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

Area of Science:

• Genetics
• Developmental Biology
• Cardiology

Background:

• Trisomy 21 (T21) causes congenital heart disease (CHD) and other phenotypes, but underlying mechanisms are unclear.
• Understanding T21's developmental impact is crucial for targeted therapies.

Purpose of the Study:

• To investigate the molecular mechanisms by which T21 perturbs cardiac development.
• To identify key genes and pathways dysregulated in T21-associated CHD.

Main Methods:

• Comparative transcriptome analysis of CHD tissues from T21 and euploid (eCHD) patients.
• Single-nucleus RNA sequencing and RNA in situ hybridization to resolve cell lineages.
• Human induced pluripotent stem cell-derived endothelial cells were used to study gene deletion effects.

Main Results:

• T21 tissues showed elevated chr21 gene expression, increased SOST (sclerostin) levels, and higher ZNF467 expression.
• T21 cardiac endothelial cells exhibited significantly higher SOST expression and downregulated Wnt pathway genes.
• DSCAM, within the chr21 CHD critical region, correlated with SOST and ZNF467; DSCAM deletion reduced sclerostin secretion.

Conclusions:

• T21 leads to increased sclerostin, inappropriately inhibiting Wnt signaling crucial for heart development and other functions.
• This mechanism likely contributes to Down syndrome phenotypes, suggesting therapeutic potential for anti-sclerostin antibodies in T21.