Reis Linda M, Tyler Rebecca C, Weh Eric, Hendee Kathryn E, Kariminejad Ariana, Abdul-Rahman Omar, Ben-Omran Tawfeg, Manning Melanie A, Yesilyurt Ahmet, McCarty Catherine A, Kitchner Terrie E, Costakos Deborah, Semina Elena V
Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI.
Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI.
Mol Vis. 2016 Oct 17;22:1229-1238. eCollection 2016.
The gene encodes an enzyme that is a member of the cytochrome P450 superfamily. Mutations in have been mainly reported in recessive pediatric ocular phenotypes, such as primary congenital glaucoma (PCG) and congenital glaucoma with anterior segment dysgenesis (CG with ASD), with some likely pathogenic variants also identified in families affected with adult-onset primary open angle glaucoma (POAG).
We examined in 158 pediatric patients affected with PCG (eight), CG with ASD (22), CG with other developmental ocular disorders (11), juvenile glaucoma with or without additional ocular anomalies (26), and ASD or other developmental ocular conditions without glaucoma (91); in addition, a large cohort of adult patients with POAG (193) and POAG-negative controls (288) was examined.
Recessive pathogenic variants in were identified in two PCG pedigrees, three cases with CG and ASD, and two families with CG and other ocular defects, such as sclerocornea in one patient and microphthalmia in another individual; neither sclerocornea nor microphthalmia has been previously associated with . Most of the identified causative mutations are new occurrences of previously reported pathogenic alleles with two novel variants identified: a c.1325delC, p.(Pro442Glnfs15) frameshift allele in a family with PCG and a c.157G>A, p.(Gly53Ser) variant identified in a proband with CG, Peters anomaly, and microphthalmia. Analysis of the family history in the -positive families revealed POAG in confirmed or presumed heterozygous relatives in one family with PCG and two families with ASD/CG; POAG was associated with the c.1064_1076del, p.(Arg355Hisfs69) allele in two of these pedigrees. Screening of an unrelated POAG cohort identified the same c.1064_1076del heterozygous allele in one individual with sporadic POAG but not in age- and ethnicity-matched POAG-negative individuals. Overall, there was no significant enrichment for mutant alleles in within the POAG cases compared to the controls.
In summary, these data expand the mutational and phenotypic spectra of to include two novel alleles and additional developmental ocular phenotypes. The contribution of to POAG is less clear, but loss-of-function variants in , especially c.1064_1076del, p.(Arg355Hisfs*69), may be associated with an increased risk for POAG.
该基因编码一种属于细胞色素P450超家族的酶。该基因的突变主要在隐性儿科眼部表型中被报道，如原发性先天性青光眼（PCG）和伴有眼前节发育异常的先天性青光眼（CG伴ASD），在成年发病的原发性开角型青光眼（POAG）患者家族中也发现了一些可能的致病变异。
我们检测了158例儿科患者，包括PCG患者（8例）、CG伴ASD患者（22例）、伴有其他发育性眼部疾病的CG患者（11例）、有或无其他眼部异常的青少年青光眼患者（26例）以及无青光眼的ASD或其他发育性眼部疾病患者（91例）；此外，还检测了一大群成年POAG患者（193例）和POAG阴性对照者（288例）。
在两个PCG家系、3例CG伴ASD患者以及两个伴有CG和其他眼部缺陷（如1例患者的巩膜角膜和另1例患者的小眼症）的家族中鉴定出该基因的隐性致病变异；此前巩膜角膜和小眼症均未与该基因相关联。大多数鉴定出的致病突变是先前报道的致病等位基因的新出现情况，还鉴定出两个新变体：一个PCG家族中的c.1325delC，p.(Pro442Glnfs15)移码等位基因，以及一名CG、彼得斯异常和小眼症先证者中鉴定出的c.157G>A，p.(Gly53Ser)变体。对该基因阳性家族的家族史分析显示，在一个PCG家族和两个ASD/CG家族中，确诊或推测为杂合子的亲属中有POAG；在其中两个家系中，POAG与c.1064_1076del，p.(Arg355Hisfs69)等位基因相关。对无关的POAG队列进行筛查，在1例散发性POAG个体中鉴定出相同的c.1064_1076del杂合等位基因，但在年龄和种族匹配的POAG阴性个体中未发现。总体而言，与对照组相比，POAG病例中该基因的突变等位基因没有显著富集。
总之，这些数据扩展了该基因的突变和表型谱，包括两个新等位基因和其他发育性眼部表型。该基因对POAG的贡献尚不清楚，但该基因的功能丧失变体，尤其是c.1064_1076del，p.(Arg355Hisfs*69)，可能与POAG风险增加有关。
