Whole exome sequencing reveals novel LEPR frameshift mutation in severely obese children from Western India
Whole exome sequencing reveals novel LEPR frameshift mutation in severely obese children from Western India
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DOI：
10.1002/mgg3.692
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发表时间：
2019-07-01
影响因子：
2
通讯作者：
Joshi, Madhvi
中科院分区：
文献类型：
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作者：
Bhatt, Arpan;Purani, Charul;Joshi, Madhvi
背景 肥胖，尤其是早发性肥胖，在发达国家和发展中国家都是一个严重的健康问题。这还与严重的合并症有关，如脂肪肝病、心血管疾病、2 型糖尿病、阻塞性睡眠呼吸暂停、肾脏并发症和呼吸系统问题。很多时候，早期肥胖与遗传性单基因、多基因和综合征形式有关。在全球范围内，有关早期肥胖相关基因作用的研究还很有限。方法 在这项研究中，招募了一个来自西印度的近亲家庭，有四个兄弟姐妹，其中一个未受影响，三个患有严重的早期肥胖症。受影响的兄弟姐妹还表现出合并症，如轻度至中度阻塞性睡眠呼吸暂停、肾阻力指数升高、少尿和严重贫血。对 Trio 的一名受影响和未受影响的兄弟姐妹进行了全外显子组测序 (WES)。进行数据分析以检查未受影响的父母与受影响和未受影响的兄弟姐妹中的致病性突变分离。结果 三人组的 WES 发现了 LEPR 基因中的新移码突变，导致瘦素受体 (LEPR) 截短。通过桑格测序，在其他受影响的兄弟姐妹和远亲的两个兄弟姐妹中也证实了相同的突变。还通过计算机分析研究了截断突变对 LEPR 功能的可能影响。结论 了解肥胖的遗传基础可能为未来更好的管理和治疗提供线索。这项工作证明了 LEPR 基因的新突变的鉴定，该突变导致肥胖的早期发作。新型人群特异性基因组学标记的发现将有助于人群筛查计划为下一代可能的治疗应用和预防这种疾病奠定基础。
Background Obesity, especially early onset of obesity is a serious health concern in both developed and developing countries. This is further associated with serious comorbidities like a fatty liver disease, cardiovascular diseases, type-2 diabetes, obstructive sleep apnea, renal complications and respiratory problems. Many times early onset of obesity is linked with heritable monogenic, polygenic and syndromic forms. Globally, studies on roles of genes involved in early onset of obesity are limited. Methods Here in this study, a consanguineous family of Western Indian origin having four siblings, one unaffected and three affected with severe early onset of obesity was enrolled. Affected siblings also displayed comorbidities like mild to moderate obstructive sleep apnea, raised Renal Resistance Index, oliguria, and severe anemia. Whole Exome Sequencing (WES) of Trio with one affected and unaffected sibling was done. Data analysis was performed to check pathogenic mutation segregation in unaffected parents with affected and unaffected sibling. Results WES of trio identified novel frameshift mutation in the LEPR gene resulting in truncated leptin receptor (LEPR). The same mutation was confirmed in other affected siblings and two siblings of distant relatives by Sanger sequencing. The possible effects of truncating mutation in LEPR function by in silico analysis were also studied. Conclusion Understanding genetic basis of obesity might provide a clue for better management and treatment in times to come. This work demonstrates identification of novel mutation in LEPR gene resulting into early onset of obesity. Discovery of novel, population-specific genomics markers will help population screening programs in creating base for possible therapeutic applications and prevention of this disease for next generations.