Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability
Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability
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DOI：
10.1016/j.ajhg.2017.01.002
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发表时间：
2017-02-02
影响因子：
9.8
通讯作者：
Schiff, Manuel
中科院分区：
文献类型：
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作者：
Anikster, Yair;Haack, Tobias B.;Schiff, Manuel
苯丙酮尿症（PKU，苯丙氨酸羟化酶缺乏症）是一种先天性代谢缺陷，可通过新生儿高苯丙氨酸血症（HPA）筛查发现。大多数HPA患者在编码苯丙氨酸羟化酶（PAH）的基因中存在突变，一小部分（2%）表现出四氢生物蝶呤（BH 4）缺乏症，伴有其他神经递质（多巴胺和5-羟色胺）缺乏症。在这里，我们报告了来自四个不相关的HPA家族的六个人，他们表现出进行性神经发育迟缓，肌张力障碍和独特的神经递质缺乏症，而没有PAH或BH 4代谢紊乱相关基因突变。在这六个受影响的个体中，全外显子组测序（WE'S）鉴定了DNAIC 12中的双等位基因突变，其编码热休克共伴侣蛋白家族成员，该热休克共伴侣蛋白家族成员与苯丙氨酸、酪氨酸和色氨酸羟化酶相互作用，分别催化苯丙氨酸转化为酪氨酸、酪氨酸转化为左旋多巴（多巴胺的前体）和色氨酸转化为5-羟基色氨酸（5-羟色胺的前体）的BH 4活化转化。DNAJC 12在来自具有无效突变的个体的成纤维细胞中是不可检测的。PAH酶活性在DNAIC 12突变的存在下降低。BH 4和/或神经递质前体的早期治疗具有显著的有益效果，并导致在症状发作前治疗的一个个体中预防神经发育延迟。因此，DNAJC 12缺陷是一种可预防和可治疗的智力残疾原因，当筛查结果为HPA阳性时，应在早期鉴别诊断中考虑。DNAIC 12测序可以解决任何不确定性，应考虑在所有儿童与未解决HPA。
Phenylketonuria (PKU, phenylalanine hydroxylase deficiency), an inborn error of metabolism, can be detected through newborn screening for hyperphenylalaninemia (HPA). Most individuals with HPA harbor mutations in the gene encoding phenylalanine hydroxylase (PAH), and a small proportion (2%) exhibit tetrahydrobiopterin (BH4) deficiency with additional neurotransmitter (dopamine and serotonin) deficiency. Here we report six individuals from four unrelated families with HPA who exhibited progressive neurodevelopmental delay, dystonia, and a unique profile of neurotransmitter deficiencies without mutations in PAH or BH4 metabolism disorder-related genes. In these six affected individuals, whole-exome sequencing (WE'S) identified biallelic mutations in DNAIC12, which encodes a heat shock co-chaperone family member that interacts with phenylalanine, tyrosine, and tryptophan hydroxylases catalyzing the BH4-activated conversion of phenylalanine into tyrosine, tyrosine into L-dopa (the precursor of dopamine), and tryptophan into 5-hydroxytryptophan (the precursor of serotonin), respectively. DNAJC12 was un-detectable in fibroblasts from the individuals with null mutations. PAH enzyme activity was reduced in the presence of DNAIC12 mutations. Early treatment with BH4 and/or neurotransmitter precursors had dramatic beneficial effects and resulted in the prevention of neurodevelopmental delay in the one individual treated before symptom onset. Thus, DNAJC12 deficiency is a preventable and treatable cause of intellectual disability that should be considered in the early differential diagnosis when screening results are positive for HPA. Sequencing of DNAIC12 may resolve any uncertainty and should be considered in all children with unresolved HPA.