FPLD is a highly heterogeneous disease with both clinical and genetic manifestations. FPLD2 mutations caused by the most common mutation in LMNA and rare FPLD3 subtypes caused by PPARG mutations are characterized by a relatively minor loss of adipose tissue, but the associated metabolic changes are more serious than those caused by other mutations5. PPARG is a nuclear transition factor activated by a ligand belonging to the type II nucleus15. It is not only a target molecule of insulin allergen (TZDS) but also an important regulatory factor for fat cell differentiation and endocrine function8. The main regulatory factors of signal transmission are expressed in the vasculature, heart, muscles, kidney, and other tissues and participate in the adjustment of pathophysiological processes such as glucose and lipid metabolism, inflammation, apoptosis, smooth muscle migration, proliferation, and atherosclerosis16,17. PPARG mutations can cause fat malnutrition and metabolic symptoms(e.g. insulin resistance, hyperinsulinemia, hypertriglyceridemia, diabetes)18.
Most pathogenic variants of PPARG associated with FPLD3 are missense mutations that disrupt receptor function at different levels, so clinical signs and symptoms may vary. Extreme fat atrophy and trunk fat accumulation are among the most common clinical features of FPLD3 upon admission and are often accompanied by varying degrees of metabolic disturbances. Available data suggest that the severity of complications is related to the degree of fat loss. Common complications include diabetes mellitus, insulin resistance, hypertriglyceridemia, hepatic steatosis, and pancreatitis. Other common complications include acanthosis nigricans, polycystic ovarian disease(PCOS), hypertension, and proteinuric nephropathy7.
Patients with preexisting FPLD3 present with symptoms that lead to a diagnosis of diabetic ketoacidosis, which is controversial in the staging of diabetes mellitus. The patient was negative for diabetic antibodies, had a multigenerational family history of hyperglycemia or diabetes mellitus; had a slightly low serum C-peptide level (0.357 nmol/l [0.37–1.47], was associated with hyperlipidemia, and had an unusual fat distribution, such as central fat accumulation and lack of fat in the extremities. Based on clinical signs and symptoms, it cannot be classified as type 1 or type 2 diabetes. Therefore, monogenic diabetes should be classified. Monogenic diabetes is a type of diabetes caused by defects in one or more loci of a single gene, accounting for 1–5% of diabetes cases. It includes maturity-onset diabetes of the young (MODY), neonatal diabetes mellitus (NDM), and diabetes of the young (MODY). NDM), mitochondrial diabetes (MD), and syndromic diabetes (Wolfram syndrome, and FPLD syndrome)2. To date, more than 40 different genetic subtypes of monogenic diabetes have been identified, each with a typical phenotype and a specific inheritance pattern, and different etiologies dictate different treatments (e.g., oral sulfonylurea for HNF1A/HNF4A diabetes in MODY, and no treatment for HNF1A/HNF4A diabetes). Wolfman syndrome can be treated with 4-phenylbutyric acid and taurine deoxycholic acid), and the clinical features of monogenic diabetes often overlap with those of type 1 and 2 diabetes. Therefore, correct diagnosis is clinically critical for some forms of monogenic diabetes. Molecular genetic testing can be used for diagnosis and classification19,20.
Accurate typing can better identify and distinguish rare monogenic diabetes, and correct and timely diagnosis is essential for the rapid treatment of most diseases, prevention of related complications, and optimization of treatment. Insulin is the first choice for most case of syndromic diabetes, while insulin sensitizers such as metformin and glitazone can be used for FPLD syndrome. Timely genetic testing should be considered for patients with monogenic diabetes, and the next-generation sequencing method can be used for rapid diagnosis. If some disease-causing genes are "manipulated," treatment can be tailored to specific genetic defects. However, genetic testing has been limited to monogenic diabetes caused by known mutations. Due to the lack of whole genome sequencing, effective sequencing cannot be performed for patients with unknown etiology. However, for suspected patients, molecular diagnosis is still an effective method for implementing precision medicine, which allows physicians to make more accurate diagnoses and provide more precise treatment.
Current treatments for FPLD3 focus on symptom improvement, including the management of diabetes mellitus, hypertriglyceridemia pancreatitis, and low-fat and low-calorie diets. Insulin sensitizers such as metformin and glitazones can be used to treat hyperglycemia, and partial loss of R212W PPARG function can be restored by agonists, as evidenced by the results of the reporter gene experiments in the present study (Fig. 4A). Recombinant leptin therapy may be considered for children with severe congenital fat metabolism disorders and may improve hyperglycemia, hypertriglyceridemia, and hepatic fat accumulation21. Currently, potential therapeutic strategies for specific defects rely heavily on understanding the effects of mutant receptors. Therefore, it is important to elucidate the correlation between the genotype and phenotype of mutant receptors and study the functional and molecular properties of these receptors.
We described a new functionally missing mutation of PPARG2, namely, ARG212TRP in a Chinese family, in which two consecutive generations have two affected members. Genetic mutations in this family include those related to subcutaneous fat on the arms and thighs; accumulation of facial, neck, and subcutaneous fat tissue; and various metabolic complications, including hyperglycemia, insulin resistance, high glycerin, and pancreatic inflammation. Mutation of PPARG2 leads to FPLD3, mainly in the DBD and LBD protein domains22. Most of the pathogenicity of PPARG mutations that cause FPLD3 is understood. Our current research revealed that the R212W mutation led to a 40% decrease in receptor transcription activity, and the mutant carriers expressed the FPLD3 phenotype, which is consistent with a non-highly severe functional defect, with no evidence of explicit negative activity of the R212W PPARG mutation. In addition, some patients with mutations that impair PPARG activity may exhibit only metabolic abnormalities. This family-based sporadic mutation study can could bring the phenotypic diversity of FPLD3 to the attention of physicians and researchers. Thus, our results highlight the importance of the functional validation of novel PPARG mutations in the context of a diabetic phenotype. The results of our study combined with clinical data, pedigree genetic analysis, and gene sequencing can help to correctly determine their pathogenic role, clarify the etiology, and develop appropriate drug treatment.