Clinical and molecular findings in osteoporosis-pseudoglioma syndrome
Clinical and molecular findings in osteoporosis-pseudoglioma syndrome
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DOI：
10.1086/497706
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发表时间：
2005-11-01
影响因子：
9.8
通讯作者：
Schelling, DK
中科院分区：
文献类型：
--
作者：
Ai, MR;Heeger, S;Schelling, DK
低密度脂蛋白受体相关蛋白5基因（LRP 5）突变可引起常染色体隐性遗传性神经胶质瘤综合征（OPPG）。我们对37例疑有OPPG的先证者的LRP 5编码外显子进行测序，这些先证者的基础是严重的先天性或儿童期发作的视力障碍与骨脆性或骨质疏松症的共同发生。我们在26名先证者中发现了两个假定的突变等位基因，4名先证者中仅发现了一个突变等位基因，7名先证者中未发现突变等位基因。为了寻找双基因遗传，我们在4个有一个突变等位基因的先证者中对编码功能相关受体LRP 6、LRP 5辅助受体FZD 4和LRP 5配体NDP的基因进行了测序，为了寻找基因座异质性，我们在7个没有突变的先证者中对FZD 4和NDP进行了测序，但我们没有发现额外的突变。当我们比较有和没有LRP 5突变的先证者之间的临床特征时，我们发现骨骼疾病的严重程度、认知障碍的患病率或家族血缘史没有差异。然而，7个没有检测到突变的先证者中有4个的眼部病理与先前描述的OPPG病理不同。由于许多LRP5突变是错义变化，为了区分致病突变和良性变体，我们测量了野生型和突变型LRP5离体抑制Wnt和Norrin信号的能力。与野生型突变相比，测试的七种OPPG突变中的每一种都具有减少的信号转导。这些结果表明，早期双侧玻璃体视网膜眼部病理学加上骨骼脆性是LRP 5突变的强有力预测因素，并且LRP 5突变通过损害Wnt和Norrin信号传导导致OPPG。
Mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) cause autosomal recessive osteoporosis-pseudoglioma syndrome (OPPG). We sequenced the coding exons of LRP5 in 37 probands suspected of having OPPG on the basis of the co-occurrence of severe congenital or childhood-onset visual impairment with bone fragility or osteoporosis recognized by young adulthood. We found two putative mutant alleles in 26 probands, only one mutant allele in 4 probands, and no mutant alleles in 7 probands. Looking for digenic inheritance, we sequenced the genes encoding the functionally related receptor LRP6, an LRP5 coreceptor FZD4, and an LRP5 ligand, NDP, in the four probands with one mutant allele, and, looking for locus heterogeneity, we sequenced FZD4 and NDP in the seven probands with no mutations, but we found no additional mutations. When we compared clinical features between probands with and without LRP5 mutations, we found no difference in the severity of skeletal disease, prevalence of cognitive impairment, or family history of consanguinity. However, four of the seven probands without detectable mutations had eye pathology that differed from pathology previously described for OPPG. Since many LRP5 mutations are missense changes, to differentiate between a disease-causing mutation and a benign variant, we measured the ability of wild-type and mutant LRP5 to transduce Wnt and Norrin signal ex vivo. Each of the seven OPPG mutations tested, had reduced signal transduction compared with wild-type mutations. These results indicate that early bilateral vitreoretinal eye pathology coupled with skeletal fragility is a strong predictor of LRP5 mutation and that mutations in LRP5 cause OPPG by impairing Wnt and Norrin signal transduction.