Smad6, an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway, plays a crucial role in various biological processes such as embryonic development, tissue homeostasis, and blood vessel maintenance [1,4,5].

In human genetic disorders, SMAD6-deficiency has been associated with congenital heart diseases, craniosynostosis, and radioulnar synostosis [1]. Heterozygous loss-of-function variants in SMAD6 increase the risk of these clinically distinct disorders without a clear genotype-phenotype correlation [1]. Pathogenic SMAD6 variants substantially increase the risk of both nonsyndromic and syndromic craniosynostosis, especially metopic synostosis [2]. In nonsyndromic craniosynostosis, SMAD6 mutations lead to poorer mathematics, performance intelligence quotient, full-scale intelligence quotient, and motor coordination [3]. Also, in nonsyndromic radioulnar synostosis, SMAD6 is frequently mutated, mostly with loss-of-function variants [6]. In cattle, SMAD6 inhibits granulosa cell proliferation and follicle growth rate [7].

In conclusion, Smad6 is essential for normal development and homeostasis through its role in the BMP signalling pathway. Studies on SMAD6-related human genetic disorders, especially those involving loss-of-function variants, have provided insights into the gene's function in the context of congenital heart diseases, craniosynostosis, and radioulnar synostosis. These findings contribute to our understanding of the underlying mechanisms of these diseases and may aid in improving molecular diagnosis, therapeutic strategies, and patient counselling.

References:

1. Luyckx, Ilse, Verstraeten, Aline, Goumans, Marie-José, Loeys, Bart. 2022. SMAD6-deficiency in human genetic disorders. In NPJ genomic medicine, 7, 68. doi:10.1038/s41525-022-00338-5. https://pubmed.ncbi.nlm.nih.gov/36414630/

2. Calpena, Eduardo, Cuellar, Araceli, Bala, Krithi, Boyadjiev, Simeon A, Wilkie, Andrew O M. 2020. SMAD6 variants in craniosynostosis: genotype and phenotype evaluation. In Genetics in medicine : official journal of the American College of Medical Genetics, 22, 1498-1506. doi:10.1038/s41436-020-0817-2. https://pubmed.ncbi.nlm.nih.gov/32499606/

3. Wu, Robin T, Timberlake, Andrew T, Abraham, Paul F, Alperovich, Michael A, Persing, John A. . SMAD6 Genotype Predicts Neurodevelopment in Nonsyndromic Craniosynostosis. In Plastic and reconstructive surgery, 145, 117e-125e. doi:10.1097/PRS.0000000000006319. https://pubmed.ncbi.nlm.nih.gov/31592950/

4. Li, Ling, Lu, Lei, Xiao, Ziqi, Wang, Weimin, Wang, Hongyan. 2024. Deamidation enables pathogenic SMAD6 variants to activate the BMP signaling pathway. In Science China. Life sciences, 67, 1915-1927. doi:10.1007/s11427-023-2532-5. https://pubmed.ncbi.nlm.nih.gov/38913236/

5. Ruter, Dana L, Liu, Ziqing, Ngo, Kimlynn M, Kidder, Elise J, Bautch, Victoria L. 2021. SMAD6 transduces endothelial cell flow responses required for blood vessel homeostasis. In Angiogenesis, 24, 387-398. doi:10.1007/s10456-021-09777-7. https://pubmed.ncbi.nlm.nih.gov/33779885/

6. Yang, Yongjia, Zheng, Yu, Li, Wangming, Zhu, Guanghui, Zhu, Yimin. 2019. SMAD6 is frequently mutated in nonsyndromic radioulnar synostosis. In Genetics in medicine : official journal of the American College of Medical Genetics, 21, 2577-2585. doi:10.1038/s41436-019-0552-8. https://pubmed.ncbi.nlm.nih.gov/31138930/

7. Domingues, Rafael R, Andrade, Fabiana S, Paulo N Andrade, Joao, Kirkpatrick, Brian W, Wiltbank, Milo C. 2023. SMAD6 inhibits granulosa cell proliferation and follicle growth rate in carrier and noncarrier heifers of the Trio allele. In Reproduction (Cambridge, England), 165, 269-279. doi:10.1530/REP-22-0232. https://pubmed.ncbi.nlm.nih.gov/36534533/