Haploinsufficiency of SF3B4, a Component of the Pre-mRNA Spliceosomal Complex, Causes Nager Syndrome
Haploinsufficiency of SF3B4, a Component of the Pre-mRNA Spliceosomal Complex, Causes Nager Syndrome
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DOI：
10.1016/j.ajhg.2012.04.004
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发表时间：
2012-05-04
影响因子：
9.8
通讯作者：
Parboosingh, Jillian S.
中科院分区：
文献类型：
--
作者：
Bernier, Francois P.;Caluseriu, Oana;Parboosingh, Jillian S.
60多年前首次描述的Nager综合征是一类称为肢面骨发育不全的疾病的原型，其特征是颅面和肢体畸形。尽管进行了大量的努力，但尚未发现Nager综合征的基因。在一项国际合作中，加拿大FORGE和美国国立卫生研究院孟德尔基因组学中心使用外显子组测序作为发现工具，发现SF3B4（U2前mRNA剪接体复合物的一个组成部分）的突变导致Nager综合征。在一个验证队列中对SF3 B4进行桑格测序后，35个Nager综合征家族中有20个（57%）有18种不同突变中的1种，几乎所有突变都是移码。这些结果表明，大多数Nager综合征病例是由SF3B4单倍不足引起的。我们的研究结果酸Nager综合征越来越多的列表中的突变引起的基因编码的剪接体的主要组成部分的疾病，也突出了国际合作的协同潜力时，外显子组测序应用于寻找基因负责罕见的孟德尔表型。
Nager syndrome, first described more than 60 years ago, is the archetype of a class of disorders called the acrofacial dysostoses, which are characterized by craniofacial and limb malformations. Despite intensive efforts, no gene for Nager syndrome has yet been identified. In an international collaboration, FORGE Canada and the National Institutes of Health Centers for Mendelian Genomics used exome sequencing as a discovery tool and found that mutations in SF3B4, a component of the U2 pre-mRNA spliceosomal complex, cause Nager syndrome. After Sanger sequencing of SF3B4 in a validation cohort, 20 of 35 (57%) families affected by Nager syndrome had 1 of 18 different mutations, nearly all of which were frameshifts. These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4. Our findings acid Nager syndrome to a growing list of disorders caused by mutations in genes that encode major components of the spliceosome and also highlight the synergistic potential of international collaboration when exome sequencing is applied in the search for genes responsible for rare Mendelian phenotypes.