas, T., Schotz, M. C., Sparkes, R. S., Lusis, A. J. Assignment of human pancreatic lipase gene (PNLIP) to chromosome 10q24-q26. Genomics 11: 1164-1166, 1991. [PubMed: 1783385] [Full Text: https://doi.org/10.1016/0888-7543(91)90048-j]
Lowe, M. E., Rosenblum, J. L., Strauss, A. W. Cloning and characterization of human pancreatic lipase cDNA. J. Biol. Chem. 264: 20042-20048, 1989. [PubMed: 2479644]
Sims, H. F., Jennens, M. L., Lowe, M. E. The human pancreatic lipase-encoding gene: structure and conservation of an Alu sequence in the lipase gene family. Gene 131: 281-285, 1993. [PubMed: 8406023] [Full Text: https://doi.org/10.1016/0378-1119(93)90307-o]
Szabo, A., Xiao, X., Haughney, M., Spector, A., Sahin-Toth, M., Lowe, M. E. A novel mutation in PNLIP causes pancreatic triglyceride lipase deficiency through protein misfolding. Biochim. Biophys. Acta 1852: 1372-1379, 2015. [PubMed: 25862608] [Full Text: https://doi.org/10.1016/j.bbadis.2015.04.002]