Michio Inoue, Divya Jayaraman, Rocio Bengoechea, Ankan Bhadra, Casie A Genetti, Abdulrahman A Aldeeri, Betül Turan, Rafael Adrian Pacheco-Orozco, Almundher Al-Maawali, Nadia Al Hashmi, Ayşe Gül Zamani, Emine Göktaş, Sevgi Pekcan, Hanife Tuğçe Çağlar, Heather True, Alan H Beggs, Conrad C Weihl
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In this study, we performed whole-exome sequencing on seven patients with early respiratory failure of unknown genetic etiology. We identified five distinct pathogenic variants in DNAJB4 in five unrelated families of diverse ethnic backgrounds: three loss-of-function variants (c.547 C > T, p.R183*; c.775 C > T, p.R259*; an exon 2 deletion) and two missense variants (c.105G > C, p.K35N; c.181 A > G, p.R61G). All patients were homozygous. Most affected individuals exhibited early respiratory failure, and patients from three families had rigid spine syndrome with axial weakness in proportion to appendicular weakness. Additional symptoms included dysphagia, ankle contractures, scoliosis, neck stiffness, and cardiac dysfunction. Notably, J-domain missense variants were associated with a more severe phenotype, including an earlier age of onset and a higher mortality rate, suggesting a strong genotype‒phenotype correlation. Consistent with a loss of function, the nonsense variants presented decreased stability. In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays. Our findings suggest that DNAJB4 is an emerging cause of myopathy with rigid spine syndrome of variable age of onset and severity. This diagnosis should be considered in individuals presenting with suggestive symptoms, particularly if they exhibit neck stiffness during infancy or experience respiratory failure in adults without significant limb muscle weakness. Missense variants in the J domain may predict a more severe phenotype.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":null,"pages":null},"PeriodicalIF":6.2000,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514740/pdf/","citationCount":"0","resultStr":"{\"title\":\"Genotype‒phenotype correlation in recessive DNAJB4 myopathy.\",\"authors\":\"Michio Inoue, Divya Jayaraman, Rocio Bengoechea, Ankan Bhadra, Casie A Genetti, Abdulrahman A Aldeeri, Betül Turan, Rafael Adrian Pacheco-Orozco, Almundher Al-Maawali, Nadia Al Hashmi, Ayşe Gül Zamani, Emine Göktaş, Sevgi Pekcan, Hanife Tuğçe Çağlar, Heather True, Alan H Beggs, Conrad C Weihl\",\"doi\":\"10.1186/s40478-024-01878-w\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Protein aggregate myopathies can result from pathogenic variants in genes encoding protein chaperones. 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Additional symptoms included dysphagia, ankle contractures, scoliosis, neck stiffness, and cardiac dysfunction. Notably, J-domain missense variants were associated with a more severe phenotype, including an earlier age of onset and a higher mortality rate, suggesting a strong genotype‒phenotype correlation. Consistent with a loss of function, the nonsense variants presented decreased stability. In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays. Our findings suggest that DNAJB4 is an emerging cause of myopathy with rigid spine syndrome of variable age of onset and severity. This diagnosis should be considered in individuals presenting with suggestive symptoms, particularly if they exhibit neck stiffness during infancy or experience respiratory failure in adults without significant limb muscle weakness. 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引用次数: 0
摘要
编码蛋白伴侣的基因中的致病变异可导致蛋白聚集性肌病。DNAJB4 是一种属于热休克蛋白-40(HSP40)家族的伴侣蛋白,在细胞蛋白稳态中发挥着重要作用。DNAJB4 的隐性功能缺失变体会导致肌病,并伴有早期呼吸衰竭和脊柱僵硬,从婴儿期一直持续到成年期。本研究调查了DNAJB4肌病更广泛的临床和遗传谱。在这项研究中,我们对七名遗传病因不明的早期呼吸衰竭患者进行了全外显子组测序。我们在五个不同种族背景的无亲属关系家庭中发现了 DNAJB4 的五个不同致病变异:三个功能缺失变异(c.547 C > T,p.R183*;c.775 C > T,p.R259*;一个外显子 2 缺失)和两个错义变异(c.105G > C,p.K35N;c.181 A > G,p.R61G)。所有患者均为同型变异。大多数患者表现出早期呼吸衰竭,三个家族的患者患有脊柱僵硬综合征,轴向无力与阑尾无力成正比。其他症状包括吞咽困难、踝关节挛缩、脊柱侧弯、颈部僵硬和心脏功能障碍。值得注意的是,J-domain 错义变异与更严重的表型有关,包括更早的发病年龄和更高的死亡率,这表明基因型与表型之间存在很强的相关性。与功能缺失相一致的是,无义变体的稳定性降低。相反,错义变体表现出正常或更高的稳定性,但在酵母互补和TDP-43分解试验中表现为功能缺失变体。我们的研究结果表明,DNAJB4 是导致发病年龄和严重程度不一的脊柱僵直综合征肌病的一个新病因。如果患者出现提示性症状,尤其是在婴儿期表现出颈部僵硬或在成年后出现呼吸衰竭而无明显四肢肌无力时,应考虑这一诊断。J 结构域的错义变异可能预示着更严重的表型。
Genotype‒phenotype correlation in recessive DNAJB4 myopathy.
Protein aggregate myopathies can result from pathogenic variants in genes encoding protein chaperones. DNAJB4 is a cochaperone belonging to the heat shock protein-40 (HSP40) family and plays a vital role in cellular proteostasis. Recessive loss-of-function variants in DNAJB4 cause myopathy with early respiratory failure and spinal rigidity, presenting from infancy to adulthood. This study investigated the broader clinical and genetic spectrum of DNAJB4 myopathy. In this study, we performed whole-exome sequencing on seven patients with early respiratory failure of unknown genetic etiology. We identified five distinct pathogenic variants in DNAJB4 in five unrelated families of diverse ethnic backgrounds: three loss-of-function variants (c.547 C > T, p.R183*; c.775 C > T, p.R259*; an exon 2 deletion) and two missense variants (c.105G > C, p.K35N; c.181 A > G, p.R61G). All patients were homozygous. Most affected individuals exhibited early respiratory failure, and patients from three families had rigid spine syndrome with axial weakness in proportion to appendicular weakness. Additional symptoms included dysphagia, ankle contractures, scoliosis, neck stiffness, and cardiac dysfunction. Notably, J-domain missense variants were associated with a more severe phenotype, including an earlier age of onset and a higher mortality rate, suggesting a strong genotype‒phenotype correlation. Consistent with a loss of function, the nonsense variants presented decreased stability. In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays. Our findings suggest that DNAJB4 is an emerging cause of myopathy with rigid spine syndrome of variable age of onset and severity. This diagnosis should be considered in individuals presenting with suggestive symptoms, particularly if they exhibit neck stiffness during infancy or experience respiratory failure in adults without significant limb muscle weakness. Missense variants in the J domain may predict a more severe phenotype.
期刊介绍:
"Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders.
ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.