Development of metabolic syndrome at a young age as a manifestation of familial partial lipodystrophy type 3 (PPARG mutation): the first description of its clinical case in Russia

Леонидовна, Соркина Екатерина; Федоровна, Калашникова Марина; Вячеславовна, Лиходей Наталья; Олеговна, Кокшарова Екатерина; Владимирович, Устюжанин Дмитрий; Юрьевич, Майоров Александр; Владимировна, Шестакова Марина; Николаевич, Тюльпаков Анатолий

doi:10.14341/dm2015399-105

Cited by 7 publications

(6 citation statements)

References 14 publications

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“…Genotype data from family members were not available. The same variant was previously reported independently in a female subject with FPLD3 but not functionally characterized 16 .…”

Section: Methodssupporting

confidence: 81%

“…1b ). Germline transmission could not be established as family members were unavailable for genotyping, but R212Q and R212W have previously been reported in FPLD3 patients by others 15 , 16 . Arginine 212 is located in the hinge region and forms interactions with the minor groove of the DNA helix immediately 5’ of the PPRE (referred to as the 5’ extension or 5’ upstream region; 5’ UR), and substitution of arginine with a glutamine residue may reduce these (Fig.…”

Section: Resultsmentioning

confidence: 99%

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PPARγ lipodystrophy mutants reveal intermolecular interactions required for enhancer activation

et al. 2022

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Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with its function cause lipodystrophy. PPARγ is a highly modular protein, and structural studies indicate that PPARγ domains engage in several intra- and inter-molecular interactions. How these interactions modulate PPARγ’s ability to activate target genes in a cellular context is currently poorly understood. Here we take advantage of two previously uncharacterized lipodystrophy mutations, R212Q and E379K, that are predicted to interfere with the interaction of the hinge of PPARγ with DNA and with the interaction of PPARγ ligand binding domain (LBD) with the DNA-binding domain (DBD) of the retinoid X receptor, respectively. Using biochemical and genome-wide approaches we show that these mutations impair PPARγ function on an overlapping subset of target enhancers. The hinge region-DNA interaction appears mostly important for binding and remodelling of target enhancers in inaccessible chromatin, whereas the PPARγ-LBD:RXR-DBD interface stabilizes the PPARγ:RXR:DNA ternary complex. Our data demonstrate how in-depth analyses of lipodystrophy mutants can unravel molecular mechanisms of PPARγ function.

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“…Genotype data from family members were not available. The same variant was previously reported independently in a female subject with FPLD3 but not functionally characterized 16 .…”

Section: Methodssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

PPARγ lipodystrophy mutants reveal intermolecular interactions required for enhancer activation

et al. 2022

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“…Hyperuricemia has not been reported in CGL, however it was found in familial partial lipodystrophy type 3 caused by PPARG mutation [16] In addition, it is a frequent component of metabolic syndrome.…”

Section: Discussionmentioning

confidence: 99%

Unusual clinical features associated with congenital generalized lipodystrophy type 4 in a patient with a novel E211X CAVIN1 gene variant

Sorkina

Макарова

Bolotskaya

et al. 2020

Clin Diabetes Endocrinol

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Background: Congenital generalized lipodystrophy (CGL) is a rare disorder characterized by the lack of adipose tissue and metabolic complications with predominantly autosomal recessive inheritance. There are 6 different genes known to cause CGL with 4 main types recognized to date, which differ by the degree of fat loss, association with mental retardation and metabolic disorders, with CGL type 1 and 2 being the most common. Twenty seven cases of СGL type 4 from Japan, Oman, UK, Turkey, Mexico, Saudi Arabia, USA were reported previously. This report details our clinical experience with the first patient from Russia with CGL type 4. Case presentation: A 36-year-old patient, who has been suffering from generalized lipoatrophy since the first months of life and myopathy and gastrointestinal dysmotility since early childhood, developed dysmenorrhea and diabetes mellitus at the age of 19, bilateral cataracts when she was only 22 y.o., osteoporosis with vitamin D deficiency and hypocalcemia at the age of 28, diabetic foot syndrome and hyperuricemia when she was 35 y.o. Sequencing of lipodystrophy candidate genes detected a novel pathogenic homozygous variant p.631G < T: p.E211X in the CAVIN1 gene, confirming the diagnosis of CGL type 4. Conclusions: In comparison with previously reported patients with CGL type 4, our patient has diabetes mellitus, vitamin D deficiency, hypocalcemia, bilateral cataracts and hyperuricemia. All these manifestations are known to be associated with other lipodystrophy syndromes, but to our knowledge it is the first time they have been reported to be associated with CGL type 4.

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“…Consistent with previous research, the DBD domain appears more susceptible to variation [ 35 ]. However, variations in the Hinge region, while less frequent, have also been associated with metabolic effects similar to those observed in other domains [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 62%

Case report: two novel PPARG pathogenic variants associated with type 3 familial partial lipodystrophy in Brazil

da Silva,

Soares,

de Oliveira Filho

et al. 2024

Diabetol Metab Syndr

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Introduction and aim Type 3 Familial Partial Lipodystrophy (FPLD3) is a rare metabolic disease related to pathogenic PPARG gene variants. FPLD3 is characterized by a loss of fatty tissue in the upper and lower limbs, hips, and face. FPLD3 pathophysiology is usually associated with metabolic comorbidities such as type 2 diabetes, insulin resistance, hypertriglyceridemia, and liver dysfunction. Here, we clinically and molecularly characterized FPLD3 patients harboring novel PPARG pathogenic variants. Materials and methods Lipodystrophy-suspected patients were recruited by clinicians from an Endocrinology Reference Center. Clinical evaluation was performed, biological samples were collected for biochemical analysis, and DNA sequencing was performed to define the pathogenic variants associated with the lipodystrophic phenotype found in our clinically diagnosed FPLD subjects. Bioinformatics predictions were conducted to characterize the novel mutated PPARγ proteins. Results We clinically described FPLD patients harboring two novel heterozygous PPARG variants in Brazil. Case 1 had the c.533T > C variant, which promotes the substitution of leucine to proline in position 178 (p.Leu178Pro), and cases 2 and 3 had the c.641 C > T variant, which results in the substitution of proline to leucine in the position 214 (p.Pro214Leu) at the PPARγ2 protein. These variants result in substantial conformational changes in the PPARγ2 protein. Conclusion Two novel PPARG pathogenic variants related to FPLD3 were identified in a Brazilian FPLD cohort. These data will provide new epidemiologic data concerning FPLD3 and help understand the genotype-phenotype relationships related to the PPARG gene.

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Development of metabolic syndrome at a young age as a manifestation of familial partial lipodystrophy type 3 (PPARG mutation): the first description of its clinical case in Russia

Cited by 7 publications

References 14 publications

PPARγ lipodystrophy mutants reveal intermolecular interactions required for enhancer activation

PPARγ lipodystrophy mutants reveal intermolecular interactions required for enhancer activation

Unusual clinical features associated with congenital generalized lipodystrophy type 4 in a patient with a novel E211X CAVIN1 gene variant

Case report: two novel PPARG pathogenic variants associated with type 3 familial partial lipodystrophy in Brazil

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