Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Sci Rep. 2017 Nov 14;7(1):15585. doi: 10.1038/s41598-017-15442-1.
The skeletal ciliopathies are a heterogeneous group of disorders with a significant clinical and genetic variability and the main clinical features are thoracic hypoplasia and short tubular bones. To date, 25 genes have been identified in association with skeletal ciliopathies. Mutations in the KIAA0753 gene have recently been associated with Joubert syndrome (JBTS) and orofaciodigital (OFD) syndrome. We report biallelic pathogenic variants in KIAA0753 in four patients with short-rib type skeletal dysplasia. The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses. We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by our findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning.
骨骼纤毛病是一组具有显著临床和遗传变异性的异质性疾病，其主要临床特征为胸壁发育不全和管状骨短缩。迄今为止，已有 25 个基因与骨骼纤毛病相关。KIAA0753 基因突变与 Joubert 综合征（JBTS）和口面指（趾）骨发育不良（OFD）综合征有关。我们报道了 4 例短肋型骨骼发育不良患者的 KIAA0753 基因双等位致病性变异。我们患者的表现各不相同，从胎儿致死到存活和中度骨骼发育不良伴胸廓狭窄和异常干骺端。我们证明 KIAA0753 在正常胎儿生长板中表达，并表明受影响的胎儿存在 KIAA0753 的复合杂合移码和无义突变，其有异常的增殖区和宽阔的肥大区。我们发现斑马鱼胚胎中 kiaa0753 的无义突变纯合子显示出软骨模式的改变，进一步证实了 KIAA0753 对正常骨骼发育的重要性。
