Identification of novel mutations in patients with Shwachman-Diamond syndrome.
Identification of novel mutations in patients with Shwachman-Diamond syndrome.
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DOI：
10.1002/humu.9324
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发表时间：
2005-04-01
期刊：
影响因子：
3.9
通讯作者：
Cipolli, Marco
中科院分区：
文献类型：
--
作者：
Nicolis, Elena;Bonizzato, Alberto;Cipolli, Marco
Shwachman-Diamond综合征（SDS）是一种罕见的常染色体隐性遗传病，主要表现为胰腺外分泌功能不全、血液系统异常和骨骼异常。SDS疾病基因定位于染色体7 q11，并在Shwachman-Bodian-Diamond综合征（SBDS）基因中报告了疾病相关突变。SBDS是一个高度保守的蛋白质家族的成员，在包括古生菌和真核生物在内的不同物种中具有推定的直系同源物。它在许多组织中广泛表达，其功能尚不清楚。在本研究中，我们分析了15个无关的意大利SDS患者的基因型。在对整个编码区进行测序后，我们能够完成所测试的SDS患者的所有基因型。共鉴定出11种不同的突变。最常见的突变是由于SBDS和其未加工的假基因（称为SBDSP）之间的基因转换事件。我们描述了四个新的基因转换涉及外显子2和三个新的突变，不是基因转换事件的结果。在15例中的2例中，家族分析证明父母和受影响儿童之间SDS等位基因的明显意外遗传。在第一种情况下，我们发现了一个新的大的基因转换事件，导致父亲的等位基因扩增失败，在第二种情况下，可以解释为从头基因转换。这两个案例对遗传咨询和分子遗传分析具有重要意义。在由可变延伸的基因转换引起的疾病中，这些发现强调了检测患者父母的必要性和引物选择的重要性。
Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disease, mainly characterized by exocrine pancreatic insufficiency, hematological dysfunction and skeletal abnormalities. The SDS disease locus was mapped to chromosome 7q11 and disease-associated mutations were reported in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. SBDS is a member of a highly conserved protein family with putative orthologs in diverse species including archaea and eukaryotes. It is widely expressed in many tissues and its function is still unknown. In the present study we analyzed the genotype of 15 unrelated Italian SDS patients. After sequencing the whole coding region we were able to complete all genotypes of the SDS patients tested. A total of eleven distinct mutations were identified. The most frequent mutations are due to gene conversion events between SBDS and its unprocessed pseudogene, named SBDSP. We described four new gene conversions involving exon 2 and three novel mutations that are not a result of gene conversion events. In two out of the fifteen cases, the family analysis evidenced an apparently unexpected inheritance of SDS alleles between parents and affected children. In the first case we found a new large gene conversion event, that caused the failure of the amplification of the father's allele and in the second what could be explained as a de novo gene conversion. Both cases have important implications for genetic counseling and molecular genetic analysis. In a disorder caused by gene conversions of variable extension these findings emphasize the necessity of testing patient's parents and the significance of the choice of primers.