Buena-Atienza Elena, Rüther Klaus, Baumann Britta, Bergholz Richard, Birch David, De Baere Elfride, Dollfus Helene, Greally Marie T, Gustavsson Peter, Hamel Christian P, Heckenlively John R, Leroy Bart P, Plomp Astrid S, Pott Jan Willem R, Rose Katherine, Rosenberg Thomas, Stark Zornitza, Verheij Joke B G M, Weleber Richard, Zobor Ditta, Weisschuh Nicole, Kohl Susanne, Wissinger Bernd
Institute for Ophthalmic Research, Centre for Ophthalmology, Tuebingen, Germany.
Sankt Gertrauden-Krankenhaus, Berlin, Germany.
Sci Rep. 2016 Jun 24;6:28253. doi: 10.1038/srep28253.
X-linked cone dysfunction disorders such as Blue Cone Monochromacy and X-linked Cone Dystrophy are characterized by complete loss (of) or reduced L- and M- cone function due to defects in the OPN1LW/OPN1MW gene cluster. Here we investigated 24 affected males from 16 families with either a structurally intact gene cluster or at least one intact single (hybrid) gene but harbouring rare combinations of common SNPs in exon 3 in single or multiple OPN1LW and OPN1MW gene copies. We assessed twelve different OPN1LW/MW exon 3 haplotypes by semi-quantitative minigene splicing assay. Nine haplotypes resulted in aberrant splicing of ≥20% of transcripts including the known pathogenic haplotypes (i.e. 'LIAVA', 'LVAVA') with absent or minute amounts of correctly spliced transcripts, respectively. De novo formation of the 'LIAVA' haplotype derived from an ancestral less deleterious 'LIAVS' haplotype was observed in one family with strikingly different phenotypes among affected family members. We could establish intrachromosomal gene conversion in the male germline as underlying mechanism. Gene conversion in the OPN1LW/OPN1MW genes has been postulated, however, we are first to demonstrate a de novo gene conversion within the lineage of a pedigree.
X连锁性视锥细胞功能障碍疾病，如蓝锥单色视和X连锁性视锥细胞营养不良，其特征是由于OPN1LW/OPN1MW基因簇缺陷导致L-视锥细胞和M-视锥细胞功能完全丧失或降低。在此，我们研究了来自16个家庭的24名患病男性，这些家庭的基因簇结构完整，或至少有一个完整的单（杂合）基因，但在单个或多个OPN1LW和OPN1MW基因拷贝的外显子3中存在常见单核苷酸多态性（SNP）的罕见组合。我们通过半定量小基因剪接试验评估了12种不同的OPN1LW/MW外显子3单倍型。9种单倍型导致≥20%的转录本出现异常剪接，包括已知的致病单倍型（即“LIAVA”、“LVAVA”），分别缺失或仅有微量正确剪接的转录本。在一个患病家庭成员之间表型差异显著的家庭中，观察到从祖先危害较小的“LIAVS”单倍型衍生而来的“LIAVA”单倍型的新生形成。我们可以确定男性生殖系中的染色体内基因转换是其潜在机制。虽然有人推测OPN1LW/OPN1MW基因中存在基因转换，但我们是首次在一个家系的谱系中证明新生基因转换。
