Clinical reportBiallelic mutations at PPARG cause a congenital, generalized lipodystrophy similar to the Berardinelli–Seip syndrome
Introduction
The familial lipodystrophies are a rare group of disorders categorized by their pattern of adipose tissue distribution and, if known, their molecular etiology [Garg and Agarwal, 2009, Hegele et al., 2007]. The congenital generalized lipodystrophies commonly present with a general lack of adipose tissue noted in early life. Individuals also develop diabetes with insulin resistance, hypertriglyceridemia and some forms can show vitamin D resistance, cardiomyopathy and mild intellectual disability [Garg and Agarwal, 2009]. The mode of inheritance is autosomal recessive and the known genes that cause CGL1-4 are AGPAT2, BSCL2, and the rarer CAV1 and PTRF respectively.
In contrast, the familial partial lipodystrophies (FPLD) have an autosomal dominant mode of inheritance. Individuals with FPLD also show a lack of subcutaneous adipose tissue primarily affecting the extremities and buttocks with a sparing, and occasional expansion, of the fat stores to the face, neck and trunk. The age of onset is at puberty and other common manifestations include diabetes and hypertriglyceridemia [Garg and Agarwal, 2009]. There are at least four forms of FPLD (Types 1–4). The genetic cause for the first form, FPLD type 1 is not known. For FPLD type 2 mutations have been identified in LMNA and for FPLD type 3, a heterozygous mutation present in the peroxisome proliferator activated receptor gamma (PPARG) gene causes the condition. FPLD type 4 is caused by dominant mutations in PLIN1 in a few, rare families. There are also several recognizable malformation syndromes with lipodystrophy as a key feature (e.g. Hallermann–Streiff syndrome, Mandibuloacral dysplasia and Mandibular hypoplasia, deafness, progeria and lipodystrophy syndrome and SHORT syndrome).
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Material and methods
The study participants gave informed consent and the genetic analyses were performed with approval of University of Western Ontario Ethics Review Board.
Results
Given the early clinical presentation, a form of CGL was considered likely, yet no mutations were observed in either AGPAT2 or BSCL2. LMNA was also sequenced and no mutations were identified. Subsequently, two mutations within PPARG, c.413_416delAATG, p.Glu138ValfsX168 and c.C490T; p.R164W, [NM_015869.4] were identified. The frameshift mutation has been reported previously in an individual with truncal obesity, diabetes, cataracts, hearing impairment and little subcutaneous fat to legs and
Discussion
We present the first case of an early onset and generalized lipodystrophy due to compound heterozygous mutations of PPARG. The clinical picture was consistent with a CGL; in particular, the distribution of facial, truncal lipoatrophy present at less than a year of age and the trace plasma leptin level. Her marked hepatomegaly and onset of diabetes and hypertriglyceridemia in early adolescence is also in keeping with a CGL, albeit with some phenotypic overlap with FPLD.
The c.413_416delAATG
Conflicts of interest
The authors have no conflicts of interests to declare.
Acknowledgments
The authors would firstly like to thank the study participant and her family – without their participation this work would not be possible. D.A.D is a recipient of a CIHR Clinical Investigator award from the Institute of Genetics. The authors would like to thank Dr. Floyd Snyder and Dr. Brian Lowry for helpful discussion.
References (6)
- et al.
Clinical and molecular characterization of a severe form of partial lipodystrophy expanding the phenotype of PPARγ deficiency
J Lipid Res
(2012) - et al.
Lipodystrophies: disorders of adipose tissue biology
Biochim Biophys Acta
(2009) - et al.
Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism
J Lipid Res
(2007)
Cited by (29)
Generalized lipoatrophy syndromes
2021, Presse MedicaleCitation Excerpt :PPARG (peroxisome proliferator-activated receptor-gamma) sequencing revealed two pathogenic mutations: c. 413_416delAATG; p.Glu138ValfsX168 and c.490C>T; p.R164W. Taking into account the clinical picture and sequencing data, the authors concluded that biallelic mutations in the PPARG gene cause CGL [45]. HGPS (OMIM # 176,670) is a rare disease which results in premature aging, usually caused by a spontaneous heterozygous mutation in the LMNA gene encoding the nuclear protein of lamin A, resulting in changes in the structure of cell nuclei [46].
Genetic Lipodystrophies
2020, Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics: Metabolic DisordersGene-gene and gene-environment interactions in lipodystrophy: Lessons learned from natural PPARγ mutants
2019, Biochimica et Biophysica Acta - Molecular and Cell Biology of LipidsCitation Excerpt :For example, it has recently been shown that heterozygous mutations in PLIN1 do not always cause overt lipodystrophy [28]. In addition, mutations in the PPARG gene – a gene previously found to be associated with partial lipodystrophy – can very rarely also cause generalized lipodystrophy [29]. Vice versa, mutations in the LMNA [30,31] and CAV1 [13,32] gene have been reported in both generalized and partial genetic lipodystrophies.
AGPAT2 deficiency impairs adipogenic differentiation in primary cultured preadipocytes in a non-autophagy or apoptosis dependent mechanism
2015, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Similarly, although our in vitro studies suggest that autophagy is not involved in the impaired adipogenic differentiation of Agpat2−/− preadipocytes, the pathophysiologic role of autophagy in the lipodystrophy of AGPAT2 deficient mice remains unknown. Recently, it has been reported that biallelic mutations in PPARG result in CGL [18], manifested by lipoatrophy, diabetes, hypertriglyceridemia and hepatomegaly. Deficiency of Seipin, (which regulates adipocyte differentiation and lipid droplet formation) also determines CGL in humans and mice as well as reduced Ppar-γ levels in adipose tissue [19].
Lipodystrophies
2015, Genetic Diagnosis of Endocrine Disorders: Second Edition