Identification of a novel mutation in the PNLIP gene in two brothers with congenital pancreatic lipase deficiency.
Identification of a novel mutation in the PNLIP gene in two brothers with congenital pancreatic lipase deficiency.
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DOI：
10.1194/jlr.p041103
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发表时间：
2014-02
影响因子：
6.5
通讯作者：
Zeharia A
中科院分区：
文献类型：
--
作者：
Behar DM;Basel-Vanagaite L;Glaser F;Kaplan M;Tzur S;Magal N;Eidlitz-Markus T;Haimi-Cohen Y;Sarig G;Bormans C;Shohat M;Zeharia A
先天性胰脂肪酶（PNLIP）缺乏症是一种罕见的单酶形式的外分泌胰腺衰竭，其特征是膳食脂肪吸收减少和油腻的大量粪便，但发育明显正常，总体健康状况良好。虽然被认为是一种常染色体隐性遗传状态，影响了世界范围内的几十个人，并涉及PNLIP基因，但迄今为止还没有报道这种表型的致病突变。在这里，我们报告的纯合子错义突变，Thr221Met [c.662C>T]，在两个兄弟从一个阿拉伯血统的血缘家庭的鉴定。在家庭成员中观察到的基因型是一致的常染色体隐性遗传模式，但此外，基因型状态和血清PNLIP活性之间的分离是明显的。基于生物物理计算工具，我们认为突变破坏了蛋白质的稳定性并损害了其正常功能。虽然PNLIP的作用是公认的，我们的观察提供了遗传证据，PNLIP突变是这种表型的原因。
Congenital pancreatic lipase (PNLIP) deficiency is a rare monoenzymatic form of exocrine pancreatic failure characterized by decreased absorption of dietary fat and greasy voluminous stools, but apparent normal development and an overall good state of health. While considered to be an autosomal recessive state affecting a few dozens of individuals world-wide and involving the PNLIP gene, no causative mutations for this phenotype were so far reported. Here, we report the identification of the homozygote missense mutation, Thr221Met [c.662C>T], in two brothers from a consanguineous family of Arab ancestry. The observed genotypes among the family members were concordant with an autosomal recessive mode of inheritance but moreover a clear segregation between the genotype state and the serum PNLIP activity was evident. Based on biophysical computational tools, we suggest the mutation disrupts the protein's stability and impairs its normal function. Although the role of PNLIP is well established, our observations provide genetic evidence that PNLIP mutations are causative for this phenotype.