■Aarskog-Scott综合征,一种罕见的X连锁遗传疾病,通过结合身材矮小的临床表现来识别,面部,骨骼,和生殖器异常。每年,两三个新病例被诊断为Aarskog-Scott综合征,与FGD1变体相关。然而,由于Aarskog-Scott综合征的机制不明确,目前尚无特异性治疗方法。
■临床数据是在患者首次就诊时收集的。针对疾病的遗传原因进行了三体全外显子组测序和Sanger测序。为了在体外评估变体的致病性,在143B细胞中使用慢病毒感染构建稳定的细胞系。此外,Westernblot用于验证信号通路相关蛋白的表达,并通过荧光素酶报告基因检测验证成骨相关基因的转录水平。
■一名7岁男孩表现为面部异常,智力残疾,身材矮小(-3.98SDS),而刺激试验的生长激素水平正常。Trio全外显子组测序和Sanger测序确定了一个变异体(c.1270A>G,p.Asn424Asp)在FGD1基因中。Asn424残基高度保守,FGD1变异蛋白中的氢键发生了变化,这导致与CDC42蛋白相互作用的减少。体外研究表明Asn424Asp变异体显著降低OCN的转录水平,COL1A1和ALP活性,它激活了JNK1的磷酸化。
■FGD1异常表达与Aarskog-Scott综合征之间的分子生物学机制仍知之甚少。在我们的研究中,c.1270A>FGD1的G变体导致Aarskog-Scott综合征,致病性分析支持该变体的有害作用。此外,我们证明了突变体FGD1和CDC42的亲和力减弱。在这项工作中还显示了成骨相关基因的表达降低和JNK1的异常激活。
UNASSIGNED: Aarskog-Scott syndrome, a rare X-linked genetic disorder, is identified by combined clinical manifestations of short stature, facial, skeletal, and genital anomalies. Annually, two or three new cases are diagnosed with Aarskog-Scott syndrome, which is associated with FGD1 variants. However, there is no specific treatment for Aarskog-Scott syndrome due to its unclear mechanism.
UNASSIGNED: Clinical data were collected when the patient first visited the hospital. Trio whole-exome sequencing and Sanger sequencing were performed for the genetic cause of disease. To evaluate the pathogenicity of the variants in vitro, stable cell lines were constructed using lentivirus infection in 143B cell. Furthermore, Western blot was used to verify the expression of signaling pathway-related proteins, and the transcription levels of osteogenic-related genes were verified by luciferase reporter gene assay.
UNASSIGNED: A 7-year-old boy was manifested with facial abnormalities, intellectual disability, and short stature (-3.98 SDS) while the growth hormone level of stimulation test was normal. Trio whole-exome sequencing and Sanger sequencing identified a variant (c.1270A>G, p.Asn424Asp) in FGD1 gene. The Asn424 residue was highly conserved and the hydrogen bond in the FGD1 variant protein has changed, which led to decrease in the interaction with CDC42 protein. In vitro study showed that the Asn424Asp variant significantly decreased the transcription levels of OCN, COL1A1, and ALP activity, and it activated the phosphorylation of
JNK1.
UNASSIGNED: Molecular biological mechanisms between abnormal expression of FGD1and Aarskog-Scott syndrome remain poorly understood. In our study, c.1270A>G variant of FGD1 resulted in Aarskog-Scott syndrome, and the analysis of pathogenicity supports the deleterious effect of the variant. Furthermore, we demonstrated the weakened affinity of the mutant FGD1 and CDC42. Decreased expression of osteogenic-related gene and abnormal activation of
JNK1 were also shown in this work.