Myotonia congenita is a non-dystrophic muscle disorder affecting the excitability of the skeletal muscle membrane. It can be inherited either as an autosomal dominant (Thomsen's myotonia) or an autosomal recessive (Becker's myotonia) trait. Both types are characterised by myotonia (muscle stiffness) and muscular hypertrophy, and are caused by mutations in the muscle chloride channel gene, CLCN1. At least 50 different CLCN1 mutations have been described worldwide, but in many studies only about half of the patients showed mutations in CLCN1. Limitations in the mutation detection methods and genetic heterogeneity might be explanations. In the current study, we sequenced the entire CLCN1 gene in 15 Northern Norwegian and three Northern Swedish MC families. Our data show a high prevalence of myotonia congenita in Northern Norway similar to Northern Finland, but with a much higher degree of mutation heterogeneity. In total, eight different mutations and three polymorphisms (T87T, D718D, and P727L) were detected. Three mutations (F287S, A331T, and 2284+5C>T) were novel while the others (IVS1+3A>T, 979G>A, F413C, A531V, and R894X) have been reported previously. The mutations F413C, A531V, and R894X predominated in our patient material. Compound heterozygosity for A531V/R894X was the predominant genotype. In two probands, three mutations cosegregated with myotonia. No CLCN1 mutations were identified in two families. Our data support the presence of genetic heterogeneity and additional modifying factors in myotonia congenita.

译文

:先天性肌强直是一种非营养性肌肉疾病,会影响骨骼肌膜的兴奋性。它可以作为常染色体显性遗传(汤姆森氏肌强直)或常染色体隐性遗传(贝克尔氏肌强直)性状遗传。两种类型均以肌强直(肌肉僵硬)和肌肉肥大为特征,并且是由肌肉氯化物通道基因CLCN1的突变引起的。全世界至少描述了50种不同的CLCN1突变,但是在许多研究中,只有大约一半的患者显示了CLCN1的突变。突变检测方法和遗传异质性的局限性可能是解释。在当前的研究中,我们对15个挪威北部和3个瑞典北部MC家族的整个CLCN1基因进行了测序。我们的数据显示,与北部芬兰相似,挪威北部先天性肌强直症患病率很高,但突变异质性程度更高。总共检测到八个不同的突变和三个多态性(T87T,D718D和P727L)。先前已经报道了三个突变(F287S,A331T和2284 5C> T),而其他突变(IVS1 3A> T,979G> A,F413C,A531V和R894X)已经报道。 F413C,A531V和R894X突变在我们的患者资料中占主导地位。 A531V / R894X的复合杂合度是主要基因型。在两个先证者中,三个突变与肌强直共分离。在两个家族中均未发现CLCN1突变。我们的数据支持先天性肌强直症中遗传异质性和其他修饰因子的存在。

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