Data_Sheet_1_A Single Complex Agpat2 Allele in a Patient With Partial Lipodystrophy.pdf

Genetic lipodystrophies are a group of rare syndromes associated with major metabolic complications – including severe insulin resistance, type 2 diabetes mellitus, and hypertriglyceridemia – which are classified according to the distribution of adipose tissue. Lipodystrophies can be present at birth or develop during life and can range from local to partial and general. With at least 18 different genes implicated so far, definite diagnosis can be challenging due to clinical and genetic heterogeneity. In an adult female patient with clinical and metabolic features of partial lipodystrophy we identified via whole genome sequencing (WGS) a single complex AGPAT2 allele [V67M;V167A], functionally equivalent to heterozygosity. AGPAT2 encodes for an acyltransferase implicated in the biosynthesis of triacylglycerol and glycerophospholipids. So far homozygous and compound heterozygous mutations in AGPAT2 have only been associated with generalized lipodystrophy. A SNP risk score analysis indicated that the index patient is not predisposed to lipodystrophy based on her genetic background. The partial phenotype in our patient is therefore more likely associated to the genetic variants in AGPAT2. To test whether the resulting double-mutant AGPAT2 protein is functional we analyzed its in vitro enzymatic activity via mass spectrometry. The resulting AGPAT2 double mutant is enzymatically inactive. Our data support the view that the current classification of lipodystrophies as strictly local, partial or generalized may have to be re-evaluated and viewed more as a continuum, both in terms of clinical presentation and underlying genetic causes. Better molecular understanding of lipodystrophies may lead to new therapies to treat adipose tissue dysfunction in common and rare diseases.

遗传性脂肪营养不良是一组罕见的综合征，常伴随严重代谢并发症——包括重度胰岛素抵抗、2型糖尿病与高甘油三酯血症，该病根据脂肪组织的分布特征进行分类。脂肪营养不良可先天发病，亦可于后天出现，病变范围可从局部性延伸至部分性乃至全身性。截至目前，已有至少18种不同基因被发现与该病相关；由于临床表型与遗传异质性的存在，明确诊断颇具挑战。本研究通过全基因组测序（whole genome sequencing, WGS），在1例表现为部分性脂肪营养不良临床与代谢特征的成年女性患者中，检出1个复合杂合型AGPAT2等位基因[V67M;V167A]，其功能等效于杂合状态。AGPAT2基因编码一种酰基转移酶，参与三酰甘油与甘油磷脂的生物合成过程。截至目前，AGPAT2基因的纯合突变与复合杂合突变仅被报道与全身性脂肪营养不良相关。单核苷酸多态性（single nucleotide polymorphism, SNP）风险评分分析显示，基于该患者的遗传背景，其并无脂肪营养不良的易感倾向。因此，该患者的部分性表型更可能与AGPAT2基因的遗传变异相关。为验证该双突变AGPAT2蛋白是否具备功能，本研究通过质谱分析法（mass spectrometry）检测了其体外酶活性，结果显示该双突变AGPAT2蛋白无酶活性。本研究数据支持如下观点：当前将脂肪营养不良严格划分为局部性、部分性与全身性的分类方式或需重新评估，而应从临床表型与潜在遗传病因两方面，将其视为一个连续的疾病谱。对脂肪营养不良更深入的分子层面认知，或可为常见与罕见疾病中的脂肪组织功能障碍提供全新治疗方案。