Astiazarán Mirena C, Cervantes-Sodi María, Rebolledo-Enríquez Erick, Chacón-Camacho Oscar, Villegas Vanessa, Zenteno Juan Carlos
1 Research Unit, Genetics Department, Institute of Ophthalmology , "Conde de Valenciana," Mexico City, Mexico .
2 Departamento Clínico de Genética Médica, Hospital de Pediatría , Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico .
Genet Test Mol Biomarkers. 2017 Dec;21(12):742-746. doi: 10.1089/gtmb.2017.0118. Epub 2017 Nov 13.
Osteoporosis-pseudoglioma syndrome (OPPG) is an uncommon autosomal recessive disorder characterized by the rare association of early-onset osteoporosis and severe ocular abnormalities such as persistent fetal vasculature and microphthalmia. Biallelic mutations in the low-density lipoprotein receptor-related protein-5 gene (LRP5) have been associated with OPPG. We present clinical and genetic data from three Mexican OPPG patients, a pair of sibs, and a sporadic case.
Three patients underwent clinical examination, including a complete ophthalmic evaluation. Based on the clinical diagnosis of OPPG, the entire coding sequence of LRP5 was polymerase chain reaction-amplified and directly Sanger-sequenced. Genetic testing was extended to the parents of the affected patients.
Phenotypic variability was observed in the familial case and molecular analysis identified a novel homozygous c.1145C>T, p.(Pro382Leu) variant in both sibs. As expected, their parents were heterozygous carriers. The sporadic patient exhibited a severe osseous phenotype, microphthalmia, and neurological symptoms. In this patient, homozygosity for the c.442C>T, p.(Gln148*) variant was demonstrated, whereas her parents were heterozygous carriers. The p.(Pro382Leu) pathogenic mutation has been previously reported only in a compound heterozygous state in OPPG patients.
Two novel homozygous missense and nonsense variants were demonstrated in three OPPG cases from Mexico. Our results expand the spectrum of disease-causing LRP5 mutations. This is the first report of OPPG in our population and our findings may potentially add to a genotype-phenotype correlation.
骨质疏松-假性胶质瘤综合征（OPPG）是一种罕见的常染色体隐性疾病，其特征是早发性骨质疏松与严重眼部异常（如永存原始玻璃体增生症和小眼症）罕见关联。低密度脂蛋白受体相关蛋白5基因（LRP5）的双等位基因突变与OPPG相关。我们展示了来自三名墨西哥OPPG患者（一对同胞和一名散发病例）的临床和遗传数据。
三名患者接受了临床检查，包括全面的眼科评估。基于OPPG的临床诊断，对LRP5的整个编码序列进行聚合酶链反应扩增并直接进行桑格测序。基因检测扩展至受影响患者的父母。
在家族性病例中观察到表型变异性，分子分析在两名同胞中均鉴定出一种新的纯合c.1145C>T，p.（Pro382Leu）变异。正如预期的那样，他们的父母是杂合携带者。散发患者表现出严重的骨表型、小眼症和神经症状。在该患者中，证实了c.442C>T，p.（Gln148*）变异的纯合性，而她的父母是杂合携带者。p.（Pro382Leu）致病突变此前仅在OPPG患者的复合杂合状态中被报道过。
在来自墨西哥的三例OPPG病例中证实了两种新的纯合错义突变和无义突变。我们的结果扩展了导致疾病的LRP5突变谱。这是我们人群中OPPG的首次报告，我们的发现可能有助于建立基因型-表型相关性。
