# Genetic and Metabolic Basis of Familial Lipodystrophies

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $688,377

## Abstract

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.

## Key facts

- **NIH application ID:** 10119702
- **Project number:** 2R01DK105448-05
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Abhimanyu Garg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $688,377
- **Award type:** 2
- **Project period:** 2015-04-16 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119702

## Citation

> US National Institutes of Health, RePORTER application 10119702, Genetic and Metabolic Basis of Familial Lipodystrophies (2R01DK105448-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10119702. Licensed CC0.

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