Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 170290

PERILIPIN 1; PLIN1

Alternative titles; symbols

PLIN

HGNC Approved Gene Symbol: PLIN1

SNOMEDCT: 783616005;

Cytogenetic location: 15q26.1 Genomic coordinates (GRCh38) : 15:89,664,367-89,679,367 (from NCBI)

Gene-Phenotype Relationships

TEXT

Description

Perilipin is a hormonally-regulated phosphoprotein that encircles the lipid storage droplet in adipocytes (Greenberg et al., 1991). It is the major cellular A-kinase substrate in adipocytes.

Cloning and Expression

Using anti-perilipin serum, Greenberg et al. (1993) isolated 2 related classes of full-length coding cDNAs, designated perilipin A and B, from a rat adipocyte cDNA expression library. The 2 cDNAs derive from 2 mRNA species that are produced by differential splicing. The mRNAs were predicted to encode perilipins A and B, proteins of 517 amino acids and 422 amino acids, respectively, which share a common 406-amino acid N-terminal sequence. These proteins exhibited a significant sequence relationship with only 1 other known protein, adipocyte differentiation-related protein (ADRP; 103195). Like the perilipins, ADRP appears to be adipocyte-specific, which suggests that they interact in a related intracellular pathway.

Nishiu et al. (1998) cloned a cDNA encoding human perilipin from an adipose tissue cDNA library. The human gene encodes a 522-amino acid polypeptide that is 79% identical to the rat homolog. The sequence contains 5 putative A-kinase sites. Northern blot analysis revealed a 3.0-kb mRNA expressed in visceral adipose tissue and mammary gland.

Lu et al. (2001) isolated cDNA sets and overlapping genomic fragments of the mouse perilipin locus, which they designated Peri. They showed that the perilipins are encoded by a single-copy gene, with alternative and tissue-specific mRNA splicing and polyadenylation yielding 4 different protein species. The perilipin proteins have identical amino termini of approximately 22 kD and distinct carboxy-terminal sequences of varying lengths.

Mapping

Nishiu et al. (1998) used fluorescence in situ hybridization to localize the PLIN1 gene to chromosome 15q26. This chromosomal region has been linked with insulin-dependent diabetes mellitus (IDDM3; 600318), making perilipin a candidate gene for this disease. Lu et al. (2001) mapped the mouse Plin1 gene to the central region of chromosome 7 between the mouse homologs of FES (190030), which is located on human 15q26.1, and NAPTB (602166), which is also located on 15q.

Gene Function

Greenberg et al. (1991) did not observe perilipin mRNA in preadipocytes but found that the message appeared at the onset of triacylglycerol accumulation in differentiating adipocytes, and levels increased in parallel with lipid accumulation. The data suggested an important role for perilipin in adipocyte lipid metabolism.

Gandotra et al. (2011) demonstrated that PLIN1 is an essential lipid droplet coat protein whose C terminus regulates ATGL (PNPLA2; 609059) activity and basal lipolysis indirectly by binding and stabilizing its coactivator, ABHD5 (604780).

Role in Leprosy Pathogenesis

Mycobacterium leprae survives and replicates within lipid droplets stored in the enlarged phagosomes of histiocytes, a typical feature of lepromatous leprosy (see 609888) thought to be an important nutrient source for the bacillus. Using immunohistochemistry, Tanigawa et al. (2008) demonstrated that ADRP and PLIN1 localized to the enlarged phagosomes of macrophages in lepromatous leprosy lesions. ADRP expression was induced in a monocyte cell line when live, but not dead, M. leprae was added. M. leprae could also inhibit the normal suppression of ADRP and PLIN1 expression mediated by peptidoglycan, a TLR2 (603028) ligand. Tanigawa et al. (2008) proposed that M. leprae can actively induce and support ADRP/PLIN1 expression to facilitate intraphagosomal lipid accumulation and a suitable environment for survival within macrophages.

Molecular Genetics

In French patients with autosomal dominant partial lipodystrophy type 4 (FPLD4; 613877), Gandotra et al. (2011) identified 2 different heterozygous mutations in the PLIN1 gene (170290.0001-170290.0002). The phenotype included partial lipodystrophy primarily affecting the limbs, insulin-resistant diabetes mellitus, and severe dyslipidemia. Transfection in preadipocytes showed that the mutant PLIN1 proteins localized correctly to lipid droplet surfaces, but were unable to inhibit basal lipolysis and failed to increase triglyceride accumulation compared to the wildtype protein. The droplets were smaller in size than normal. The authors concluded that their data suggested that the dominantly inherited phenotype resulted from haploinsufficiency.

In in vitro studies with cells transfected with the PLIN1 mutations identified by Gandotra et al. (2011), Gandotra et al. (2011) found that the mutations at the C terminus failed to suppress basal lipolysis and resulted in decreased PLIN1 levels. There was also a decrease in ABHD5 (604780) protein levels, suggesting that PLIN1 is important for stabilization of ABHD5. The C terminus of PLIN1 was found to bind to ABHD5 in normal cells, and this interaction was disturbed by the C-terminal mutations. ABHD5 was thus freely able to bind ATGL and facilitate its actions in the basal state. The findings indicated that the C terminus of PLIN1 is required for effective suppression of basal ATGL activity and that human mutations that affect this region of the protein impair triglyceride storage because of their inability to sequester ABHD5 and thereby to suppress ATGL activity in the basal state.

In 6 patients from 2 unrelated families with FPLD4, Kozusko et al. (2015) identified a heterozygous 2-bp deletion (c.1298delTG) in exon 9 of the PLIN1 gene (170290.0003), resulting in a translational frameshift and the incorporation of 125 aberrant amino acids from residue 439 onward (439fs), producing an elongated protein of 563 amino acids. The mutation segregated with the disorder in both families. Adipose tissue derived from 1 patient showed decreased levels of PLIN1 compared to controls. In vitro expression studies in preadipocytes indicated that the mutant protein is likely degraded by the proteasome. Expression of the mutant protein resulted in smaller lipid droplets and inefficient inhibition of basal lipolysis despite retention of its ability to bind ABHD5 (604780). The authors hypothesized that the reduced expression of the protein was a major factor in the pathogenesis. The patients had partial lipodystrophy, severe insulin resistance, severe dyslipidemia, and nonalcoholic fatty liver disease. Gestational hypertension was present in affected women.

In a 15-year-old Chinese girl and her mother with FPLD4, Chen et al. (2018) identified a heterozygous frameshift mutation in the PLIN1 gene (170290.0004), leading to the synthesis of 165 aberrant amino acids (Tyr401LeufsTer165) and a mutated protein with an aberrant C terminal. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was absent from public databases, including gnomAD. Functional studies of the variant were not performed, but it was predicted to interfere with binding to ABHD5. The proband presented with partial lipodystrophy, insulin resistance, polycystic ovaries, hypertriglyceridemia, hepatic steatosis, and proteinuria associated with secondary focal segmental glomerulosclerosis (FSGS) on renal biopsy.

To investigate whether null variants in PLIN1 cause partial lipodystrophy, Laver et al. (2018) sequenced 2,208 individuals who had a clinical suspicion of maturity-onset diabetes of the young (MODY; see 125850) or had neonatal diabetes or hyperinsulinism. They identified 6 with null (nonsense or frameshift) variants in the PLIN1 gene. None had clinical or biochemical evidence of lipodystrophy. An additional 14 of 17,000 individuals with PLIN1 null variants in the Type 2 Diabetes Knowledge Portal had no associated lipodystrophy biomarkers. The authors further argued that the frequency of null variants in PLIN1 in gnomAD (126/138,632 or 1 in 1,100) is too high to be responsible for a rare overt monogenic lipodystrophy. However, they noted that their findings did not negate the role of the protein-extending frameshift variants reported to cause FPLD4 (e.g., Gandotra et al., 2011, 170290.0001 and 170290.0002), as those mutations operate with a different mechanism, and that PLIN1 is an example of a gene in which only variants with specific genetic mechanisms are likely to be pathogenic.

Animal Model

Martinez-Botas et al. (2000) showed that targeted disruption of the Plin gene results in healthy mice with constitutively activated fat cell hormone-sensitive lipase (HSL; 151750). Plin-null mice consumed more food than control mice, but had normal body weight. They were much leaner and more muscular than controls, had 62% smaller white adipocytes, showed elevated basal lipolysis that was resistant to beta-adrenergic agonist stimulation, and were cold sensitive except when fed. They also were resistant to diet-induced obesity. Breeding the Plin-null alleles into mice homozygous for the db allele at the leptin receptor gene (601007) reversed the obesity by increasing the metabolic rate of the mice. The results demonstrated a role for perilipin in reining in basal HSL activity and regulating lipolysis and energy balance. Thus, the authors concluded that agents that inactivate perilipin may prove useful in antiobesity medications.

To study the role of perilipin in vivo, Tansey et al. (2001) created a perilipin knockout mouse. Homozygous null and wildtype mice consumed equal amounts of food, but the adipose tissue mass in the null animals was reduced to approximately 30% of that in wildtype animals. Isolated adipocytes of perilipin-null mice exhibited elevated basal lipolysis because of the loss of the protective function of perilipin. They also exhibited dramatically attenuated stimulated lipolytic activity, indicating that perilipin was required for maximal lipolytic activity. Plasma leptin (164160) concentrations in null animals were greater than expected for the reduced adipose mass. The null animals had a greater lean body mass and increased metabolic rate but they also showed an increased tendency to develop glucose intolerance and peripheral insulin resistance. When fed a high-fat diet, the perilipin-null animals were resistant to diet-induced obesity but not to glucose intolerance. The data demonstrated a major role for perilipin in adipose lipid metabolism and suggested perilipin as a potential target for attacking problems associated with obesity.

ALLELIC VARIANTS 4 Selected Examples):

.0001 LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 4

PLIN1, IVS8AS, G-T, -1
SNP: rs1567075176, ClinVar: RCV000022703

In a French woman and her 2 daughters with autosomal dominant partial lipodystrophy type 4 (FPLD4; 613877), Gandotra et al. (2011) identified a heterozygous G-to-T transversion in intron 8 (1210-1G-T) of the PLIN1 gene, resulting in frameshift with alternative splicing and incorporation of 158 aberrant amino acid residues (Leu404AlafsTer158). Coincidentally, the mutation resulted in the synthesis of the same longer mutated protein as another pathogenic mutation (170290.0002). The mutation was not found in 203 unrelated controls. Patient adipose tissue showed a reduction in expression of wildtype perilipin as well as decreased adipocyte size, increased macrophage infiltration, and increased fibrosis, compared to controls. Transfection in preadipocytes studies showed that the mutant protein localized correctly to lipid droplet surfaces, but was unable to inhibit basal lipolysis and failed to increase triglyceride accumulation compared to the wildtype protein. The droplets were smaller in size than normal. The authors concluded that their data suggested that the phenotype resulted from haploinsufficiency. The clinical phenotype included partial lipodystrophy primarily affecting the limbs, insulin-resistant diabetes mellitus, and severe dyslipidemia.

.0002 LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 4

PLIN1, 2-BP DEL, 1191AG
SNP: rs1567075667, ClinVar: RCV000022704

In 2 unrelated French women with autosomal dominant partial lipodystrophy type 4 (FPLD4; 613877), Gandotra et al. (2011) identified a heterozygous 2-bp deletion (1191delAG) in exon 8 of the PLIN1 gene, predicted to result in frameshift and synthesis of 166 additional aberrant amino acids (Val398GlyfsTer166). Coincidentally, the mutation resulted in the synthesis of the same longer mutated protein as another pathogenic mutation (170290.0001). The mutation was not found in 203 unrelated controls. Patient adipose tissue showed a reduction in expression of wildtype perilipin as well as decreased adipocyte size, increased macrophage infiltration, and increased fibrosis, compared to controls. Transfection in preadipocytes showed that the mutant protein localized correctly to lipid droplet surfaces, but was unable to inhibit basal lipolysis and failed to increase triglyceride accumulation compared to the wildtype protein. The droplets were smaller in size than normal. The authors concluded that their data suggested that the phenotype resulted from haploinsufficiency. The clinical phenotype included partial lipodystrophy primarily affecting the limbs, insulin-resistant diabetes mellitus, and severe dyslipidemia.

.0003 LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 4

PLIN1, 2-BP DEL, 1298TG
SNP: rs2141523598, ClinVar: RCV001837713

In 6 patients from 2 unrelated families with autosomal dominant partial lipodystrophy type 4 (FPLD4; 613877), Kozusko et al. (2015) identified a heterozygous 2-bp deletion (c.1298delTG) in exon 9 of the PLIN1 gene, resulting in a translational frameshift and the incorporation of 125 aberrant amino acids from residue 439 onward (439fs), producing an elongated protein of 563 amino acids. The mutation segregated with the disorder in both families. Adipose tissue derived from 1 patient showed decreased levels of PLIN1 compared to controls. In vitro expression studies in preadipocytes indicated that the mutant protein is likely degraded by the proteasome. Expression of the mutant protein resulted in smaller lipid droplets and inefficient inhibition of basal lipolysis despite retention of its ability to bind ABHD5 (604780). Levels of PLIN2 (103195) were increased. The authors hypothesized that the reduced expression of the protein was a major factor in the pathogenesis. The patients had partial lipodystrophy, severe insulin resistance, severe dyslipidemia, and nonalcoholic fatty liver disease. Gestational hypertension was present in affected women.

.0004 LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 4

PLIN1, 1-BP INS, 1201T
SNP: rs2141525540, ClinVar: RCV001837714

In a 15-year-old Chinese girl and her mother with autosomal dominant partial lipodystrophy type 4 (FPLD4; 613877), Chen et al. (2018) identified a heterozygous 1-bp insertion (c.1201_1202insT) in exon 8 of the PLIN1 gene, predicted to result in a frameshift leading to the synthesis of 165 aberrant amino acids (Tyr401LeufsTer165) and a mutated protein with an aberrant C terminal. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was absent from public databases, including gnomAD. Functional studies of the variant were not performed, but it was predicted to interfere with binding to ABHD5 (605780). The proband presented with partial lipodystrophy, insulin resistance, polycystic ovaries, hypertriglyceridemia, hepatic steatosis, and proteinuria associated with secondary focal segmental glomerulosclerosis on renal biopsy.

REFERENCES

1. Chen, R.-X., Zhang, L., Ye, W., Wen, Y.-B., Si, N., Li, H., Li, M.-X., Li, X.-M., Zheng, K.The renal manifestations of type 4 familial partial lipodystrophy: a case report and review of literature. BMC Nephrol. 19: 111, 2018. [PubMed: 29747582] [Full Text: https://doi.org/10.1186/s12882-018-0913-6\]
2. Gandotra, S., Le Dour, C., Bottomley, W., Cervera, P., Giral, P., Reznik, Y., Charpentier, G., Auclair, M., Delepine, M., Barroso, I., Semple, R. K., Lathrop, M., Lascols, O., Capeau, J., O'Rahilly, S., Magre, J., Savage, D. B., Vigouroux, C.Perilipin deficiency and autosomal dominant partial lipodystrophy. New Eng. J. Med. 364: 740-748, 2011. [PubMed: 21345103] [Full Text: https://doi.org/10.1056/NEJMoa1007487\]
3. Gandotra, S., Lim, K., Girousse, A., Saudek, V., O'Rahilly, S., Savage, D. B.Human frame shift mutations affecting the carboxyl terminus of perilipin increase lipolysis by failing to sequester the adipose triglyceride lipase (ATGL) coactivator AB-hydrolase-containing 5 (ABHD5). J. Biol. Chem. 286: 34998-35006, 2011. [PubMed: 21757733] [Full Text: https://doi.org/10.1074/jbc.M111.278853\]
4. Greenberg, A. S., Egan, J. J., Wek, S. A., Moos, M. C., Jr., Londos, C., Kimmel, A. R.Isolation of cDNAs for perilipins A and B: sequence and expression of lipid droplet-associated proteins of adipocytes. Proc. Nat. Acad. Sci. 90: 12035-12039, 1993. [PubMed: 7505452] [Full Text: https://doi.org/10.1073/pnas.90.24.12035\]
5. Greenberg, A. S., Egan, J. J., Wek, S. A., Takeda, T., Londos, C., Kimmel, A. K.Perilipin, a lipid droplet-associated, adipocyte specific protein; cDNA cloning and expression. (Abstract) Clin. Res. 39: 287A only, 1991.
6. Kozusko, K., Tsang, V. H. M., Bottomley, W., Cho, Y.-H., Gandotra, S., Mimmack, M. L., Lim, K., Isaac, I., Patel, S., Saudek, V., O'Rahilly, S., Srinivasan, S., Greenfield, J. R., Barroso, I., Campbell, L. V., Savage, D. B.Clinical and molecular characterization of a novel PLIN1 frameshift mutation identified in patients with familial partial lipodystrophy. Diabetes 64: 299-310, 2015. [PubMed: 25114292] [Full Text: https://doi.org/10.2337/db14-0104\]
7. Laver, T. W., Patel, K. A., Colclough, K., Curran, J., Dale, J., Davis, N., Savage, D. B., Flanagan, S. E., Ellard, S., Hattersley, A. T., Weedon, M. N.PLIN1 haploinsufficiency is not associated with lipodystrophy. J. Clin. Endocr. Metab. 103: 3225-3230, 2018. [PubMed: 30020498] [Full Text: https://doi.org/10.1210/jc.2017-02662\]
8. Lu, X., Gruia-Gray, J., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Londos, C., Kimmel, A. R.The murine perilipin gene: the lipid droplet-associated perilipins derive from tissue-specific, mRNA splice variants and define a gene family of ancient origin. Mammalian Genome 12: 741-749, 2001. [PubMed: 11641724] [Full Text: https://doi.org/10.1007/s00335-01-2055-5\]
9. Martinez-Botas, J., Anderson, J. B., Tessier, D., Lapillonne, A., Chang, B. H.-J., Quast, M. J., Gorenstein, D., Chen, K.-H., Chan, L.Absence of perilipin results in leanness and reverses obesity in Lepr(db/db) mice. Nature Genet. 26: 474-479, 2000. [PubMed: 11101849] [Full Text: https://doi.org/10.1038/82630\]
10. Nishiu, J., Tanaka, T., Nakamura, Y.Isolation and chromosomal mapping of the human homolog of perilipin (PLIN), a rat adipose tissue-specific gene, by differential display method. Genomics 48: 254-257, 1998. [PubMed: 9521880] [Full Text: https://doi.org/10.1006/geno.1997.5179\]
11. Tanigawa, K., Suzuki, K., Nakamura, K., Akama, T., Kawashima, A., Wu, H., Hayashi, M., Takahashi, S.-I., Ikuyama, S., Ito, T., Ishii, N.Expression of adipose differentiation-related protein (ADRP) and perilipin in macrophages infected with Mycobacterium leprae. FEMS Microbiol. Lett. 289: 72-79, 2008. [PubMed: 19054096] [Full Text: https://doi.org/10.1111/j.1574-6968.2008.01369.x\]
12. Tansey, J. T., Sztalryd, C., Gruia-Gray, J., Roush, D. L., Zee, J. V., Gavrilova, O., Reitman, M. L., Deng, C.-X., Li, C., Kimmel, A. R., Londos, C.Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity. Proc. Nat. Acad. Sci. 98: 6494-6499, 2001. [PubMed: 11371650] [Full Text: https://doi.org/10.1073/pnas.101042998\]

Contributors:

Cassandra L. Kniffin - updated : 02/15/2022
Ada Hamosh - updated : 02/11/2022
Cassandra L. Kniffin - updated : 4/13/2011
Paul J. Converse - updated : 2/16/2010
Victor A. McKusick - updated : 12/4/2001
Victor A. McKusick - updated : 6/27/2001
Victor A. McKusick - updated : 11/27/2000
Jennifer P. Macke - updated : 7/12/1999

Creation Date:

Victor A. McKusick : 5/9/1991

Edit History:

carol : 04/21/2025
carol : 01/19/2024
alopez : 02/21/2022
alopez : 02/21/2022
ckniffin : 02/15/2022
alopez : 02/11/2022
wwang : 04/13/2011
ckniffin : 4/13/2011
mgross : 2/16/2010
mgross : 2/4/2010
terry : 3/16/2005
carol : 12/10/2001
mcapotos : 12/4/2001
alopez : 10/30/2001
cwells : 7/12/2001
cwells : 7/6/2001
terry : 6/27/2001
mgross : 11/27/2000
terry : 11/27/2000
alopez : 7/12/1999
carol : 1/14/1994
supermim : 3/16/1992
carol : 5/9/1991