由 TBCK 中的新型纯合突变引起的伴有精神运动发育迟缓和癫痫的肌病改变。
Myopathic changes associated with psychomotor delay and seizures caused by a novel homozygous mutation in TBCK.
机构信息
Neuromuscular Disease and Immunology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Neurologico Carlo Besta, Milan, Italy.
Institute for Neuroscience and Department of Pharmacology and Physiology, George Washington University, Washington, DC.
出版信息
Muscle Nerve. 2020 Aug;62(2):266-271. doi: 10.1002/mus.26907. Epub 2020 May 27.
BACKGROUND
Biallelic mutations in TBC1-domain containing kinase (TBCK) lead to hypotonia, global developmental delay with severe cognitive and motor deficits, and variable presentation of dysmorphic facial features and brain malformations. It remains unclear whether hypotonia in these individuals is purely neurogenic, or also caused by progressive muscle disease.
METHODS
Whole exome sequencing was performed on a family diagnosed with nonspecific myopathic changes by means of histological analysis and immunohistochemistry of muscle biopsy samples.
RESULTS
A novel homozygous truncation in TBCK was found in two sisters diagnosed with muscle disease and severe psychomotor delay. TBCK was completely absent in these patients.
CONCLUSIONS
Our findings identify a novel early truncating variant in TBCK associated with a severe presentation and add muscle disease to the variability of phenotypes associated with TBCK mutations. Inconsistent genotype/phenotype correlation could be ascribed to the multiple roles of TBCK in intracellular signaling and endolysosomal function in different tissues.
背景
TBC1 结构域包含激酶 (TBCK) 的双等位基因突变导致张力减退、伴有严重认知和运动功能障碍的全面发育迟缓，以及不同表现的畸形面部特征和脑畸形。目前尚不清楚这些个体的张力减退是否纯粹是神经源性的，还是也由进行性肌肉疾病引起。
方法
通过对肌肉活检样本的组织学分析和免疫组织化学检查，对一个被诊断为非特异性肌病变化的家族进行了全外显子组测序。
结果
在两名被诊断为肌肉疾病和严重精神运动迟缓的姐妹中发现了 TBCK 中的一种新型纯合截断。这些患者中 TBCK 完全缺失。
结论
我们的发现确定了一种与严重表现相关的 TBCK 新型早期截断变异体，并将肌肉疾病添加到与 TBCK 突变相关的表型变异性中。不一致的基因型/表型相关性可归因于 TBCK 在不同组织中的细胞内信号转导和内溶酶体功能中的多种作用。
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