Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia
Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia
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DOI：
10.1093/brain/awab041
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发表时间：
2021-05-10
期刊：
影响因子：
14.5
通讯作者：
Senderek, Jan
中科院分区：
文献类型：
--
作者：
Wiessner, Manuela;Maroofian, Reza;Senderek, Jan
人4-羟苯丙酮酸双加氧酶样（HPDL）是一种特异性和生物学意义未知的含铁非血红素加氧酶。我们报告了25个家庭，其中34人与神经系统疾病相关的双等位基因HPDL变异。表型范围从青少年发病的纯遗传性痉挛性截瘫，痉挛发作和全球发展迟缓，有时并发神经和呼吸失代偿发作。变体包括真正的致病性截短变化，尽管大多数是错义替换。由于HPDL的酶特异性未知，因此无法直接确定变体的功能;然而，当将HPDL错义取代引入4-羟基苯丙酮酸双加氧酶（HPPD，HPDL直向同源物）时，它们损害了HPPD将4-羟基苯丙酮酸转化为尿黑酸的能力。此外，另外三组实验为HPDL在神经系统中的作用提供了证据，并进一步支持其与神经疾病的联系：（i）HPDL在神经系统中表达，并且在神经分化期间表达增加;（ii）斑马鱼hPDL的敲低导致异常运动行为，复制人类疾病的方面;和（iii）HPDL定位于线粒体，与通常与神经学表现相关的线粒体疾病一致。我们的研究结果表明，双等位基因HPDL变异引起的综合征从青少年发病的纯遗传性痉挛性截瘫到与全球发育迟缓相关的痉挛性四肢瘫痪。
Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.