Overexpression of the C-type natriuretlic peptide (CNP) is associated with overgrowth and bone anomalies in an individual with balanced t(2;7) translocation
Overexpression of the C-type natriuretlic peptide (CNP) is associated with overgrowth and bone anomalies in an individual with balanced t(2;7) translocation
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DOI：
10.1002/humu.20511
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发表时间：
2007-07-01
期刊：
影响因子：
3.9
通讯作者：
Gimellio, Giorgio
中科院分区：
文献类型：
--
作者：
Bocciardi, Renata;Giorda, Roberto;Gimellio, Giorgio
纵向骨生长是由软骨生长板中的软骨内骨化过程决定的，软骨生长板位于椎骨和长骨的两端，涉及许多全身激素和局部调节剂。我们报告一个从头平衡t（2;7）（q37.1;q21.3）易位的分子特征与马凡体型和骨骼异常的年轻女性。易位的特点是荧光原位杂交（FISH），检查其他异常的阵列比较基因组杂交（CGH），最后，断点进行克隆，测序，并比较。采用生化剂量法研究了引起先证者表型改变的可能机制。2号染色体上的断裂点破坏了假设的基因MGC 42174（HUGO批准的符号DIS 3L 2），并位于编码C型利钠肽（CNP）的NPPC基因附近，CNP是一种调节软骨内骨生长的分子。与5名正常对照相比，先证者的CNP血浆浓度加倍，而NPPC在其成纤维细胞中显著过表达。一种针对骨中NPPC过表达的转基因小鼠显示出与患者表型高度相似的表型。7号染色体上的断裂点位于距COL 1A 2基因约75 kb处。衍生染色体上的COL 1A 2等位基因在成纤维细胞中强烈表达不足，但总胶原与对照组无显著差异。多项证据支持先证者的异常表型与C型利钠肽过度表达相关的结论。
Longitudinal bone growth is determined by the process of endochondral ossification in the cartilaginous growth plate, which is located at both ends of vertebrae and long bones and involves many systemic hormones and local regulators. We report the molecular characterization of a de novo balanced t(2;7) (q37.1;q21.3) translocation in a young female with Marfanoid habitus and skeletal anomalies. The translocation was characterized by fluorescence in situ hybridization (FISH), checked for other abnormalities by array-comparative genomic hybridization (CGH), and finally, the breakpoints were cloned, sequenced, and compared. Biochemical dosage was applied to study the possible mechanisms that may cause the proposita's phenotype. The breakpoint on chromosome 2 disrupts the hypothetical gene MGC42174 (HUGO-approved symbol DIS3L2) and is located in the proximity of the NPPC gene coding for C-type natriuretic peptide (CNP), a molecule that regulates endochondral bone growth. CNP plasma concentration was doubled in the proband compared to five normal controls, while NPPC was substantially overexpressed in her fibroblasts. A transgenic mouse generated to target NPPC overexpression in bone showed a phenotype highly reminiscent of the patient's phenotype. The breakpoint on chromosome 7 is localized proximally at about 75 kb from the COL1A2 gene. The COL1A2 allele on the derivative chromosome was strongly underexpressed in fibroblasts, but total collagen was not significantly different from controls. Several evidences support the conclusion that the proband's abnormal phenotype is associated with C-type natriuretic peptide overexpression.