Niazi Robina Khan, Gjesing Anette P, Hollensted Mette, Have Christian Theil, Grarup Niels, Pedersen Oluf, Ullah Asmat, Shahid Gulbin, Ahmad Wasim, Gul Asma, Hansen Torben
Department of Bioinformatics and Biotechnology, International Islamic University, Islamabad, Pakistan.
Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
BMC Med Genet. 2018 Nov 15;19(1):199. doi: 10.1186/s12881-018-0710-x.
Mutations in the genes encoding leptin (LEP), the leptin receptor (LEPR), and the melanocortin 4 receptor (MC4R) are known to cause severe early-onset childhood obesity. The aim of the current study was to examine the prevalence of damaging LEP, LEPR, and MC4R mutations in Pakistani families having a recessive heritance of early-onset obesity.
Using targeted resequencing, the presence of rare mutations in LEP, LEPR, and MC4R, was investigated in individuals from 25 families suspected of having autosomal recessive early-onset obesity. Segregation patterns of variants were assessed based on chip-based genotyping.
Homozygous LEPR variants were identified in two probands. One carried a deletion (c.3260AG) resulting in the frameshift mutation p.Ser1090Trpfs*6, and the second carried a substitution (c.2675C > G) resulting in the missense mutation p.Pro892Arg. Both mutations were located within regions of homozygosity shared only among affected individuals. Both probands displayed early-onset obesity, hyperphagia and diabetes. No mutations were found in LEP and MC4R.
The current study highlights the implication of LEPR mutations in cases of severe early-onset obesity in consanguineous Pakistani families. Through targeted resequencing, we identified novel damaging mutations, and our approach may therefore be utilized in clinical testing or diagnosis of known forms of monogenic obesity with the aim of optimizing obesity treatment.
已知编码瘦素（LEP）、瘦素受体（LEPR）和黑皮质素4受体（MC4R）的基因突变会导致严重的早发性儿童肥胖。本研究的目的是调查在具有早发性肥胖隐性遗传的巴基斯坦家庭中，LEP、LEPR和MC4R有害突变的发生率。
采用靶向重测序技术，对25个疑似患有常染色体隐性早发性肥胖家庭的个体进行LEP、LEPR和MC4R罕见突变检测。基于芯片基因分型评估变异的分离模式。
在两名先证者中鉴定出纯合子LEPR变异。其中一个携带缺失突变（c.3260A>G），导致移码突变p.Ser1090Trpfs*6，另一个携带替换突变（c.2675C>G），导致错义突变p.Pro892Arg。这两种突变均位于仅在受影响个体中共享的纯合区域内。两名先证者均表现出早发性肥胖、食欲亢进和糖尿病。在LEP和MC4R中未发现突变。
本研究强调了LEPR突变在近亲结婚的巴基斯坦家庭严重早发性肥胖病例中的意义。通过靶向重测序，我们鉴定出了新的有害突变，因此我们的方法可用于已知形式的单基因肥胖的临床检测或诊断，以优化肥胖治疗。
