Ocular malformations, postaxial polydactyly, and delayed intramembranous ossification: a new autosomal dominant condition.
Ocular malformations, postaxial polydactyly, and delayed intramembranous ossification: a new autosomal dominant condition.
复制标题
眼部畸形、轴后多指畸形和膜内骨化延迟：一种新的常染色体显性病症。
DOI：
10.1136/jmg.38.8.547
复制
发表时间：
2001
影响因子：
4
通讯作者：
Gorski,JL
中科院分区：
文献类型：
--
作者：
Martin,DM;Gorski,JL
编辑-糖原贮存病II型是一种由酸性α-葡萄糖苷酶缺乏引起的常染色体隐性遗传性溶酶体储存障碍。酶的缺乏导致骨骼肌和其他组织中糖原在溶酶体内的积累。根据发病年龄、器官受累程度和临床病程的不同，有早发和晚发的表型。1最近在普通人群中进行突变筛查，发现GSD II的基因频率为40000人中有1人，高于先前的估计。2酸性α-葡萄糖苷酶基因已有40多个不同突变的报道。4大多数突变是罕见的，仅在少数患者中发现。然而，已有报道在几名有明确种族来源的无关患者中发现了一些突变。C1935A基因颠换在中国婴儿2型GSD患者中经常发现，似乎起源于一个共同的创始人。5其他常见突变包括非裔美国人的R854X突变，6土耳其患者的2741AG→CAGG插入，7和欧洲患者的G925A突变。8这些频繁的突变是否代表共同的血统，或者是独立复发的结果，还有待确定。IVS1(−13T→G)突变是不同民族晚发性胃轻瘫患者中最常见的突变。在荷兰，大多数晚发性GSD II患者携带IVS1(−13T→G)突变和525delT或del外显子18突变，而婴儿GSD II患者通常表现出525delT和del外显子18突变的纯合或复合杂合性。10后一种突变是完全有害的，并与酶活性的完全丧失有关。12 13外显子18的缺失从IVS17延伸至IVS18，包含外显子18的编码序列。对缺失连接的分析表明，在缺失的两侧有一个直接的八核苷酸重复序列，其中一个直接重复在缺失中，第二个直接重复在缺失连接处。14 15该重复序列可能在突变事件中起作用。到目前为止，还没有非白人来源的患者出现这种突变的报道。525delT突变在非白人患者中也未见报道，在“非荷兰人”患者中相对罕见。16为了确定525delT和del外显子18突变是代表创始事件还是独立的从头突变，我们利用GAA基因的四个单核苷酸多态(SNPs)构建了单倍型。我们使用了一组28名无关的GSD II患者来确定携带相同突变的个体患者之间的单倍型共享程度。患者群体包括来自26个家系的26名荷兰白人患者及其父母，以及来自两个成年GSD II家庭的3名荷兰白人患者及其父母。所有患者都携带至少一个频繁突变(525delT或del外显子18)，并在成纤维细胞和白细胞中检测到GAA活性低下。用标准程序从培养的皮肤成纤维细胞和外周血细胞中提取基因组DNA。17突变分析如上所述。11我们分析了4个基因内单核苷酸多态(SNPs)，然后用适当的限制性内切酶对扩增产物进行消化(表1)。为了扩增外显子3、8、11和17，从Martiniuk等人那里获得了信息。18个片段在2%琼脂糖凝胶上进行电泳。GSD II患者的基因分型父母指定了等位基因的时相。SNPs和…的顺序
EDITOR—Glycogen storage disease type II (GSD II) is an autosomal recessive lysosomal storage disorder caused by deficiency of acid α-glucosidase. The enzyme deficiency results in intralysosomal accumulation of glycogen in skeletal muscle and in other tissues. There are early and late onset phenotypes which diVer with respect to age at onset, extent of organ involvement, and clinical course of the disease. 1 The genotype frequency of GSD II was recently shown to be 1 in 40 000 by mutation screening in the general population, which is higher than previously estimated. 2 3 Over 40 diVerent mutations in the acid α-glucosidase (GAA) gene have been reported. 4 Most mutations are rare and have been found in only a few patients. However, some mutations have been reported in several unrelated patients with defined ethnic origins. The C1935A transversion, frequently found in Chinese patients with infantile GSD II, appears to originate from a common founder. 5 Other frequent mutations include the R854X mutation in Afro-Americans, 6 the 2741AG→ CAGG insertion in Turkish patients, 7 and the G925A mutation in European patients. 8 It remains to be determined whether these frequent mutations represent common descent or result from independent recurrence. The IVS1 (− 13T→ G) mutation is the most frequent mutation in late onset GSD II patients from diVerent ethnic origins. 9–11 In The Netherlands, most late onset GSD II patients carry the IVS1 (− 13T→ G) mutation in combination with either the 525delT or the del exon 18 mutation, whereas infantile GSD II patients often show homozygosity or compound heterozygosity for the 525delT and the del exon 18 mutations. 10 The latter mutations are fully deleterious and are associated with complete loss of enzyme activity. 12 13 The deletion of exon 18 extends from IVS17 to IVS18 and includes the coding sequence of exon 18.Analysis of the deletion junction showed a direct eight nucleotide repeat sequence flanking the deletion, with one direct repeat included in the deletion and the second direct repeat at the deletion junction. 14 15 This repeat sequence could be instrumental in the mutation event. So far, the mutation has not been reported in patients of non-white origin. The 525delT mutation has also not been reported in non-white patients, and is relatively rare in “non-Dutch” patients. 16 In order to determine whether the 525delT and del exon 18 mutations represent founder events or independent, de novo mutations, we constructed haplotypes using four single nucleotide polymorphisms (SNPs) in the GAA gene. We used a set of 28 unrelated GSD II patients to determine the extent of haplotype sharing between the individual patients carrying identical mutations. The patient population included 26 white Dutch patients and their parents from 26 families with infantile GSD II, and three white Dutch patients and their parents from two families with adult GSD II. All patients carried at least one frequent mutation (525delT or del exon 18) and had deficient GAA activity, measured in fibroblasts and leucocytes. Genomic DNA was extracted from cultured skin fibroblasts and from peripheral blood cells using standard procedures. 17 Mutation analysis was performed as described previously. 11 We analysed four intragenic single nucleotide polymorphisms (SNPs) by PCR amplification, followed by digestion of the PCR product with the appropriate restriction enzyme (table 1). To amplify exons 3, 8, 11, and 17, information was obtained from Martiniuk et al. 18 Fragments were electrophoresed on a 2% agarose gel. Genotyping parents of GSD II patients assigned the phase of the alleles. The order of SNPs and …