Feingold syndrome type 1 leads to multiple developmental problems, but the most detrimental is intestinal atresia -- incomplete gastrointestinal tract development. This disorder was known to be caused by loss-of-function mutations in the Mycn gene, which encodes a critical transcription factor regulating many gene activities. However, the mechanism was unclear.

Researchers used CRISPR genome editing to delete a portion of the Mycn gene in zebrafish, whose gut development is similar to humans. They found that the resulting loss of gene activity in these Mycn mutants led to a dramatic reduction in their intestine size, both in length and in the folding that provides the intestine's enormous absorptive surface area.

Within an affected subgroup of developing intestine cells, they found a significant down-regulation of numerous ribosomal genes, leading to reduced gene translation and protein synthesis. Particularly affected were genes in the mammalian target of rapamycin (mTOR) signaling pathway, a central protein synthesis regulator.

Treating zebrafish with an mTOR inhibitor recapitulated the intestinal developmental defects seen in Mycn mutants. However, when treated with the nutritional supplement leucine, an amino acid that activates the mTOR pathway, the mutant zebrafish showed partial normalization of their intestinal size.

"This suggests a possible treatment strategy for the intestinal symptoms in patients with Feingold syndrome type 1, although confirmation in a human intestinal organoid system is essential," corresponding authors Peng-Fei Xu and Xi Jin of Zhejiang University School of Medicine in China, said in a statement.

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