Recurrent De Novo Mutations Affecting Residue Arg1 38 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa
Recurrent De Novo Mutations Affecting Residue Arg1 38 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa
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DOI：
10.1016/j.ajhg.2015.08.001
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发表时间：
2015-09-03
影响因子：
9.8
通讯作者：
Kornak, Uwe
中科院分区：
文献类型：
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作者：
Fischer-Zirnsak, Bjoern;Escande-Beillard, Nathalie;Kornak, Uwe
与De Barsy综合征(DBS)重叠的程序性疾病统称为常染色体隐性遗传性皮肤松弛3型(ARCL3)。它们是由PYCR1或ALDH18A1的双等位基因突变引起的，PYCR1或ALDH18A1分别编码吡咯烷-5-羧酸还原酶1和吡咯烷-5-羧酸合成酶(P5CS)，这两种酶都在线粒体的脯氨酸循环中工作。我们在这里报告了8名出生于非血缘家庭的无血缘关系的人，他们被临床诊断为DBS或皱纹皮肤综合征。我们在ALDH18A1中发现了三个杂合突变，导致P5CS中相同的高度保守残基Arg138的氨基酸替换。所有6个先证者的亲本DNA都被证实是从头开始的，我们发现P5CS-p.Arg138Trp蛋白是稳定的，能够与野生型P5CS相互作用，但显示出改变的亚线粒体分布。天然凝胶电泳法显示P5CS突变复合体的结构或组成发生了改变。此外，我们还发现突变细胞的P5CS酶活性降低，导致脯氨酸积累延迟。总之，反复的从头突变，影响P5CS的高度保守残基Arg138，导致一种常染色体显性的带有孕激素特征的皮肤松弛形式。我们的数据为皮肤松弛病的病因提供了洞察力，并将对诊断和遗传咨询产生直接影响。
Progeroid disorders overlapping with De Barsy syndrome (DBS) are collectively denoted as autosomal-recessive cutis laxa type 3 (ARCL3). They are caused by biallelic mutations in PYCR1 or ALDH18A1, encoding pyrroline-5-carboxylate reductase 1 and pyrroline-5-carboxylate synthase (P5CS), respectively, which both operate in the mitochondrial proline cycle. We report here on eight unrelated individuals born to non-consanguineous families clinically diagnosed with DBS or wrinkly skin syndrome. We found three heterozygous mutations in ALDH18A1 leading to amino acid substitutions of the same highly conserved residue, Arg138 in P5CS. A de novo origin was confirmed in all six probands for whom parental DNA was available Using fibroblasts from affected individuals and heterologous overexpression, we found that the P5CS-p.Arg138Trp protein was stable and able to interact with wild-type P5CS but showed an altered sub-mitochondrial distribution. A reduced size upon native gel electrophoresis indicated an alteration of the structure or composition of P5CS mutant complex. Furthermore, we found that the mutant cells had a reduced P5CS enzymatic activity leading to a delayed proline accumulation. In summary, recurrent de novo mutations, affecting the highly conserved residue Arg138 of P5 CS, cause an autosomal-dominant form of cutis laxa with progeroid features. Our data provide insights into the etiology of cutis laxa diseases and will have immediate impact on diagnostics and genetic counseling.