A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
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型BMPR1B突变会引起丙烯酸骨膜异常发育不良。
DOI：
10.1186/s13023-015-0299-5
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发表时间：
2015-06-24
影响因子：
3.7
通讯作者：
Borck G
中科院分区：
文献类型：
--
作者：
Stange K;Désir J;Kakar N;Mueller TD;Budde BS;Gordon CT;Horn D;Seemann P;Borck G
Grebe发育不良、Hunter-Thompson发育不良和du Pan发育不良构成了一系列骨骼发育不良，这些骨骼发育不良作为常染色体隐性遗传性状遗传，其特征为身材矮小、四肢严重的肢端中肢缩短和正常的中轴骨骼。大多数患有这些疾病的患者具有GDF 5的双等位基因功能丧失突变。在单一情况下，Grebe发育不良和具有生殖器异常的Grebe发育不良样表型已被证明是由编码GDF 5受体的BMPR 1B突变引起的。我们的临床和放射学特征的肢端中肢软骨发育不良的成年女性所生的近亲的父母。我们对先证者DNA上的GDF 5和BMPR 1B进行了测序。我们进行了三维结构分析和荧光素酶报告基因检测，以功能研究所确定的BMPR 1B突变。我们扩展了基因型-表型相关的肢端中肢软骨发育不良，表明轻度杜潘发育不良可以引起的亚型BMPR 1B突变。我们发现纯合子c.91C>T，p.（Arg 31 Cys）突变引起杜潘发育不良导致BMPR 1B功能的显著丧失，但程度低于先前报道的导致更严重的发育不良的p.Cys53Arg突变。骨骼疾病的临床和放射学相关的肢端中肢软骨发育不良谱的表型严重度梯度可能是由于配体-受体对GDF 5-BMPR 1B的功能受损程度。
Grebe dysplasia, Hunter-Thompson dysplasia, and du Pan dysplasia constitute a spectrum of skeletal dysplasias inherited as an autosomal recessive trait characterized by short stature, severe acromesomelic shortening of the limbs, and normal axial skeleton. The majority of patients with these disorders have biallelic loss-of-function mutations of GDF5. In single instances, Grebe dysplasia and a Grebe dysplasia-like phenotype with genital anomalies have been shown to be caused by mutations in BMPR1B, encoding a GDF5 receptor. We clinically and radiologically characterised an acromesomelic chondrodysplasia in an adult woman born to consanguineous parents. We sequenced GDF5 and BMPR1B on DNA of the proposita. We performed 3D structural analysis and luciferase reporter assays to functionally investigate the identified BMPR1B mutation. We extend the genotype-phenotype correlation in the acromesomelic chondrodysplasias by showing that the milder du Pan dysplasia can be caused by a hypomorphic BMPR1B mutation. We show that the homozygous c.91C>T, p.(Arg31Cys) mutation causing du Pan dysplasia leads to a significant loss of BMPR1B function, but to a lesser extent than the previously reported p.Cys53Arg mutation that results in the more severe Grebe dysplasia. The phenotypic severity gradient of the clinically and radiologically related acromesomelic chondrodysplasia spectrum of skeletal disorders may be due to the extent of functional impairment of the ligand-receptor pair GDF5-BMPR1B.
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