Submission Details

PLIN1 (previously known as PERI; PLIN; FPLD4) was first reported in relation to autosomal dominant familial partial lipodystrophy (FPLD4, OMIM: 613877) in 2011 (Gandotra et al., PMID: 21345103). The authors described 3 families with familial partial lipodystrophy, insulin resistance, hepatic steatosis, and dyslipidemia that cosegregates with 2 different heterozygous PLIN1 mutations [c.1210-1G > T (p.Leu404Alafs) and c.1191_1192delAG (p.Val398Glyfs)], leading to elongated perilipin 1. Typically, FPLD4 patients are characterized by lipoatrophy predominantly affecting the gluteal region and lower limbs, muscular hypertrophy, most notable on the lower limbs and no lipodystrophy in face and neck. Insulin-resistant diabetes mellitus, polycystic ovary syndrome, acanthosis nigricans, hypertriglyceridemia, hypertension, and hepatic steatosis are also present (Gandorta et al., PMID: 21345103; Kozusko et al., PMID: 25114292; Chen et al., PMID: 29747582). Renal disease has been reported once (Chen et al., PMID: 29747582). At least 5 frame shifting variants that result in the inclusion of aberrant C-terminal amino acids (125-166 amino acids) have been reported in cases of FPLD4, namely c.1191_1192del (p.Val398Glyfs; PMIDs: 21345103, 31504636), c.1201_1202dup (p.Val402Thrfs, PMID: 29747582), c.1202_1205dup (p.Pro403Argfs; PMID: 31504636), c.1308_1309del (p.Pro439Valfs; PMID: 25114292) and c.1210-1G-T (p.Leu404Alafs; PMID: 21345103) in at least 10 probands in different publications (PMIDs: 21345103; 25114292; 29747582; 31504636). Of note, histological examination of subcutaneous adipose tissue from patients revealed a significant decrease in adipocyte size, macrophage infiltration, and increased fibrosis (PMID: 21345103). For the purpose of this curation, all 10 probands are included. *Heterozygous null variants predicted to undergo nonsense-mediated decay (NMD) are relatively frequent in the population and clinical datasets and are not associated with FPLD4, thus indicating that haploinsufficiency is not a disease mechanism PLIN1-related lipodystrophy (Laver et al., PMID: 30020498, Koprulu et al. PMID: 34875679, Patel et al., PMID: 35235652); rather, it is associated with a favorable lipid profile. *Instead, the disorder results specifically from dominant-negative effects of C-terminal elongating frameshift variants predicted to escape NMD. Mechanistic studies suggest that subcutaneous patients’ adipose tissues show reduced full-length perilipin-1 and an extended perilipin-1 form compatible with the predicted elongated C-terminal tail of the mutant proteins (PMIDs: 21345103; 25114292; 31504636). Patients’ adipose tissues are also characterized by smaller adipocytes, increased macrophage infiltration and fibrosis (PMIDs: 21345103; 31504636). All but one (i.e. (p.Pro439Valfs; PMID:25114292) FPLD4-associated PLIN1 variants [p.(Val398Glyfs), p.(Pro403Argfs), p.(Leu404Alafs)] alter the interaction domain of perilipin-1 with ABHD5 (PMIDs: 21757733; 31504636). Consistently, the p.(Val398Glyfs) and p.(Leu404Alafs) mutants fail to interact with ABHD5, leading to constitutive activation of adipocyte triglyceride lipase (PMIDs: 21345103). Although the p.(Pro439Valfs) mutant binds ABHD5, it fails to inhibit basal lipolysis probably by an alternate still unknown mechanism (PMID:25114292). Plin1 homozygous knockout mice display a significant reduction in adipose tissue mass, approximately 30% of that observed in wild-type counterpart. Their Isolated adipocytes show elevated basal lipolysis because of the loss of the protective function of perilipin. In addition, these adipocytes show markedly reduced stimulated lipolytic activity, thus suggesting that perilipin is essential for maximal lipolysis. Plin1 homozygous knockout mice also exhibit greater lean body mass, elevated metabolic rates, and are more prone to glucose intolerance and peripheral insulin resistance (Tansey et al., PMID: 11371650). Furthermore, adipogenic signaling is disrupted in these mice, resulting in abnormal lipid droplet growth and differentiation (Lyu et al., PMID:25695774, Patel et al., PMID: 35235652). Heterozygous knockout mice have a non-significantly lower fat mass. Experimental evidence: 6 points. Total evidence: 18 points. In summary, there is definitive evidence supporting the relationship between PLIN1 and autosomal dominant familial partial lipodystrophy (FPLD4, OMIM: 613877). *Only frameshift variants extending the C-terminus have to date been implicated in humans. Homozgyous null variants have not been observed in humans, and heterozgyous null variants are not associated with lipodystrophy in humans. * This classification was approved by the ClinGen Monogenic Diabetes GCEP on September 10, 2025 (Gene-Disease Clinical Validity Standard Operating Procedures (SOP) - SOP11).