A polyadenylation site variant causes transcript-specific BMP1 deficiency and frequent fractures in children
A polyadenylation site variant causes transcript-specific BMP1 deficiency and frequent fractures in children
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DOI：
10.1093/hmg/ddu471
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发表时间：
2015-01-15
影响因子：
3.5
通讯作者：
Rauch, Frank
中科院分区：
文献类型：
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作者：
Fahiminiya, Somayyeh;Al-Jallad, Hadil;Rauch, Frank
我们以前曾发表过儿童骨脆性疾病的临床特征，其特征主要是下肢骨折和骨组织矿化缺陷，但不是生长板水平。我们现在已经对四个具有这种表型的无关个体进行了全外显子组测序。三个个体对于BMP 1中的核苷酸变化是纯合的，影响编码BMP 1的短同种型（BMP 1 -1）的转录物的多腺苷酸化信号（c.* 241T>C）。在这些个体的皮肤成纤维细胞中，我们发现低水平的BMP 1 -1转录物和蛋白质。第四个个体是c的复合杂合子。241 T>C变体和BMP 1外显子15中的变体（c.2107G>C），其影响BMP 1 -1和BMP 1的长同种型（BMP 1 -3）中的剪接。纯合3 'UTR变体和复合杂合变体均与受损的I型前胶原C-前肽裂解相关，因为皮肤成纤维细胞上清液中游离C-前肽的量少于对照。外周定量计算机断层扫描显示，所有个体的体积皮质骨密度升高。通过组织形态计量学和定量背散射电子成像评估髂骨样本表明，骨形成部位的矿化开始延迟，但矿化基质过度矿化。这些结果表明，BMP 1 -1的孤立缺乏导致儿童骨脆性。
We had previously published the clinical characteristics of a bone fragility disorder in children that was characterized mainly by lower extremity fractures and a mineralization defect in bone tissue but not on the growth plate level. We have now performed whole-exome sequencing on four unrelated individuals with this phenotype. Three individuals were homozygous for a nucleotide change in BMP1, affecting the polyadenylation signal of the transcript that codes for the short isoform of BMP1 (BMP1-1) (c.*241T>C). In skin fibroblasts of these individuals, we found low levels of BMP1-1 transcript and protein. The fourth individual was compound heterozygous for the c.*241T>C variant in BMP1-1 and a variant in BMP1 exon 15 (c.2107G>C) that affected splicing in both BMP1-1 and the long isoform of BMP1(BMP1-3). Both the homozygous 3'UTR variant and the compound heterozygous variants were associated with impaired procollagen type I C-propeptide cleavage, as the amount of free C-propeptide in the supernatant of skin fibroblasts was less than in controls. Peripheral quantitative computed tomography showed that all individuals had elevated volumetric cortical bone mineral density. Assessment of iliac bone samples by histomorphometry and quantitative backscattered electron imaging indicated that the onset of mineralization at bone formation sites was delayed, but that mineralized matrix was hypermineralized. These results show that isolated lack of BMP1-1 causes bone fragility in children.