ADAMTS19, also known as ADAM Metallopeptidase with Thrombospondin Type 1 Motif 19, is a member of the ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family of proteases. This family plays a critical role in the regulation of extracellular matrix (ECM) proteins and has been implicated in various physiological and pathological processes, including cardiovascular development, cancer progression, and tissue homeostasis. ADAMTS19 is particularly interesting due to its association with heart valve disease and its potential roles in other conditions, such as cancer and ovarian function.

ADAMTS19 has been identified as a causative gene for autosomal recessive heart valve disease (HVD), primarily affecting the aortic and pulmonary valves. Studies have shown that loss of function (LoF) variants in ADAMTS19 lead to a specific cardiac phenotype characterized by thickening of valve leaflets, stenosis, insufficiency, and other cardiac anomalies [1,3]. These findings highlight the importance of ADAMTS19 in the development and maintenance of heart valves. Moreover, the discovery of ADAMTS19's role in heart valve disease has implications for genetic testing and diagnosis, particularly in patients with multiple semilunar valve abnormalities and subaortic membranes [1].

In addition to its role in cardiovascular development, ADAMTS19 has also been implicated in cancer biology. Research has shown that ADAMTS19 is downregulated in gastric cancer (GC) tissues and correlates with distant metastasis and perineural invasion [2]. Functional studies demonstrated that ADAMTS19 suppresses cell migration and invasion in vitro, suggesting a potential tumor-suppressive role. ADAMTS19 exerts its effects by targeting S100A16 via the NF-κB pathway, highlighting a novel mechanism of cancer progression regulation [2]. These findings suggest that ADAMTS19 and S100A16 could serve as potential prognostic and therapeutic targets for GC.

Furthermore, ADAMTS19 has been associated with other conditions, such as premature ovarian failure (POF). Studies have shown that epistasis between polymorphisms in ACVR2B and ADAMTS19 is significantly associated with POF susceptibility [4]. Similarly, epistasis between IGF2R and ADAMTS19 polymorphisms has also been linked to POF [6]. These findings suggest that ADAMTS19 may play a role in ovarian function and fertility, providing new insights into the genetic basis of POF.

ADAMTS19 has also been implicated in ocular growth regulation. Studies have shown that Adamts19 expression is significantly upregulated in the retina of mice lacking either Prss56 or Mfrp, suggesting a potential role in counteracting impaired ocular growth [5]. This finding highlights the involvement of ADAMTS19 in the molecular network regulating ocular axial growth and refractive development.

In conclusion, ADAMTS19 is a multifaceted gene with diverse roles in cardiovascular development, cancer progression, ovarian function, and ocular growth regulation. Its association with heart valve disease and its potential roles in other conditions make it an important target for further research. Understanding the functions and mechanisms of ADAMTS19 could lead to the development of novel diagnostic tools, prognostic markers, and therapeutic strategies for various diseases.

References:

1. Massadeh, Salam, Alhashem, Amal, van de Laar, Ingrid M B H, Alaamery, Manal, Bertoli-Avella, Aida M. 2020. ADAMTS19-associated heart valve defects: Novel genetic variants consolidating a recognizable cardiac phenotype. In Clinical genetics, 98, 56-63. doi:10.1111/cge.13760. https://pubmed.ncbi.nlm.nih.gov/32323311/

2. Jiang, Yingming, Yu, Xihu, Zhao, Yandong, Huang, Zhenze, Yang, Zuli. 2021. ADAMTS19 Suppresses Cell Migration and Invasion by Targeting S100A16 via the NF-κB Pathway in Human Gastric Cancer. In Biomolecules, 11, . doi:10.3390/biom11040561. https://pubmed.ncbi.nlm.nih.gov/33921267/

3. Wünnemann, Florian, Ta-Shma, Asaf, Preuss, Christoph, Hitz, Marc-Phillip, Andelfinger, Gregor. 2019. Loss of ADAMTS19 causes progressive non-syndromic heart valve disease. In Nature genetics, 52, 40-47. doi:10.1038/s41588-019-0536-2. https://pubmed.ncbi.nlm.nih.gov/31844321/

4. Pyun, Jung-A, Kim, Sunshin, Kwack, KyuBum. . Epistasis between polymorphisms in ACVR2B and ADAMTS19 is associated with premature ovarian failure. In Menopause (New York, N.Y.), 22, 212-6. doi:10.1097/GME.0000000000000285. https://pubmed.ncbi.nlm.nih.gov/25051287/

5. Koli, Swanand, Labelle-Dumais, Cassandre, Zhao, Yin, Paylakhi, Seyyedhassan, Nair, K Saidas. 2021. Identification of MFRP and the secreted serine proteases PRSS56 and ADAMTS19 as part of a molecular network involved in ocular growth regulation. In PLoS genetics, 17, e1009458. doi:10.1371/journal.pgen.1009458. https://pubmed.ncbi.nlm.nih.gov/33755662/

6. Pyun, J-A, Kim, S, Cha, D H, Kwack, K. 2013. Epistasis between IGF2R and ADAMTS19 polymorphisms associates with premature ovarian failure. In Human reproduction (Oxford, England), 28, 3146-54. doi:10.1093/humrep/det365. https://pubmed.ncbi.nlm.nih.gov/24014609/