Mamatha Gandra, Umashankar Vetrivel, Kasinathan Nachiappan, Krishnan Tandava, Sathyabaarathi Ravichandran, Karthiyayini Thirumalai, Amali John, Rao Chetan, Madhavan Jagadeesan
SN ONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Sankara Nethralaya, Chennai, India.
Mol Vis. 2011;17:1970-7. Epub 2011 Jul 20.
Bietti crystalline dystrophy (BCD) is an autosomal recessive disease characterized by intraretinal deposits of multiple small crystals, with or without associated crystal deposits in the cornea. The disease is caused by mutation in the cytochrome p450, family 4, subfamily v, polypeptide 2 (CYP4V2) gene. Choroidal neovascularization (CNV) is a rare event in BCD. We report two cases of BCD associated with CNV. CYP4V2 and exon 5 of tissue inhibitor of metalloproteinase 3 (TIMP3) were screened in both cases. A patient with BCD, but without CNV, was also screened to identify pathogenic variations.
Three BCD families of Asian Indian origin were recruited after a comprehensive ophthalmic examination. Genomic DNA was isolated from blood leukocytes, and coding exons and flanking introns of CYP4V2 and exon 5 of TIMP3 were amplified via polymerase chain reaction (PCR) and were sequenced. Family segregation, control screening, and bioinformatics tools were used to assess the pathogenicity of the novel variations.
Of the three BCD patients, two had parafoveal CNV. The patient with BCD, but without CNV had novel single base-pair duplication (c.1062_1063dupA). This mutation results in a structurally defective and unstable protein with impaired protein function. Four novel benign variations (three in exons and one in an intron) were observed in the cohort. Screening of exon 5 of TIMP3 did not reveal any variation in these families.
A novel mutation was found in a patient with BCD but without CNV, while patients with BCD and CNV did not show any pathogenic variation. The modifier role of TIMP3 in the pathogenesis of CNV in BCD was partly ruled out, as no variation was observed in exon 5 of the gene. A larger BCD cohort with CNV needs to be studied and screened to understand the genetics of CNV in BCD.
比埃蒂结晶状营养不良（BCD）是一种常染色体隐性疾病，其特征为视网膜内有多个小晶体沉积，角膜可有或无相关晶体沉积。该疾病由细胞色素P450 4家族V亚族多肽2（CYP4V2）基因突变引起。脉络膜新生血管形成（CNV）在BCD中是一种罕见情况。我们报告两例与CNV相关的BCD病例。对这两例病例进行了CYP4V2和金属蛋白酶组织抑制剂3（TIMP3）第5外显子的筛查。还对一名患有BCD但无CNV的患者进行了筛查以确定致病变异。
对三个亚洲印度裔的BCD家族进行全面眼科检查后招募入组。从血液白细胞中分离基因组DNA，通过聚合酶链反应（PCR）扩增CYP4V2的编码外显子和侧翼内含子以及TIMP3的第5外显子并进行测序。采用家系分离分析、对照筛查和生物信息学工具评估新变异的致病性。
三名BCD患者中，两名有黄斑旁CNV。患有BCD但无CNV的患者有新的单碱基对重复（c.1062_1063dupA）。该突变导致蛋白质结构缺陷且不稳定，功能受损。在该队列中观察到四个新的良性变异（三个在外显子中，一个在内含子中）。TIMP3第5外显子的筛查在这些家族中未发现任何变异。
在一名患有BCD但无CNV的患者中发现了一个新突变，而患有BCD和CNV的患者未显示任何致病变异。由于在该基因的第5外显子中未观察到变异，部分排除了TIMP3在BCD中CNV发病机制中的修饰作用。需要对更大的伴有CNV的BCD队列进行研究和筛查，以了解BCD中CNV的遗传学情况。
