Sun C, Tranebjaerg L, Torbergsen T, Holmgren G, Van Ghelue M
Department of Medical Genetics, University Hospital of Tromsø, Tromsø, Norway.
Eur J Hum Genet. 2001 Dec;9(12):903-9. doi: 10.1038/sj.ejhg.5200736.
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.
先天性肌强直是一种非营养不良性肌肉疾病，会影响骨骼肌膜的兴奋性。它可以作为常染色体显性遗传（汤姆森肌强直）或常染色体隐性遗传（贝克尔肌强直）特征进行遗传。两种类型都以肌强直（肌肉僵硬）和肌肉肥大为特征，并且由肌肉氯通道基因CLCN1中的突变引起。全世界已描述了至少50种不同的CLCN1突变，但在许多研究中，只有约一半的患者显示CLCN1存在突变。突变检测方法的局限性和遗传异质性可能是原因。在当前研究中，我们对15个挪威北部和3个瑞典北部的先天性肌强直（MC）家族的整个CLCN1基因进行了测序。我们的数据显示，挪威北部先天性肌强直的患病率与芬兰北部相似，但突变异质性程度要高得多。总共检测到8种不同的突变和3种多态性（T87T、D718D和P727L）。三种突变（F287S、A331T和2284 + 5C>T）是新发现的，而其他突变（IVS1 + 3A>T、979G>A、F413C、A531V和R894X）此前已有报道。突变F413C、A531V和R894X在我们的患者材料中占主导地位。A531V/R894X的复合杂合性是主要基因型。在两名先证者中，三种突变与肌强直共分离。在两个家族中未鉴定出CLCN1突变。我们的数据支持先天性肌强直中存在遗传异质性和其他修饰因素。
