A mutation in the receptor binding site of GDF5 causes Mohr-Wriedt brachydactyly type A2
A mutation in the receptor binding site of GDF5 causes Mohr-Wriedt brachydactyly type A2
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DOI：
10.1136/jmg.2005.034058
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发表时间：
2006-03-01
影响因子：
4
通讯作者：
Mundlos, S
中科院分区：
文献类型：
--
作者：
Kjaer, KW;Eiberg, H;Mundlos, S
背景资料：短指（趾）畸形A2型（OMIM 112600）的特征是食指第二中节指骨发育不全/发育不全，有时是小指。BDA 2首先描述了莫尔和Wriedt在一个大的丹麦/挪威的亲属和突变BMPR 1B最近表现出在两个受影响的family.Methods：我们发现和审查莫尔和Wriedt的原始未发表的注释，更新的家庭系谱，并检查了37个家庭成员的临床和放射学构建的掌指骨轮廓（MCPP）模式在9个受影响的主题。分子分析包括BMPR 1B的测序、GDF 5侧翼STS标记的连锁分析、GDF 5的测序、通过限制性内切酶测定确认突变、以及从最近报道的GDF 5晶体结构推断的突变的定位，以及通过将GDF 5蛋白序列叠加到与Bmpr 1a结合的BMP 2的晶体结构上。所有受影响的人都发现食指中节指骨较短，但偶尔也累及其他手指。第四个手指是典型的幸免于难。这将Mohr-Wriedt型BDA 2与由BMPR 1B突变引起的BDA 2区分开来。MCPP分析最有效地检测突变携带者状态。我们发现了一个错义突变，c。1322 T>C，导致GDF 5的活性信号传导结构域内氨基酸残基441处的亮氨酸被脯氨酸取代。结论：GDF 5是一个新的BDA 2致病基因。这表明BMPR 1B的活性受损是负责BDA 2表型的分子机制。
Background: Brachydactyly type A2 (OMIM 112600) is characterised by hypoplasia/ aplasia of the second middle phalanx of the index finger and sometimes the little finger. BDA2 was first described by Mohr and Wriedt in a large Danish/Norwegian kindred and mutations in BMPR1B were recently demonstrated in two affected families.Methods: We found and reviewed Mohr and Wriedt's original unpublished annotations, updated the family pedigree, and examined 37 family members clinically, and radiologically by constructing the metacarpo-phalangeal profile (MCPP) pattern in nine affected subjects. Molecular analyses included sequencing of BMPR1B, linkage analysis for STS markers flanking GDF5, sequencing of GDF5, confirmation of the mutation by a restriction enzyme assay, and localisation of the mutation inferred from the very recently reported GDF5 crystal structure, and by superimposing the GDF5 protein sequence onto the crystal structure of BMP2 bound to Bmpr1a.Results: A short middle phalanx of the index finger was found in all affected individuals, but other fingers were occasionally involved. The fourth finger was characteristically spared. This distinguishes Mohr-Wriedt type BDA2 from BDA2 caused by mutations in BMPR1B. An MCPP analysis most efficiently detected mutation carrier status. We identified a missense mutation, c. 1322T>C, causing substitution of a leucine with a proline at amino acid residue 441 within the active signalling domain of GDF5. The mutation was predicted to reside in the binding site for BMP type 1 receptors.Conclusion: GDF5 is a novel BDA2 causing gene. It is suggested that impaired activity of BMPR1B is the molecular mechanism responsible for the BDA2 phenotype.