Increased endothelial sclerostin caused by elevated DSCAM mediates multiple trisomy 21 phenotypes
David M. McKean, … , J.G. Seidman, Christine E. Seidman
David M. McKean, … , J.G. Seidman, Christine E. Seidman
Published June 3, 2024
Citation Information: J Clin Invest. 2024;134(11):e167811. https://doi.org/10.1172/JCI167811.
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Research Article Cardiology Genetics

Increased endothelial sclerostin caused by elevated DSCAM mediates multiple trisomy 21 phenotypes

Abstract

Trisomy 21 (T21), a recurrent aneuploidy occurring in 1:800 births, predisposes to congenital heart disease (CHD) and multiple extracardiac phenotypes. Despite a definitive genetic etiology, the mechanisms by which T21 perturbs development and homeostasis remain poorly understood. We compared the transcriptome of CHD tissues from 49 patients with T21 and 226 with euploid CHD (eCHD). We resolved cell lineages that misexpressed T21 transcripts by cardiac single-nucleus RNA sequencing and RNA in situ hybridization. Compared with eCHD samples, T21 samples had increased chr21 gene expression; 11-fold-greater levels (P = 1.2 × 10–8) of SOST (chr17), encoding the Wnt inhibitor sclerostin; and 1.4-fold-higher levels (P = 8.7 × 10–8) of the SOST transcriptional activator ZNF467 (chr7). Euploid and T21 cardiac endothelial cells coexpressed SOST and ZNF467; however, T21 endothelial cells expressed 6.9-fold more SOST than euploid endothelial cells (P = 2.7 × 10–27). Wnt pathway genes were downregulated in T21 endothelial cells. Expression of DSCAM, residing within the chr21 CHD critical region, correlated with SOST (P = 1.9 × 10–5) and ZNF467 (P = 2.9 × 10–4). Deletion of DSCAM from T21 endothelial cells derived from human induced pluripotent stem cells diminished sclerostin secretion. As Wnt signaling is critical for atrioventricular canal formation, bone health, and pulmonary vascular homeostasis, we concluded that T21-mediated increased sclerostin levels would inappropriately inhibit Wnt activities and promote Down syndrome phenotypes. These findings imply therapeutic potential for anti-sclerostin antibodies in T21.

Authors

David M. McKean, Qi Zhang, Priyanka Narayan, Sarah U. Morton, Viktoria Strohmenger, Vi T. Tang, Sophie McAllister, Ananya Sharma, Daniel Quiat, Daniel Reichart, Daniel M. DeLaughter, Hiroko Wakimoto, Joshua M. Gorham, Kemar Brown, Barbara McDonough, Jon A. Willcox, Min Young Jang, Steven R. DePalma, Tarsha Ward, Pediatric Cardiac Genomics Consortium Investigators, Richard Kim, John D. Cleveland, J.G. Seidman, Christine E. Seidman

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Figure 1

Genome-wide transcript analyses identifies increased expression of SOST and ZNF467 in T21 cardiac tissues.

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Genome-wide transcript analyses identifies increased expression of SOST ...
(A) Graphical representation of the log2 fold change in RNA expression z score for all autosomal genes in 51 tissues from 49 individuals with T21 compared with and 236 tissues from 226 individuals with eCHD. ZNF467 is represented by the black dot within the red circle. (B and C) Standard (z) scores for differentially expressed chr21 genes in T21 (B) and eCHD (C) tissues, excluding genes with 1.35 < z score < 0.65 or 2-tailed t test P > 0.002. (D) Quantification of SOST expression (RPKM) demonstrates 11.03-fold-higher expression in T21 than eCHD (2-tailed t test P = 1.2 × 10–8) RA tissues. (E) Quantification of SOST expression (RPKM) is based on rs6503474 genotypes of RA tissues from eCHD (A/A n = 12; A/G n = 29; G/G n = 21) and T21 (A/A n = 7; A/G n = 20; G/G n = 10) patients and indicates a similar effect size in T21 (42%) and euploid (35%) tissues. (F) Expression of ZNF467 and SOST transcripts (RPKM) is correlated in eCHD (black) and T21 (red) tissues. In D and E, the box represents the first quartile (bottom) and third quartile (top) values, while the line represents 1.5 times the interquartile range beyond those values.