Heterozygous de novo variants in HSPD1 cause hypomyelinating leukodystrophy through impaired HSP60 oligomerisation.

IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Journal of Medical Genetics Pub Date : 2024-11-05 DOI:10.1136/jmg-2024-109862
Marina Eskin-Schwartz, Shaikah Seraidy, Eyal Paz, Maism Molhem, Emmanuelle Ranza, Stylianos E Antonarakis, Xavier Blanc, Kristin Herman, William S Benko, Stephanie Libzon, Liat Ben Sira, Aviva Fattal-Valevski, Vadim Dolgin, Ohad S Birk, Amit Kessel, Peter Bross, Celeste Weiss, Abdussalam Azem, Ayelet Zerem
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Abstract

Introduction: Hypomyelinating leukodystrophies are a group of genetic disorders, characterised by severe permanent myelin deficiency. Their clinical features include developmental delay with or without neuroregression, nystagmus, central hypotonia, progressing to spasticity and ataxia. HSPD1 encodes the HSP60 chaperonin protein, mediating ATP-dependent folding of imported proteins in the mitochondrial matrix. Pathogenic variants in HSPD1 have been related to a number of neurological phenotypes, including the dominantly inherited pure hereditary spastic paraplegia (MIM 605280) and the recessively inherited hypomyelinating leukodystrophy 4 (MIM 612233). Subsequently, an additional phenotype of hypomyelinating leukodystrophy has been reported due to de novo heterozygous HSPD1 variants.In the current work, we expand the clinical and genetic spectrum of this hypomyelinating disorder by describing a cohort of three patients, being heterozygous for HSPD1 variants involving residue Ala536 of HSP60 (the novel p.Ala536Pro variant and the previously reported p.Ala536Val).

Methods: Clinical and radiological evaluation; whole exome sequencing, in vitro reconstitution assay and patient fibroblast cell lysate analysis.

Results: Clinical manifestation was of early-onset nystagmus, tremor and hypotonia evolving into spasticity and ataxia and childhood-onset neuroregression in one case. Brain MRI studies revealed diffuse hypomyelination.The 3D protein structure showed these variants to lie in spatial proximity to the previously reported Leu47Val variant, associated with a similar clinical phenotype. In vitro reconstitution assay and patient fibroblast cell lysate analysis demonstrated that these mutants display aberrant chaperonin protein complex assembly.

Discussion: We provide evidence that impaired oligomerisation of the chaperonin complex might underlie this HSPD1-related phenotype, possibly through exerting a dominant negative effect.

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HSPD1的杂合子从头变异体通过损害HSP60的寡聚作用导致骨髓营养不良性白质营养不良症。
导言髓鞘膜下白质营养不良症是一组遗传性疾病,以严重的永久性髓鞘缺乏为特征。其临床特征包括发育迟缓,伴有或不伴有神经退化、眼球震颤、中枢性肌张力低下,并逐渐发展为痉挛和共济失调。HSPD1 编码 HSP60 合子蛋白,介导线粒体基质中进口蛋白质的 ATP 依赖性折叠。HSPD1 的致病变体与多种神经系统表型有关,包括显性遗传的纯合子遗传性痉挛性截瘫(MIM 605280)和隐性遗传的髓鞘下白质营养不良症 4(MIM 612233)。在目前的研究中,我们描述了一组由三名患者组成的队列,他们都是涉及 HSP60 残基 Ala536 的 HSPD1 变异体(新的 p.Ala536Pro 变异体和之前报道的 p.Ala536Val),从而扩展了这种骨髓营养不良性疾病的临床和遗传谱:临床和放射学评估、全外显子组测序、体外重组试验和患者成纤维细胞裂解物分析:结果:临床表现为早发性眼球震颤、震颤和肌张力低下,并逐渐发展为痉挛和共济失调,其中一例患者为儿童期神经退化。三维蛋白质结构显示,这些变异体与之前报道的Leu47Val变异体在空间上非常接近,且具有相似的临床表型。体外重组测定和患者成纤维细胞裂解物分析表明,这些突变体显示出伴侣蛋白复合物组装异常:讨论:我们提供的证据表明,合子蛋白复合物的低聚作用受损可能是 HSPD1 相关表型的基础,可能是通过发挥显性负效应造成的。
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来源期刊
Journal of Medical Genetics
Journal of Medical Genetics 医学-遗传学
CiteScore
7.60
自引率
2.50%
发文量
92
审稿时长
4-8 weeks
期刊介绍: Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.
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