Genetic and Metabolic Basis of Familial Lipodystrophies

 描述(申请人提供)：肥胖在美国仍然是一个主要的健康问题，并会导致代谢并发症，如糖尿病、血脂异常和胰岛素抵抗。类似的并发症也发生在以部分(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)为特征的家族性脂肪营养不良患者。在过去的几年里，几个CGL基因(AGPAT2、BSCL2、CAV1和PTRF)；FPL(LMNA、PPARG、AKT2、CIDEC和PLIN1)；下颌骨球颈发育不良(MAD；LMNA和ZMPSTE24)；自体炎症(PSMB8)；矮小综合征(身材矮小、伸展过度/疝气、眼球抑郁、Rieger异常和拔牙延迟；PIK3R1)；以及MDP(下颌发育不良、耳聋和黄体特征)综合征(POLD1)与脂肪营养不良相关。然而，来自大约200个患有CGL、MAD、尤其是FPL的家系的受试者在这些基因中缺乏突变，提示存在额外的基因座。此外，许多极罕见的脂肪营养不良与短和新生儿黄体综合征相关的遗传基础仍不清楚。因此，本研究的第一个目的是鉴定与脂肪细胞生物学相关的导致脂肪营养不良的额外基因(S)，并确定其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。第二个目的是利用表型良好的先证者、家系和人群来确定脂肪营养不良基因中的分子缺陷与代谢紊乱之间的关系。这些研究将揭开导致脂肪营养不良、胰岛素抵抗及其相关疾病的分子机制。这一新知识可能为开发治疗糖尿病、血脂异常和肝脏脂肪变性的新药提供靶点。

 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.