Genetic and Metabolic Basis of Familial Lipodystrophies

家族性脂肪营养不良的遗传和代谢基础

• 批准号: 10264148
• 负责人: Abhimanyu Garg
• 金额: $ 69.05万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-16 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10264148
• 关键词: AKT2 gene; Acanthosis Nigricans; Adipose tissue; Affect; BSCL2 gene; Biochemical; Biological; Biological Models; Biological Process; Body fat; CAV1 gene; Cell Line; Cell model; Cessation of life; Characteristics; Clinical; Defect; Development; Diabetes Mellitus; Disease; Dual-Energy X-Ray Absorptiometry; Dyslipidemias; Dysplasia; Etiology; FBN1; Familial generalized lipodystrophy; Familial partial lipodystrophy; Family; Family member; Fatty Liver; Fibroblasts; Genes; Genetic; Genomics; Genotype; Goals; Grant; HIV-Associated Lipodystrophy Syndrome; Health; Hernia; Hypertriglyceridemia; Insulin Resistance; Knowledge; Laboratories; Lead; Light; Lipodystrophy; Magnetic Resonance Imaging; Mandible; Measurement; Mendelian disorder; Mental Depression; Metabolic; Molecular; Molecular Genetics; Morbidity - disease rate; Mutation; NOTCH3 gene; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PPARG gene; Pathway interactions; Patients; Phenotype; Polymerase Chain Reaction; Process; Rieger syndrome; Role; Skin; Skinfold Thickness; Syndrome; Technology; Teething; Therapeutic Intervention; Tissues; United States; Variant; Wiedemann-Rautenstrauch syndrome; Work; adipocyte biology; adipocyte differentiation; autoinflammatory; base; causal variant; clinical phenotype; deafness; design; early onset; gene function; genetic approach; genetic pedigree; genetic variant; genome sequencing; genomic locus; in vitro Assay; insight; lymphoblast; metabolic abnormality assessment; new therapeutic target; next generation sequencing; novel; novel therapeutics; proband; recruit; transcriptome; transcriptome sequencing; whole genome

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.

摘要 肥胖仍然是美国的一个主要健康问题，并导致代谢并发症 如2型糖尿病、血脂异常、肝脂肪变性和胰岛素抵抗。类似 以部分（家族性）为特征的家族性脂肪营养不良患者也会出现并发症 部分脂肪营养不良，FPLD）或几乎完全（先天性全身性脂肪营养不良，CGL）缺乏 身体脂肪。在过去的二十年里，已经发现了几个脂肪营养不良的致病基因 包括CGL的AGPAT 2、BSCL 2、CAV 1和CAV IN 1的综合征; LMNA、PPARG、ADRA 2A， AKT 2、CIDEC、LIPE、MFN 2、PCYT 1A和PLIN 1用于FPLD; LMNA和ZMPSTE 24用于 下颌骨肢端发育不良（MAD）; PSMB 8用于自身炎性脂肪营养不良;简称PIK 3R 1 身高、过伸性/疝、眼凹陷、Rieger异常和出牙延迟（短） MDP（下颌发育不全、耳聋和早衰样特征）综合征的POLD 1; FBN 1、CAV 1和POL 3RA用于Weidemann-Rautenstrauch综合征（WRS）。本实验室 一直处于这些研究的前沿，并确定了AGPAT 2，PPARG，ZMPSTE 24， 用于各种类型脂肪营养不良的PSMB 8基因。此外，在过去五年中，我们 鉴定了新的脂肪营养不良基因，例如ADRA 2A、POLR 3A、PRRT 3、MTX 2、TOMM 7， COL 3A 1和NOTCH 3;以及新的变体，如杂合的p.R571S和纯合的p.R571S。 LMNA中的p.R545H，以及CAV 1中的杂合p.Q142* 和p.F160*，与独特的 脂肪营养不良综合征然而，大约210名极其罕见的 遗传性脂肪营养不良的各种亚型，包括179个具有FPLD表型的家系， 未知因此，该提议的第一个目的是鉴定涉及以下的新基因/变体： 引起脂肪营养不良的脂肪细胞生物学、发育和分化， 在脂肪细胞生物学中的功能。我们将使用最先进的 基因组测序结合组织转录组分析以鉴定分子缺陷。 第二个目的是确定脂肪营养不良基因中的分子缺陷与 使用表型良好的先证者和家族进行代谢紊乱。我们将深入 使用皮褶厚度测量进行表型分型，双能X线吸收测定法用于局部 体脂肪，用于体脂肪分布的全身磁共振成像，以及生物化学 代谢并发症的参数。这些研究将揭开涉及的分子机制 导致脂肪营养不良和胰岛素抵抗及其相关疾病。这个新 这些知识可以为开发治疗糖尿病代谢并发症的新药提供靶点。 肥胖症包括糖尿病、血脂异常和肝脂肪变性。