Majid Alfadhel, Bashayr S Alhubayshi, Muhammad Umair, Ahmed Alfaidi, Deemah Alwadaani, Essra Aloyouni, Safdar Abbas, Abdulkareem Al Abdulrahman, Mohammed Aldrees, Abeer Al Tuwaijri, Ruaa S Alharithy, Abdulaziz Alajlan, Abdulrahman Alswaid, Saad Almohrij, Sultan Al-Khenaizan
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Whole genome sequencing (WGS) in families A and B revealed a homozygous frameshift variant (c.903del; p.Phe301Leufs*2) in the SPAG9 gene. Sanger sequencing of both families revealed perfect segregation of the identified variant in all family members. 3D protein modeling revealed substantial changes in the protein's secondary structure. Furthermore, RT-qPCR revealed a substantial reduction of SPAG9 gene expression at the mRNA level in the affected individuals of both families, thus supporting the pathogenic nature of the identified variant. For the first time in the literature, biallelic SPAG9 gene variation was linked to multisystem-exhibiting features like coarse facial features, albinism, cataracts, skeletal abnormalities, and developmental delay. 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引用次数: 0
摘要
精子相关抗原9 (Sperm-associated antigen 9, SPAG9)是癌睾丸抗原的一员,具有支架蛋白的特性,参与c-Jun n -末端激酶JNK信号通路,提示其参与不同的生理过程,如生存、凋亡、肿瘤发生和细胞增殖。我们确定了两个家族(A和B)具有多系统特征,如粗糙的面部特征、白化病、白内障、骨骼异常和发育迟缓。全基因组测序(WGS)在A和B家族中发现一个纯合子移码变异(c.903del;p.Phe301Leufs*2)在SPAG9基因中的表达。两个家族的Sanger测序结果显示,在所有家族成员中,所鉴定的变异完全分离。3D蛋白质模型显示了蛋白质二级结构的实质性变化。此外,RT-qPCR显示,在两个家族的受影响个体中,SPAG9基因mRNA水平的表达显著减少,从而支持鉴定的变异的致病性。在文献中,双等位基因SPAG9变异首次与多系统特征联系起来,如面部粗糙、白化病、白内障、骨骼异常和发育迟缓。因此,这些数据支持了SPAG9在人类多系统疾病中起重要作用的观点。
Truncated SPAG9 as a novel candidate gene for a new syndrome: Coarse facial features, albinism, cataract and developmental delay (CACD syndrome).
Sperm-associated antigen 9 (SPAG9) is a member of cancer-testis antigen, having characteristics of a scaffold protein, which is involved in the c-Jun N-terminal kinase JNK signaling pathway, suggesting its key involvement in different physiological processes, such as survival, apoptosis, tumorigenesis, and cell proliferation. We identified two families (A and B) having multisystem features like coarse facial features, albinism, cataracts, skeletal abnormalities, and developmental delay. Whole genome sequencing (WGS) in families A and B revealed a homozygous frameshift variant (c.903del; p.Phe301Leufs*2) in the SPAG9 gene. Sanger sequencing of both families revealed perfect segregation of the identified variant in all family members. 3D protein modeling revealed substantial changes in the protein's secondary structure. Furthermore, RT-qPCR revealed a substantial reduction of SPAG9 gene expression at the mRNA level in the affected individuals of both families, thus supporting the pathogenic nature of the identified variant. For the first time in the literature, biallelic SPAG9 gene variation was linked to multisystem-exhibiting features like coarse facial features, albinism, cataracts, skeletal abnormalities, and developmental delay. Thus, this data supports the notion that SPAG9 plays an important role in a multisystemic disorder in humans.
期刊介绍:
Genetics and Molecular Biology (formerly named Revista Brasileira de Genética/Brazilian Journal of Genetics - ISSN 0100-8455) is published by the Sociedade Brasileira de Genética (Brazilian Society of Genetics).
The Journal considers contributions that present the results of original research in genetics, evolution and related scientific disciplines. Manuscripts presenting methods and applications only, without an analysis of genetic data, will not be considered.