Primary acid-labile subunit deficiency due to recessive IGFALS mutations results in postnatal growth deficit associated with low circulating insulin growth factor (IGF)-I, IGF binding protein-3 levels, and hyperinsulinemia
Primary acid-labile subunit deficiency due to recessive IGFALS mutations results in postnatal growth deficit associated with low circulating insulin growth factor (IGF)-I, IGF binding protein-3 levels, and hyperinsulinemia
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DOI：
10.1210/jc.2007-2678
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发表时间：
2008-05-01
影响因子：
5.8
通讯作者：
Campos-Barros, Angel
中科院分区：
文献类型：
--
作者：
Heath, Karen E.;Argente, Jesus;Campos-Barros, Angel
内容：高达90%的循环IGF-I和IGF-II与IGF结合蛋白（IGFBP）-3或IGFBP-5和酸不稳定亚基（ALS）以三级复合物的形式结合，延长其循环半衰期。最近报道了3例ALS完全缺乏症，这些患者的循环IGF-I和IGFBP-3水平非常低，ALS编码基因存在纯合或复合杂合突变（IGFALS; 16p13.3），从而支持ALS在出生后生长期间调节IGFs生物利用度的作用。目的：我们目前的分子和临床特征的两个新的IGFALS突变，导致完全ALS缺乏症在三个无关的患者与出生后生长缺陷，低IGF-I和IGFBP-3水平，并没有GH缺乏症。IGFALS突变筛查发现了一种新的纯合子IGFALS错义突变，它改变了两个先证者的保守残基N276 S。第三个先证者提出了一个新的纯合无义突变，Q320 X，预计产生严重截短的ALS蛋白。受影响的先证者提出了一个类似的表型，其特征在于与不可检测的ALS，低IGF-I，IGF-II，IGFBP-3，和高胰岛素血症，并在两种情况下，延迟publication.Conclusions：原发性ALS缺陷由于IGFALS突变应被认为是一个可能的原因IGF-I缺陷的患者在GH缺乏或不敏感的情况下，出生后的生长缺陷。血清ALS水平和基础胰岛素水平的测定有助于特发性IGF-I缺乏症患者的鉴别诊断。
Context: Up to 90% of circulating IGF-I and IGF-II are carried bound to either IGF binding protein (IGFBP)-3 or IGFBP-5 and the acid-labile subunit (ALS) in the form of tertiary complexes that extend their circulating half-life. Three cases of complete ALS deficiency have been recently reported in short-stature patients with very low circulating IGF-I and IGFBP-3 levels who presented with homozygous or compound heterozygous mutations in the ALS encoding gene (IGFALS; 16p13.3), thus supporting a role for ALS in the regulation of the bioavailability of IGFs during postnatal growth.Objective: We present the molecular and clinical characterization of two novel IGFALS mutations that caused complete ALS deficiency in three unrelated patients with postnatal growth deficit, low IGF-I and IGFBP-3 levels, and no GH deficiency.Results: IGFALS mutation screening identified a novel homozygous IGFALS missense mutation, which altered a conserved residue, N276S, in two of the probands. The third proband presented a novel homozygous nonsense mutation, Q320X, that is predicted to generate a severely truncated ALS protein. The affected probands presented a similar phenotype characterized by a moderate postnatal growth deficit associated with undetectable ALS, low IGF-I, IGF-II, and IGFBP-3, and hyperinsulinemia, and, in two cases, delayed puberty.Conclusions: Primary ALS deficiency due to IGFALS mutations should be considered as a possible cause of postnatal growth deficit in IGF-I-deficient patients in the absence of GH deficiency or insensitivity. Determination of serum ALS levels and basal insulinemia can be helpful in the differential diagnosis of patients with idiopathic IGF-I deficiency.