Saha Bidisha, Lessel Davor, Nampoothiri Sheela, Rao Anuradha S, Hisama Fuki M, Peter Dincy, Bennett Chris, Nürnberg Gudrun, Nürnberg Peter, Martin George M, Kubisch Christian, Oshima Junko
Department of Pathology and Division of Medical Genetics, University of Washington, Seattle, WA, USA.
Mol Genet Genomic Med. 2013 May 1;1(1):7-14. doi: 10.1002/mgg3.1.
Werner syndrome is a rare autosomal recessive disorder characterized by multiple features consistent with accelerated aging. It is caused by mutations in the gene, which encodes a RecQ type helicase. To date, more than 70 disease-causing mutations have been reported. While founder mutations and a corresponding relatively high incidence of WS have been reported in Japan and Sardinia, such mutations have not been previously described among patients of South Asian descent. Here we report two novel mutations in three pedigrees. A homozygous c.561A>G mutation in exon 6 was identified both in a pedigree from Kerala, India and in a British patient of Pakistani ancestry. Although c.561A>G does not alter the corresponding amino acid (p.K187K), it creates a cryptic splice site resulting in a 98bp deletion at the mRNA level (r.557-654del98) followed by a frameshift (p.K187fs). These two cases shared the same haplotype across the gene, and were distinct from another Indian Werner patient with a homozygous stop codon mutation, c.2855 C>A (p.S952*) in exon 24. As the Indian population increases and the awareness of Werner syndrome grows, we anticipate that more cases will be identified with these founder mutations among South Asian Werner syndrome patients.
沃纳综合征是一种罕见的常染色体隐性疾病，其特征是具有多种与加速衰老相符的特征。它由编码RecQ型解旋酶的基因发生突变引起。迄今为止，已报道了70多种致病突变。虽然在日本和撒丁岛报道了奠基者突变以及相应较高的沃纳综合征发病率，但此前在南亚裔患者中尚未描述此类突变。在此，我们报告了三个家系中的两个新的突变。在来自印度喀拉拉邦的一个家系以及一名有巴基斯坦血统的英国患者中均鉴定出第6外显子的纯合c.561A>G突变。虽然c.561A>G不会改变相应的氨基酸（p.K187K），但它会产生一个隐蔽剪接位点，导致mRNA水平上98bp的缺失（r.557 - 654del98），随后发生移码（p.K187fs）。这两个病例在整个基因上共享相同的单倍型，并且与另一名患有纯合终止密码子突变c.2855 C>A（p.S952*）位于第24外显子的印度沃纳患者不同。随着印度人口的增加以及对沃纳综合征认识的提高，我们预计在南亚沃纳综合征患者中会发现更多携带这些奠基者突变的病例。
