Alternative splicing has been implied in the development and progression of pediatric liver diseases such as Alagille syndrome (ALGS), according to a new review published in Frontiers in Molecular Biosciences.

The current knowledge on ALGS etiology estimates that most patients (94%) have variants of the JAG1 gene. A smaller percentage (1%-2%) of patients present alterations in the NOTCH2 gene. The number of splicing mutations in JAG1 reported in ALGS is superior to 40, according to the review by Zhou et al. On the other hand, only 1 splice site mutation had been described for NOTCH2, the c.5930−1G→A, which affects exon 33.

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JAG1 and NOTCH2 are transmembrane proteins that interact with each other. The success of the interaction depends on additional functional motifs, including the C2-like domain, the delta-Serate-lag2 (DSL) domain, the epidermal growth factor-like (EGF-like) repeats of JAG1, and the extracellular EGF-like repeats on NOTCH2. Therefore, mutations in these mediators are also likely to contribute to misguided signaling.

However, it is still unknown how these splicing mutations contribute to ALGS pathogenesis at the molecular level due to the lack of functional studies.

“Therefore, an in-depth study should be carried out to verify their roles in the corresponding diseases, evaluate the potential of these targets for drug development, and establish a noninvasive early diagnosis method,” according to Zhou et al. They said they might have diagnostic potential in diseases such as ALGS.

Alternative splicing is a gene regulatory mechanism that modifies pre-messenger RNA (mRNA) constructs prior to their translation into mRNA. This molecular process can produce a variety of mRNAs from a single gene by rearranging exons within the molecule with the help of splice sites and associated sequences.


Zhou J-L, Zhao Y-Z, Wang S-S, Chen M-X, Zhou S, Chen C. RNA splicing: a versatile regulatory mechanism in pediatric liver diseases. Front Mol Biosci. 2021;8:863. doi:10.3389/fmolb.2021.725308