Whole exome sequencing identified a novel DAG1 mutation in a patient with rare, mild and late age of onset muscular dystrophy-dystroglycanopathy
Whole exome sequencing identified a novel DAG1 mutation in a patient with rare, mild and late age of onset muscular dystrophy-dystroglycanopathy
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DOI：
10.1111/jcmm.13979
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发表时间：
2019-02-01
影响因子：
5.3
通讯作者：
Banerjee, Santasree
中科院分区：
文献类型：
--
作者：
Dai, Yi;Liang, Shengran;Banerjee, Santasree
9型肌营养不良症是最罕见的常染色体隐性遗传性肌营养不良症。MDDGC9表现为儿童时期起病早。MDDGC9患者通常被诊断为DAG1糖基化缺陷，因此被称为“血糖营养不良症”。在此，我们报告一个轻度MDDGC9的中国家系。先证者是一名的中国男子。在这个家庭中，先证者和先证者的弟弟都患有轻度和晚发性MDDGC9。肌肉活检显示左侧三角肌呈晚期营养不良改变。肌营养不良蛋白、α-肌聚糖、β-肌聚糖和脱铁蛋白的免疫组织化学染色均正常。先证者的分子遗传分析已经完成了整个外显子组测序。在先证者中发现了DAG1基因外显子3的一种新的纯合错义突变(c.2326C>；T；p.R776C)。Sanger测序显示，这种错义突变在受影响的和未受影响的(携带者)家庭成员中很好地共分离。在200名正常健康对照个体中没有检测到这种突变。这种新的纯合错义突变(c.2326C>；T)导致776位(p.R776C)的胱氨酸取代精氨酸，这在进化上是高度保守的。免疫印迹研究显示，肌肉组织中α-肌营养不良蛋白的表达显著减少。本研究的创新之处在于，首次报道了DAG1相关性肌营养不良-糖营养不良症(肢带型)，9型(MDDGC9)，起病年龄较轻和较晚。在中国人群中，这是首次报道与DAG1相关的MDDGC9。
Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9 (MDDGC9) is the rarest type of autosomal recessive muscular dystrophies. MDDGC9 is manifested with an early onset in childhood. Patients with MDDGC9 usually identified with defective glycosylation of DAG1, hence it is known as "dystroglycanopathies". Here, we report a Chinese pedigree presented with mild MDDGC9. The proband is a 64 years old Chinese man. In this family, both the proband and proband's younger brother have been suffering from mild and late onset MDDGC9. Muscle biopsy showed that the left deltoid muscle with an advanced stage of dystrophic change. Immunohistochemistry staining of dystrophin, alpha-sarcoglycan, beta-sarcoglycan and dysferlin are normal. Molecular genetic analysis of the proband has been done with whole exome sequencing. A homozygous novel missense mutation (c.2326C>T; p.R776C) in the exon 3 of the DAG1 gene has been identified in the proband. Sanger sequencing revealed that this missense mutation is co-segregated well among the affected and unaffected (carrier) family members. This mutation is not detected in 200 normal healthy control individuals. This novel homozygous missense mutation (c.2326C>T) causes substitution of arginine by cystine at the position of 776 (p.R776C) which is evolutionarily highly conserved. Immunoblotting studies revealed that a significant reduction of alpha-dystroglycan expression in the muscle tissue. The novelty of our study is that it is a first report of DAG1 associated muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9 (MDDGC9) with mild and late age of onset. In Chinese population this is the first report of DAG1 associated MDDGC9.