PDF(Pubmed)
Abstract：
Baraitser-Winter cerebrofrontofacial syndrome (BWCFF, OMIM: 243310) is a rare autosomal-dominant developmental disorder associated with variants in the genes ACTB or ACTG1. It is characterized by brain malformations, a distinctive facial appearance, ocular coloboma, and intellectual disability. However, the phenotypes of BWCFF are heterogenous, and its molecular pathogenesis has not been fully elucidated. In the present study, we conducted detailed clinical examinations on a Chinese patient with BWCFF and found novel ocular manifestations including pseudoduplication of the optic disc and nystagmus. Targeted gene panel sequencing and Sanger sequencing identified a de novo heterozygous missense c.478A > G (p.Thr160Ala) variant in ACTB. The mRNA and protein expression of ACTB was assessed by quantitative reverse transcription PCR and Western blots. Furthermore, the functional effects of the pathogenic variant were analyzed by protein structure analysis, which indicated that the variant may affect the active site for ATP hydrolysis by the actin ATPase, resulting in abnormal filamentous actin organization in peripheral blood mononuclear cells. This discovery extends the ACTB variant spectrum, which will improve genetic counseling and diagnosis, and may contribute to understanding the pathogenic mechanisms of actin-related diseases.
摘要：
Baraitser-Winter脑额面部综合征（BWCFF，OMIM：243310）是一种罕见的常染色体显性遗传发育障碍，与ACTB或ACTG1基因的变异相关。它的特点是大脑畸形，独特的面部外观，眼部缺损，智力残疾。然而,BWCFF的表型是异质的，其分子发病机制尚未完全阐明。在本研究中,我们对一名中国BWCFF患者进行了详细的临床检查，发现了新的眼部表现，包括视盘假性重复和眼球震颤。靶向基因组测序和Sanger测序鉴定出从头杂合错义c.478A>G（p。ACTB中的Thr160Ala）变体。通过定量逆转录PCR和Western印迹评估ACTB的mRNA和蛋白表达。此外，通过蛋白质结构分析分析致病变异体的功能效应，这表明该变体可能会影响肌动蛋白ATP酶水解的活性位点，导致外周血单个核细胞中异常的丝状肌动蛋白组织。这一发现扩展了ACTB变异谱,这将改善遗传咨询和诊断，可能有助于了解肌动蛋白相关疾病的致病机制。
