Genetic and Metabolic Basis of Familial Lipodystrophies

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Abstract Obesity remains a major health problem in the United States and causes metabolic complications such as type 2 diabetes mellitus, dyslipidemia, hepatic steatosis and insulin resistance. Similar complications also occur in patients with familial lipodystrophies characterized by partial (familial partial lipodystrophy, FPLD) or almost complete (congenital generalized lipodystrophy, CGL) lack of body fat. In the last two decades, several causal genes have been discovered for lipodystrophy syndromes including AGPAT2, BSCL2, CAV1 and CAVIN1 for CGL; LMNA, PPARG, ADRA2A, AKT2, CIDEC, LIPE, MFN2, PCYT1A and PLIN1 for FPLD; LMNA and ZMPSTE24 for mandibuloacral dysplasia (MAD); PSMB8 for autoinflammatory lipodystrophy; PIK3R1 for short stature, hyperextensibility/hernias, ocular depression, Rieger anomaly and teething delay (SHORT) syndrome; POLD1 for MDP (mandibular hypoplasia, deafness and progeroid features) syndrome; and FBN1, CAV1, and POL3RA for Weidemann-Rautenstrauch syndrome (WRS). Our laboratory has been at the forefront of these studies and identified AGPAT2, PPARG, ZMPSTE24, and PSMB8 genes for various types of lipodystrophies. In addition, during the last five years, we have identified novel lipodystrophy genes, such as ADRA2A, POLR3A, PRRT3, MTX2, TOMM7, COL3A1 and NOTCH3; and novel variants, such as heterozygous p.R571S and homozygous p.R545H in LMNA, and heterozygous p.Q142* and p.F160* in CAV1 associated with unique lipodystrophy syndromes. However, the genetic basis of about 210 extremely rare patients with various subtypes of genetic lipodystrophies, including 179 pedigrees with FPLD phenotype, remains unknown. Thus, the first aim of this proposal is to identify novel gene(s)/variants involved in adipocyte biology, development and differentiation that cause lipodystrophies and to determine their function in adipocyte biology by using cellular model system. We will use the state-of-the-art whole genome sequencing combined with tissue transcriptome analysis to identify the molecular defects. The second aim is to ascertain relationships between molecular defects in lipodystrophy genes with metabolic derangements using well-phenotyped probands and families. We will conduct deep phenotyping using skinfold thickness measurements, dual-energy X-ray absorptiometry for regional body fat, whole-body magnetic resonance imaging for body fat distribution, and biochemical parameters for metabolic complications. These studies will unravel molecular mechanisms involved in causation of lipodystrophy, and insulin resistance and its associated morbidities. This new knowledge may provide targets for developing novel drugs for treating metabolic complications of obesity including diabetes, dyslipidemias and hepatic steatosis.