Stange Katja, Désir Julie, Kakar Naseebullah, Mueller Thomas D, Budde Birgit S, Gordon Christopher T, Horn Denise, Seemann Petra, Borck Guntram
Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353, Berlin, Germany.
Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany.
Orphanet J Rare Dis. 2015 Jun 24;10:84. doi: 10.1186/s13023-015-0299-5.
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.
Grebe发育不全、Hunter-Thompson发育不全和du Pan发育不全构成了一系列骨骼发育不全，其遗传方式为常染色体隐性遗传，特征为身材矮小、四肢严重肢端中间段缩短以及中轴骨骼正常。这些疾病的大多数患者存在生长分化因子5（GDF5）的双等位基因功能丧失突变。在个别病例中，Grebe发育不全以及伴有生殖器异常的Grebe发育不全样表型已被证明是由骨形态发生蛋白受体1B（BMPR1B）（一种GDF5受体）的突变引起的。
我们对一名近亲结婚父母所生成年女性的肢端中间段软骨发育不全进行了临床和放射学特征分析。我们对先证者的DNA进行了GDF5和BMPR1B测序。我们进行了三维结构分析和荧光素酶报告基因检测，以从功能上研究鉴定出的BMPR1B突变。
我们通过证明较轻的du Pan发育不全可能由BMPR1B的亚效突变引起，扩展了肢端中间段软骨发育不全的基因型-表型相关性。我们表明，导致du Pan发育不全的纯合c.91C>T，p.(Arg31Cys)突变会导致BMPR1B功能显著丧失，但程度小于先前报道的导致更严重Grebe发育不全的p.Cys53Arg突变。
骨骼疾病中临床和放射学相关的肢端中间段软骨发育不全谱系的表型严重程度梯度可能归因于配体-受体对GDF5-BMPR1B功能受损的程度。
