Cheung W M W, Jin L Y, Smith D K, Cheung P T, Kwan E Y W, Low L, Kung A W C
Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
Bone. 2006 Sep;39(3):470-6. doi: 10.1016/j.bone.2006.02.069. Epub 2006 May 6.
Osteoporosis pseudoglioma syndrome (OPPG) is an autosomal recessive disorder due to mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene. Here, we report two novel missense mutations found in a southern Chinese family of a non-consanguineous marriage. Three out of four children had blindness, low bone mineral density (BMD) and multiple fractures in their childhood. Genotyping by DNA sequencing demonstrated 2 new mutations in exon 7 of the LRP5 gene. Tryptophans at amino acid residue positions 478 and 504 were replaced by arginine (W478R) and cysteine (W504C), respectively. While the parents that possessed either heterozygous W478R or W504C were apparently normal, all affected subjects were compound heterozygotes for the W478R and W504C mutations in the LRP5 gene. W478R is located immediately C-terminal to the third YWTD repeat of the second YWTD/EGF domain in LRP5, while W504C is located between the third and the fourth YWTD repeats of the second YWTD/EGF domain in LRP5. Using LRP5-related proteins, such as the low-density lipoprotein receptor (LDLR) and nidogen as reference models, a homology model of LRP5 suggested that the observed mutations may affect the molecular interactions of LRP5 and so lead to the observed OPPG phenotypes.
骨质疏松-假性胶质瘤综合征（OPPG）是一种常染色体隐性疾病，由低密度脂蛋白受体相关蛋白5（LRP5）基因突变引起。在此，我们报告在中国南方一个非近亲结婚的家庭中发现的两个新的错义突变。四个孩子中有三个在童年时出现失明、低骨密度（BMD）和多处骨折。通过DNA测序进行基因分型显示LRP5基因第7外显子有2个新突变。氨基酸残基位置478和504处的色氨酸分别被精氨酸（W478R）和半胱氨酸（W504C）取代。虽然携带杂合子W478R或W504C的父母明显正常，但所有受影响的受试者都是LRP5基因中W478R和W504C突变的复合杂合子。W478R位于LRP5第二个YWTD/EGF结构域第三个YWTD重复序列的紧邻C末端，而W504C位于LRP5第二个YWTD/EGF结构域第三个和第四个YWTD重复序列之间。以LRP5相关蛋白，如低密度脂蛋白受体（LDLR）和巢蛋白为参考模型，LRP5的同源模型表明观察到的突变可能影响LRP5的分子相互作用，从而导致观察到的OPPG表型。
