Idiopathic hyperphosphatasia and TNFRSF11B mutations:: Relationships between phenotype and genotype
Idiopathic hyperphosphatasia and TNFRSF11B mutations:: Relationships between phenotype and genotype
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DOI：
10.1359/jbmr.2003.18.12.2095
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发表时间：
2003-12-01
影响因子：
6.2
通讯作者：
Cundy, T
中科院分区：
文献类型：
--
作者：
Chong, B;Hegde, M;Cundy, T
简介：特发性高磷酸酶症（IH）是一种罕见的高骨转换先天性骨病，受影响的儿童出生时正常，但发展为进行性长骨畸形、骨折、椎体塌陷、颅骨增大和耳聋。然而，从婴儿期表现为严重进行性畸形到儿童晚期表现为轻微畸形，存在相当大的表型变异。最近的两份报告已链接特发性高磷酸酶症的缺失，或突变，TNFRSF 11B基因编码的骨保护素（OPG），一个重要的旁分泌调节RANKL介导的骨resorption.Materials和方法：我们研究了主题的临床诊断IH和未受影响的家庭成员从9个不相关的家庭。收集临床、生化和放射学数据，并检查基因组DNA中TNFRSF 11B的突变。突变之间的关系，他们对OPG功能的预测影响，和表型examined.Results：的9个家庭研究，受影响的受试者从6个纯合子的新突变TNFRSF 11B。其双亲均为杂合子，符合常染色体隐性遗传。6个突变中有4个发生在富含半胱氨酸的配体结合结构域，预计会破坏OPG与RANKL的结合。半胱氨酸残基中的错义突变，预测会导致配体结合区的重大破坏，与严重表型（18个月龄前发生畸形和严重残疾）相关，因为是一个大的缺失突变。配体结合域中的非半胱氨酸错义突变与中间表型相关（5岁左右发现畸形，长骨骨折率增加）。TNFRSF 11B基因的C端插入/缺失突变与最轻的表型相关。结论：TNFRSF 11B基因突变是IH的主要基因型，但不是全部，且存在明显的基因型-表型关系。
Introduction: Idiopathic hyperphosphatasia (IH) is a rare high bone turnover congenital bone disease in which affected children are normal at birth but develop progressive long bone deformities, fractures, vertebral collapse, skull enlargement, and deafness. There is, however, considerable phenotypic variation from presentation in infancy with severe progressive deformity through to presentation in late childhood with minimal deformity. Two recent reports have linked idiopathic hyperphosphatasia with deletion of, or mutation in, the TNFRSF11B gene that encodes osteoprotegerin (OPG), an important paracrine modulator of RANKL-mediated bone resorption.Materials and Methods: We studied subjects with a clinical diagnosis of IH and unaffected family members from nine unrelated families. Clinical, biochemical, and radiographic data were collected, and genomic DNA examined for mutations in TNFRSF11B. The relationship between the mutations, their predicted effects on OPG function, and the phenotype were then examined.Results: Of the nine families studied, affected subjects from six were homozygous for novel mutations in TNFRSF11B. Their parents were heterozygous, consistent with autosomal recessive inheritance. Four of the six mutations occurred in the cysteine-rich ligand-binding domain and are predicted to disrupt binding of OPG to RANKL. Missense mutations in the cysteine residues, predicted to cause major disruption to the ligand-binding region, were associated with a severe phenotype (deformity developing before 18 months age and severe disability), as was a large deletion mutation. Non-cysteine missense mutations in the ligand-binding domain were associated with an intermediate phenotype (deformity recognized around the age of 5 years and an increased rate of long bone fracture). An insertion/deletion mutation at the C-terminal end of the protein was associated with the mildest phenotype.Conclusion: Mutations in TNFRSF11B account for the majority of, but not all, cases of IH, and there are distinct genotype-phenotype relationships.