Founder effect in different European countries for the recurrent P392L SQSTM1 mutation in Paget's disease of bone
Founder effect in different European countries for the recurrent P392L SQSTM1 mutation in Paget's disease of bone
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DOI：
10.1007/s00223-008-9137-2
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发表时间：
2008-07-01
影响因子：
4.2
通讯作者：
Van Hul, Wim
中科院分区：
文献类型：
--
作者：
Chung, Pui Yan Jenny;Beyens, Greet;Van Hul, Wim
佩吉特骨病（PDB）是最常见的代谢性骨病之一，影响1 - 5%的55岁以上的西方人群。隔离体1（SQSTM 1）基因的突变在大约三分之一的家族性PDB病例和2.4 - 9.3%的非家族性PDB病例中引起PDB，其中1215 C-> T（P392 L）突变是最常见的突变。我们调查了无PDB家族史的比利时（n = 233）、荷兰（n = 82）和西班牙（n = 64）患者中P392 L SQSTM 1突变的奠基者效应是否存在。首先，在这三个群体中，外显子8的直接测序分析显示，17名比利时患者（7.3%）、3名无家族史的荷兰患者（3.7%）和2名有家族史的荷兰患者发生了P392 L突变。在西班牙人群中，15.6%的患者（n = 10）有P392 L突变，包括一个纯合子突变。这是迄今为止调查的所有人群中突变频率最高的。接下来，我们通过分析单倍型检查了33条突变染色体的遗传背景。我们对SQSTM 1第6外显子和3 '端非翻译区的4个单核苷酸多态性（SNP）（rs 4935 C/T、rs 4797 G/A、rs 10277 T/C和rs 1065154 G/T）进行了基因分型，并使用软件程序WHAP和PHASE重建单倍型。最后，等位基因特异性引物使我们能够将突变分配给每个个体的两种单倍型之一。测序结果显示33个P392 L突变均位于CGTG（H2）单倍型上。由于33个独立突变事件而获得该结果的机会为3.97 x 10（-14），为比利时、荷兰和西班牙PDB患者中P392 L SQSTM 1突变的奠基者效应提供了强有力的证据。
Paget's Disease of Bone ( PDB) is one of the most frequent metabolic bone diseases, affecting 1 - 5% of Western populations older than 55 years. Mutations in the sequestosome1 (SQSTM1) gene cause PDB in about one-third of familial PDB cases and in 2.4 - 9.3% of nonfamilial PDB cases, with the 1215C -> T (P392L) mutation being the most frequent one. We investigated whether a founder effect of the P392L SQSTM1 mutation was present in Belgian (n = 233), Dutch ( n = 82), and Spanish ( n = 64) patients without a PDB family history. First, direct sequencing analysis of exon 8 in these three populations showed that the P392L mutation occurred in 17 Belgian patients ( 7.3%), three Dutch patients without a family history ( 3.7%), and two Dutch patients with a family history. In the Spanish population, 15.6% of patients (n = 10) had the P392L mutation, including one homozygous mutant. This is by far the highest mutation frequency of all populations investigated so far. Next, we examined the genetic background of 33 mutated chromosomes by analyzing haplotypes. We genotyped four single-nucleotide polymorphisms ( SNPs) in exon 6 and the 3'-untranslated region of SQSTM1 (rs4935C/T, rs4797G/A, rs10277T/C, and rs1065154G/T) and used software programs WHAP and PHASE to reconstruct haplotypes. Finally, allele-specific primers allowed us to assign the mutation to one of the two haplotypes from each individual. Sequencing results revealed that all 33 P392L mutations were on the CGTG ( H2) haplotype. The chance to obtain this result due to 33 independent mutation events is 3.97 x 10(-14), providing strong evidence for a founder effect of the P392L SQSTM1 mutation in Belgian, Dutch, and Spanish patients with PDB.