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: 9237269
• 负责人: Abhimanyu Garg
• 金额: $ 55.44万
• 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 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237269
• 关键词: 1q21; AKT2 gene; Acanthosis Nigricans; Acyltransferase; Adipocytes; Adipose tissue; Affect; Body fat; Candidate Disease Gene; Cell Death; Cessation of life; Characteristics; Chromosomes; Clinical; Contracture; DNA Fragmentation; Defect; Development; Diabetes Mellitus; Disease; Dyslipidemias; Dysplasia; Etiology; Familial generalized lipodystrophy; Familial partial lipodystrophy; Family; Family member; Fatty Liver; Genes; Genetic; Genomics; Goals; Grant; HIV-Associated Lipodystrophy Syndrome; Health; Hernia; Homologous Gene; Hypertriglyceridemia; Insulin Resistance; Joints; Knowledge; Laboratories; Lamin Type A; Lead; Light; Link; Lipodystrophy; Mandible; Mendelian disorder; Mental Depression; Metabolic; Metalloproteases; Modernization; Molecular; Morbidity - disease rate; Mus; Muscular Atrophy; Mutation; Neonatal; Obesity; Oncogenes; PPAR gamma; Panniculitis; Paris, France; Pathway interactions; Patients; Phenotype; Phosphatidylinositols; Phosphotransferases; Polymerase; Population; Process; Proto-Oncogene Proteins c-akt; Reporting; Rieger syndrome; Role; Syndrome; Technology; Teething; Therapeutic Intervention; Thymoma; Transcript; Variant; Wiedemann-Rautenstrauch syndrome; Work; Zinc; adipocyte biology; adipocyte differentiation; autoinflammatory; caveolin 1; clinical phenotype; deafness; disease-causing mutation; early onset; exome sequencing; factor A; genetic linkage analysis; genetic pedigree; genetic variant; genome-wide linkage; in vitro Assay; inorganic phosphate; insight; metabolic abnormality assessment; microcytic anemia; multicatalytic endopeptidase complex; new therapeutic target; next generation; novel; novel therapeutics; perilipin; positional cloning; proband; public health relevance; release factor

 DESCRIPTION (provided by applicant): Obesity remains a major health problem in US and causes metabolic complications such as diabetes, dyslipidemia and insulin resistance. Similar complications also occur in patients with familial lipodystrophies characterized by partial (familil partial lipodystrophy, FPL) or almost complete (congenital generalized lipodystrophy, CGL) lack of body fat. In the last few years, several genes for CGL (AGPAT2, BSCL2, CAV1 and PTRF); FPL (LMNA, PPARG, AKT2, CIDEC and PLIN1); mandibuloacral dysplasia (MAD; LMNA and ZMPSTE24); autoinflammatory (PSMB8); SHORT syndrome (short stature, hyperextensibility/hernias, ocular depression, Rieger anomaly and teething delay; PIK3R1); and MDP (mandibular hypoplasia, deafness and progeroid features) syndrome (POLD1) associated lipodystrophies have been identified. However, affected subjects from approximately 200 pedigrees with CGL, MAD and especially FPL lack mutations in these genes suggesting additional loci. Furthermore, the genetic basis of many extremely rare varieties of lipodystrophies associated with SHORT and neonatal progeroid syndromes remains unknown. Thus, the first aim of this proposal is to identify additional gene(s) involved in adipocyte biolog, development and differentiation that cause lipodystrophies and to determine their function in adipocyte biology. We will use state-of-the-art whole exome sequencing to identify the molecular defects in these families. The second aim is to ascertain relationships between molecular defects in lipodystrophy genes with metabolic derangements using well-phenotyped probands, families, and populations. 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 diabetes, dyslipidemias and hepatic steatosis.

 描述（由申请人提供）：肥胖仍然是美国的主要健康问题，并导致代谢并发症，如糖尿病、血脂异常和胰岛素抵抗。类似的并发症也发生在家族性脂肪营养不良的患者中，其特征在于部分（家族性部分脂肪营养不良，FPL）或几乎完全（先天性全身性脂肪营养不良，CGL）缺乏体脂。在过去的几年里，几个基因的CGL（AGPAT 2、BSCL 2、CAV 1和PTRF）; FPL（LMNA、PPARG、AKT 2、CIDEC和PLIN 1）;下颌骨肢端发育不良（MAD; LMNA和ZMPSTE 24）;自身炎症（PSMB 8）; SHORT综合征（身材矮小、伸展过度/疝、眼凹陷、Rieger异常和出牙延迟; PIK 3R 1）;和MDP（下颌发育不全、耳聋和早衰样特征）综合征（POLD 1）相关的脂肪营养不良。然而，来自大约200个CGL、MAD尤其是FPL家系的受影响受试者在这些基因中缺乏突变，表明存在其他基因座。此外，与SHORT和新生儿早老综合征相关的许多极其罕见的脂肪营养不良的遗传基础仍然未知。因此，该提议的第一个目的是鉴定参与引起脂肪营养不良的脂肪细胞生物学、发育和分化的另外的基因，并确定它们在脂肪细胞生物学中的功能。我们将使用最先进的全外显子组测序来鉴定这些家族中的分子缺陷。第二个目的是确定脂肪代谢障碍基因的分子缺陷与代谢紊乱之间的关系，使用良好的表型先证者，家庭和人口。这些研究将揭示脂肪代谢障碍、胰岛素抵抗及其相关疾病的分子机制。这一新的知识可能为开发治疗糖尿病、血脂异常和肝脂肪变性的新药提供靶点。