PDF(Pubmed)
Abstract：
Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions.
We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGUeye) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants.
Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease.
Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants.
We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGUeye) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants.
Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease.
Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants.
摘要：
大多数经典无虹膜是由PAX6单倍体不足引起的。PAX6错义变体可以是双态的或模拟单倍体不足。我们假设错义变体还通过改变PAX6基因组相互作用的亲和力和/或特异性而导致先前未描述的疾病。
我们在372例双侧小眼症患者中筛查了PAX6，无眼炎,或来自医学研究理事会人类遗传学单位眼畸形队列（HGUeye）的结肠瘤（MAC），并审查了解密发育障碍研究的数据。我们通过86种不同PAX6致病错义变异的结构影响的变异类型和分子模型对PAX6相关眼部表型进行了聚类分析。
在17个患有MAC的个体（15个家族）中鉴定出8种不同的PAX6错义变异，占我们队列的4%(15/372)。七个改变了配对的结构域（p。[Arg26Gln]x1，p。[Gly36Val]x1，p。[Arg38Trp]x2，p。[Arg38Gln]x1，p。[Gly51Arg]x2，p。[Ser54Arg]x2，p。[Asn124Lys]x5）和一个同源域（p。[Asn260Tyr]x1）。p.Ser54Arg和p.Asn124Lys与严重的双侧小眼症仅相关。预测MAC相关变体会改变但不会消融DNA相互作用，与使用具有良好表征的PAX6结合位点的突变配对结构域观察到的电泳迁移率变化一致。我们没有发现新的PAX6相关眼外疾病的有力证据。
改变PAX6结合全基因组的亲和力和特异性为MAC相关错义变体的劣于零效应提供了一种合理的机制。
我们在372例双侧小眼症患者中筛查了PAX6，无眼炎,或来自医学研究理事会人类遗传学单位眼畸形队列（HGUeye）的结肠瘤（MAC），并审查了解密发育障碍研究的数据。我们通过86种不同PAX6致病错义变异的结构影响的变异类型和分子模型对PAX6相关眼部表型进行了聚类分析。
在17个患有MAC的个体（15个家族）中鉴定出8种不同的PAX6错义变异，占我们队列的4%(15/372)。七个改变了配对的结构域（p。[Arg26Gln]x1，p。[Gly36Val]x1，p。[Arg38Trp]x2，p。[Arg38Gln]x1，p。[Gly51Arg]x2，p。[Ser54Arg]x2，p。[Asn124Lys]x5）和一个同源域（p。[Asn260Tyr]x1）。p.Ser54Arg和p.Asn124Lys与严重的双侧小眼症仅相关。预测MAC相关变体会改变但不会消融DNA相互作用，与使用具有良好表征的PAX6结合位点的突变配对结构域观察到的电泳迁移率变化一致。我们没有发现新的PAX6相关眼外疾病的有力证据。
改变PAX6结合全基因组的亲和力和特异性为MAC相关错义变体的劣于零效应提供了一种合理的机制。
