Biallelic variants of the gene DNAJC12 , which encodes a cochaperone, were recently described in patients with hyperphenylalaninemia (HPA). This paper reports the retrospective genetic analysis of a cohort of unsolved cases of HPA. Biallelic variants of DNAJC12 were identified in 20 patients (generally neurologically asymptomatic) previously diagnosed with phenylalanine hydroxylase (PAH) deficiency (phenylketonuria [PKU]). Further, mutations of DNAJC12 were identified in four carriers of a pathogenic variant of PAH . The genetic spectrum of DNAJC12 in the present patients included four new variants, two intronic changes c.298‐2A>C and c.502+1G>C, presumably affecting the splicing process, and two exonic changes c.309G>T (p.Trp103Cys) and c.524G>A (p.Trp175Ter), classified as variants of unknown clinical significance (VUS). The variant p.Trp175Ter was detected in 83% of the mutant alleles, with 14 cases homozygous, and was present in 0.3% of a Spanish control population. Functional analysis indicated a significant reduction in PAH and its activity, reduced tyrosine hydroxylase stability, but no effect on tryptophan hydroxylase 2 stability, classifying the two VUS as pathogenic variants. Additionally, the effect of the overexpression of DNAJC12 on some destabilizing PAH mutations was examined and a mutation‐specific effect on stabilization was detected suggesting that the proteostasis network could be a genetic modifier of PAH deficiency and a potential target for developing mutation‐specific treatments for PKU.

中文翻译：

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DNAJC12 的致病变异和编码的辅助伴侣作为高苯丙氨酸血症的遗传修饰剂的评估。

最近在高苯丙氨酸血症 (HPA) 患者中描述了基因DNAJC12 的双等位变体，该基因编码辅助伴侣。本文报告了一组未解决的 HPA 病例的回顾性遗传分析。在 20 名先前诊断为苯丙氨酸羟化酶 (PAH) 缺乏症（苯丙酮尿症 [PKU]）的患者（通常无神经系统症状）中鉴定出DNAJC12 的双等位基因变异体。此外，在PAH致病性变异的四个携带者中发现了DNAJC12突变。DNAJC12的遗传谱在目前的患者中包括四个新变体，两个内含子变化 c.298-2A>C 和 c.502+1G>C，大概影响剪接过程，以及两个外显子变化 c.309G>T (p.Trp103Cys) 和 c .524G>A (p.Trp175Ter)，归类为临床意义未知 (VUS) 的变异。在 83% 的突变等位基因中检测到变体 p.Trp175Ter，其中 14 例为纯合子，并且存在于 0.3% 的西班牙对照人群中。功能分析表明 PAH 及其活性显着降低，酪氨酸羟化酶稳定性降低，但对色氨酸羟化酶 2 稳定性没有影响，将两个 VUS 归类为致病变异。此外，