|Title||Functional characteristics of a broad spectrum of TBX6 variants in Mayer-Rokitansky-Küster-Hauser syndrome.|
|Publication Type||Journal Article|
|Year of Publication||2022|
|Authors||Ma, C, Chen, N, Jolly, A, Zhao, S, Coban-Akdemir, Z, Tian, W, Kang, J, Ye, Y, Wang, Y, Koch, A, Zhang, Y, Qin, C, Bonilla, X, Borel, C, Rall, K, Chen, Z, Jhangiani, S, Niu, Y, Li, X, Qiu, G, Zhang, S, Luo, G, Wu, Z, Bacopoulou, F, Deligeoroglou, E, Zhang, TJianguo, Rosenberg, C, Gibbs, RA, Dietrich, JE, Dimas, AS, Liu, P, Antonarakis, SE, Brucker, SY, Posey, JE, Lupski, JR, Wu, N, Zhu, L|
|Corporate Authors||Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) Study Group|
|Date Published||2022 Nov|
|Keywords||46, XX Disorders of Sex Development, Congenital Abnormalities, Female, Humans, Mullerian Ducts, RNA, Messenger, T-Box Domain Proteins, Vagina|
PURPOSE: Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterized by congenital absence of the uterus, cervix, and the upper part of the vagina in females. Whole-gene deletion and loss-of-function variants in TBX6 have been identified in association with MRKHS. We aimed to expand the spectrum of TBX6 variants in MRKHS and explore the biological effect of the variant alleles.
METHODS: Rare variants in TBX6 were called from a combined multiethnic cohort of 622 probands with MRKHS who underwent exome sequencing or genome sequencing. Multiple in vitro functional experiments were performed, including messenger RNA analysis, western blotting, transcriptional activity assay, and immunofluorescence staining.
RESULTS: We identified 16 rare variants in TBX6 from the combined cohort, including 1 protein-truncating variant reported in our previous study and 15 variants with unknown effects. By comparing the prevalence of TBX6 variants in the Chinese MRKHS cohort vs 1038 female controls, we observed a significant mutational burden of TBX6 in affected individuals (P = .0004, odds ratio = 5.25), suggesting a causal role of TBX6 variants in MRKHS. Of the 15 variants with uncertain effects, 7 were shown to induce a loss-of-function effect through various mechanisms. The c.423G>A (p.Leu141=) and c.839+5G>A variants impaired the normal splicing of TBX6 messenger RNA, c.422T>C (p.Leu141Pro) and c.745G>A (p.Val249Met) led to decreased protein expression, c.10C>T (p.Pro4Ser) and c.400G>A (p.Glu134Lys) resulted in perturbed transcriptional activity, and c.356G>A (p.Arg119His) caused protein mislocalization. We observed incomplete penetrance and variable expressivity in families carrying deleterious variants, which indicates a more complex genetic mechanism than classical Mendelian inheritance.
CONCLUSION: Our study expands the mutational spectrum of TBX6 in MRKHS and delineates the molecular pathogenesis of TBX6 variants, supporting the association between deleterious variants in TBX6 and MRKHS.
|Alternate Journal||Genet Med|
Functional characteristics of a broad spectrum of TBX6 variants in Mayer-Rokitansky-Küster-Hauser syndrome.
|Molecular basis of retinal remodeling in a zebrafish model of retinitis pigmentosa. Cell Mol Life Sci. 2023;80(12):362..|
|Single-cell multiomics of the human retina reveals hierarchical transcription factor collaboration in mediating cell type-specific effects of genetic variants on gene regulation. Genome Biol. 2023;24(1):269..|
|PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects. Am J Hum Genet. 2023;110(10):1787-1803..|