BMPR1A 纯合错义变异导致 BMPR 信号中断和综合征特征。
Homozygous missense variant in BMPR1A resulting in BMPR signaling disruption and syndromic features.
机构信息
Division of Human Genetics, Cincinnati Children's Hospital and University of Cincinnati College of Medicine Department of Pediatrics, Cincinnati, OH, USA.
Department of Molecular, Cell & Developmental Biology, UCLA, Los Angeles, CA, USA.
出版信息
Mol Genet Genomic Med. 2019 Nov;7(11):e969. doi: 10.1002/mgg3.969. Epub 2019 Sep 7.
BACKGROUND
The bone morphogenetic protein (BMP) pathway is known to play an imperative role in bone, cartilage, and cardiac tissue formation. Truncating, heterozygous variants, and deletions of one of the essential receptors in this pathway, Bone Morphogenetic Protein Receptor Type1A (BMPR1A), have been associated with autosomal dominant juvenile polyposis. Heterozygous deletions have also been associated with cardiac and minor skeletal anomalies. Populations with atrioventricular septal defects are enriched for rare missense BMPR1A variants.
METHODS
We report on a patient with a homozygous missense variant in BMPR1A causing skeletal abnormalities, growth failure a large atrial septal defect, severe subglottic stenosis, laryngomalacia, facial dysmorphisms, and developmental delays.
RESULTS
Functional analysis of this variant shows increased chondrocyte death for cells with the mutated receptor, increased phosphorylated R-Smads1/5/8, and loss of Sox9 expression mediated by decreased phosphorylation of p38.
CONCLUSION
This homozygous missense variant in BMPR1A appears to cause a distinct clinical phenotype.
背景
骨形态发生蛋白（BMP）途径在骨骼、软骨和心脏组织形成中起着至关重要的作用。该途径的一个必需受体——骨形态发生蛋白受体 1A（BMPR1A）的截断、杂合变体和缺失与常染色体显性遗传的青少年型息肉病有关。杂合缺失也与心脏和小骨骼异常有关。存在房间隔缺损的人群中富含罕见的错义 BMPR1A 变体。
方法
我们报告了一名患者，其 BMPR1A 存在纯合错义变异，导致骨骼异常、生长发育迟缓、巨大房间隔缺损、严重的声门下狭窄、喉软骨软化、面部畸形和发育迟缓。
结果
该变异的功能分析显示，突变受体的软骨细胞死亡增加，磷酸化的 R-Smads1/5/8 增加，Sox9 表达减少，这是由 p38 磷酸化减少介导的。
结论
BMPR1A 中的这种纯合错义变异似乎导致了一种独特的临床表型。
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