A missense mutation in the splicing factor gene DHX38 is associated with early-onset retinitis pigmentosa with macular coloboma
A missense mutation in the splicing factor gene DHX38 is associated with early-onset retinitis pigmentosa with macular coloboma
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DOI：
10.1136/jmedgenet-2014-102316
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发表时间：
2014-07-01
影响因子：
4
通讯作者：
Cremers, Frans P. M.
中科院分区：
文献类型：
--
作者：
Ajmal, Muhammad;Khan, Muhammad Imran;Cremers, Frans P. M.
背景色素性视网膜炎（RP）是最常见的遗传性视网膜疾病，在巴基斯坦常染色体隐性遗传病的发病率相对较高。方法采用全基因组高密度单核苷酸多态性（SNP）微阵列来识别一个近亲家族受影响个体共有的纯合子区域。三个受影响兄弟姐妹和两个健康兄弟姐妹的 DNA 用于 SNP 基因分型。然后通过纯合性映射器分析基因分型数据。采用外显子组测序进一步分析先证者的 DNA。结果纯合性作图显示 16 号染色体上有一个纯合区域，由三个受影响个体共有。随后的外显子组测序发现了一种新的错义突变，c.995G>A； p.(Gly332Asp)，在 DHX38 中。发现这种突变以纯合状态存在于四个受影响的个体中，而两个健康的兄弟姐妹和受影响者的父母则为这种突变的杂合子。因此，该变体产生的赔率对数 (LOD) 分数为 3.25，这对于连锁具有很强的暗示性。在 180 名种族匹配的对照个体、7540 名非洲人或白种人以及包含 400 名个体外显子组数据的内部数据库中均未检测到该变异。 结论 通过结合全基因组纯合性作图和外显子组测序，在一个患有早发常染色体隐性遗传的巴基斯坦家族中，在编码前 mRNA 剪接因子 PRP16 的 DHX38 基因中发现了一种新的错义突变。 RP。该表型与其他视网膜前 mRNA 剪接因子相关的表型不同，DHX38 是第一个被认为与常染色体隐性遗传性 RP 相关的前 mRNA 剪接基因。
Background Retinitis pigmentosa (RP) is the most frequent inherited retinal disease, which shows a relatively high incidence of the autosomal-recessive form in Pakistan.Methods Genome-wide high-density single-nucleotide polymorphism (SNP) microarrays were used to identify homozygous regions shared by affected individuals of one consanguineous family. DNA of three affected and two healthy siblings was used for SNP genotyping. Genotyping data were then analysed by Homozygosity Mapper. DNA of the proband was further analysed employing exome sequencing.Results Homozygosity mapping revealed a single homozygous region on chromosome 16, shared by three affected individuals. Subsequent exome sequencing identified a novel missense mutation, c.995G>A; p.(Gly332Asp), in DHX38. This mutation was found to be present in a homozygous state in four affected individuals while two healthy siblings and the parents of the affected persons were heterozygous for this mutation. This variant thereby yields a logarithm of the odds (LOD) score of 3.25, which is highly suggestive for linkage. This variant was neither detected in 180 ethnically matched control individuals, nor in 7540 Africans or Caucasians and an in-house database that contained the exome data of 400 individuals.Conclusions By combining genome-wide homozygosity mapping and exome sequencing, a novel missense mutation was identified in the DHX38 gene that encodes the pre-mRNA splicing factor PRP16, in a Pakistani family with early-onset autosomal-recessive RP. The phenotype is different from those associated with other retinal pre-mRNA splicing factors and DHX38 is the first pre-mRNA splicing gene that is putatively associated with autosomal-recessive inherited RP.