Paun Codrut C, Pijl Benjamin J, Siemiatkowska Anna M, Collin Rob W J, Cremers Frans P M, Hoyng Carel B, den Hollander Anneke I
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Mol Vis. 2012;18:2447-53. Epub 2012 Oct 4.
The purpose of this study is to identify the genetic defect in a Turkish family with autosomal recessive retinitis pigmentosa, nanophthalmos, and optic disc drusen.
Ophthalmological examinations consisted of measuring the best-corrected visual acuity and the refractive error, electroretinography, optical coherence tomography, B-mode ultrasonography, and fundus photography. The involvement of the membrane frizzled-related protein (MFRP) gene in this family was studied with direct DNA sequencing of the coding exons of MFRP and with linkage analysis with microsatellite markers. After MFRP was excluded, genome-wide homozygosity mapping was performed with 250 K single nucleotide polymorphism (SNP) microarrays. Mutation analysis of the crumbs homolog 1 (CRB1) gene was performed with direct sequencing.
Ophthalmological evaluation of both affected individuals in the family revealed a decreased axial length (18-19 mm), retinal dystrophy, macular edema, and hyperopia of >+8.0 diopters. Sequencing of MFRP did not reveal any pathogenic changes, and microsatellite marker analysis showed that the chromosomal region did not segregate within the disease in this family. Genome-wide homozygosity mapping using single nucleotide polymorphism microarrays revealed a 28-Mb homozygous region encompassing the CRB1 gene, and direct sequencing disclosed a novel homozygous missense mutation (p.Gly833Asp) in CRB1.
Previous studies associated mutations in the MFRP gene with the syndrome nanophthalmos-retinitis pigmentosa-foveoschisis-optic disc drusen. In this study, we demonstrated that a similar disease complex can be caused by mutations in the CRB1 gene.
本研究旨在确定一个患有常染色体隐性遗传性视网膜色素变性、小眼球和视盘玻璃膜疣的土耳其家族的基因缺陷。
眼科检查包括测量最佳矫正视力和屈光不正、视网膜电图、光学相干断层扫描、B型超声检查和眼底摄影。通过对膜卷曲相关蛋白（MFRP）基因编码外显子进行直接DNA测序以及使用微卫星标记进行连锁分析，研究该家族中MFRP基因的情况。在排除MFRP基因后，使用250K单核苷酸多态性（SNP）微阵列进行全基因组纯合性定位。通过直接测序对crumbs同源物1（CRB1）基因进行突变分析。
对该家族中两名患病个体的眼科评估显示眼轴长度缩短（18 - 19毫米）、视网膜营养不良、黄斑水肿和大于+8.0屈光度的远视。MFRP基因测序未发现任何致病变化，微卫星标记分析表明该家族中该染色体区域在疾病中未发生分离。使用单核苷酸多态性微阵列进行的全基因组纯合性定位显示一个包含CRB1基因的28兆碱基纯合区域，直接测序揭示CRB1基因中存在一个新的纯合错义突变（p.Gly833Asp）。
先前的研究将MFRP基因突变与小眼球 - 视网膜色素变性 - 黄斑劈裂 - 视盘玻璃膜疣综合征相关联。在本研究中，我们证明类似的疾病复合体可由CRB1基因突变引起。
