Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients
Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients
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DOI：
10.1002/humu.20642
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发表时间：
2008-02-01
期刊：
影响因子：
3.9
通讯作者：
Comi, Giacomo R.
中科院分区：
文献类型：
--
作者：
Guglieri, Michela;Magri, Francesca;Comi, Giacomo R.
肢带型肌营养不良症（LGMD）的特点是遗传和临床异质性：7个常染色体显性和12个常染色体隐性基因座，迄今已确定。本研究的目的是评估181例主要为意大利LGMD患者（代表155个独立家族）中不同类型LGMD的相对比例，描述不同形式的临床模式，并确定基因型、表型和蛋白表达水平之间可能的相关性，作为预后因素。基于蛋白质数据，大多数先证者（n = 72）呈现钙蛋白酶-3缺乏;其他缺陷如下：dysferlin（n = 31）、肌聚糖（n = 32）、a-肌营养不良聚糖（n = 4）和小窝蛋白，3（n = 2）。基因分析发现了111种不同的突变，其中包括47种新的突变。LGMD相对频率如下：LGMD 1C（小窝蛋白-3）1.3%; LGMD 2A（钙蛋白酶-3）28.4%; LGMD 2B（dysferlin）18.7%; LGMD2C（γ-肌聚糖）4.5%; LGMD 2D（α-肌聚糖）8.4%; LGMD 2 E（β-肌聚糖）4.5%; LGMD 2F（δ-肌聚糖）0.7%; LGMD 21（Fukutin相关蛋白）6.4%;和未确定的27.1%。与北方欧洲人群相比，意大利患者不太可能受到LGMD 21的影响。临床严重程度降低的顺序为：肌聚糖病、钙蛋白病、dysferlin病和小窝病。LGMD 21例患者表现为婴儿期非先天性和轻度迟发性表现。发病年龄与LGMD 2B基因型和蛋白水平的变异性相关。截短突变比错义替换更早发生（20 +/- 5.1年vs. 36.7 +/- 11.1年; P = 0.0037）。类似地，与部分缺乏相比，dysferlin缺乏与更早的发作相关（20.2 +/-标准差[SD] 5.2年vs. 28.4 +/- SD 11.2年; P = 0.014）。
Limb girdle muscular dystrophies (LGMD) are characterized by genetic and clinical heterogeneity: seven autosomal dominant and 12 autosomal recessive loci have so far been identified. Aims of this study were to evaluate the relative proportion of the different types of LGMD in 181 predominantly Italian LGMD patients (representing 155 independent families), to describe the clinical pattern of the different forms, and to identify possible correlations between genotype, phenotype, and protein expression levels, as prognostic factors. Based on protein data, the majority of probands (n = 72) presented calpain-3 deficiency; other defects were as follows: dysferlin (n = 3 1), sarcoglycans (n = 32), a-dystroglycan (n = 4), and caveolin,3 (n = 2). Genetic analysis identified 111 different mutations, including 47 novel ones. LGMD relative frequency was as follows: LGMD1C (caveolin-3) 1.3%; LGMD2A (calpain-3) 28.4%; LGMD2B (dysferlin) 18.7%; LGMD2C (gamma-sarcoglycan) 4.5%; LGMD2D (alpha-sarcoglycan) 8.4%; LGMD2E (beta-sarcoglycan) 4.5%; LGMD2F (delta-sarcoglycan) 0.7%; LGMD21 (Fukutin-related protein) 6.4%; and undetermined 27.1%. Compared to Northern European populations, Italian patients are less likely to be affected with LGMD21. The order of decreasing clinical severity was: sarcoglycanopathy, calpainopathy, dysferlinopathy, and caveolinopathy. LGMD21 patients showed both infantile noncongenital and mild late-onset presentations. Age at disease onset correlated with variability of genotype and protein levels in LGMD2B. Truncating mutations determined earlier onset than missense substitutions (20 +/- 5.1 years vs. 36.7 +/- 11.1 years; P = 0.0037). Similarly, dysferlin absence was associated with an earlier onset when compared to partial deficiency (20.2 +/- standard deviation [SD] 5.2 years vs. 28.4 +/- SD 11.2 years; P = 0.014).