Knierim Ellen, Gill Esther, Seifert Franziska, Morales-Gonzalez Susanne, Unudurthi Sathya D, Hund Thomas J, Stenzel Werner, Schuelke Markus
NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
Department of Neuropediatrics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Augustenburger Platz 1, 13353, Berlin, Germany.
Hum Genet. 2017 Jul;136(7):903-910. doi: 10.1007/s00439-017-1814-7. Epub 2017 May 24.
Congenital myopathies are a heterogeneous group of muscle disorders that are often genetically determined. Here, we investigated a boy with congenital myopathy, deafness, and neuropathy from a consanguineous Kurdish family by autozygosity mapping and whole exome sequencing. We found a homozygous nonsense mutation in SPTBN4 [c.1597C>T, NM_020971.2; p.(Q533*), NP_066022.2; ClinVar SUB2292235] encoding βIV-spectrin, a non-erythrocytic member of the β-spectrin family. Western blot confirmed the absence of the full-length 288 kDa isoform in muscle and of a specific 72 kDa isoform in fibroblasts. Clinical symptoms of the patient largely corresponded to those described for the quivering mouse, a loss-of-function animal model. Since the human phenotype of βIV-spectrin deficiency included a myopathy with incomplete congenital fiber-type disproportion, we investigated muscle of the quivering (qv4J) mouse and found complete absence of type 1 fibers (fiber-type 2 uniformity). Immunohistology confirmed expression of βIV-spectrin in normal human and mouse muscle at the sarcolemma and its absence in patient and quivering (qv4J) mouse. SPTBN4 mRNA-expression levels in healthy skeletal muscle were found in the range of other regulatory proteins. More patients have to be described to confirm the triad of congenital myopathy, neuropathy and deafness as the defining symptom complex for βIV-spectrin deficiency.
先天性肌病是一组异质性的肌肉疾病，通常由基因决定。在此，我们通过纯合性定位和全外显子组测序，对一个来自近亲库尔德家庭的患有先天性肌病、耳聋和神经病变的男孩进行了研究。我们在编码βIV-血影蛋白（β-血影蛋白家族的一种非红细胞成员）的SPTBN4基因中发现了一个纯合的无义突变[c.1597C>T，NM_020971.2；p.(Q533*)，NP_066022.2；ClinVar SUB2292235]。蛋白质免疫印迹法证实，肌肉中不存在全长288 kDa的异构体，成纤维细胞中不存在一种特定的72 kDa异构体。该患者的临床症状与功能丧失动物模型——颤抖小鼠所描述的症状基本相符。由于βIV-血影蛋白缺乏的人类表型包括一种先天性纤维类型比例不完全失调的肌病，我们对颤抖（qv4J）小鼠的肌肉进行了研究，发现完全没有1型纤维（纤维类型2均匀）。免疫组织化学证实βIV-血影蛋白在正常人和小鼠肌肉的肌膜处表达，而在患者和颤抖（qv4J）小鼠中不表达。在健康骨骼肌中发现SPTBN4 mRNA表达水平与其他调节蛋白的水平范围相当。需要描述更多患者，以确认先天性肌病、神经病变和耳聋三联征是βIV-血影蛋白缺乏的典型症状复合体。
