Membrane-bound serine protease inhibitor HAI-1 is required for maintenance of intestinal epithelial integrity.

Hepatocyte growth factor activator inhibitor type 1 (HAI-1), encoded by the serine protease inhibitor Kunitz type 1 (SPINT1) gene, is a membrane-bound serine protease inhibitor expressed in epithelial tissues. Mutant mouse models revealed that HAI-1/SPINT1 is essential for placental labyrinth formation and is critically involved in regulating epidermal keratinization through interaction with its cognate cell surface protease, matriptase. HAI-1/SPINT1 is abundantly expressed in both human and mouse intestinal epithelium; therefore, we analyzed its role in intestinal function using mice with intestinal epithelial cell-specific deletion of Spint1 generated by interbreeding mice carrying Spint1(LoxP) homozygous alleles with transgenic mice carrying the Cre recombinase gene controlled by the intestine-specific Villin promoter.

MBNL and CELF proteins regulate alternative splicing of the skeletal muscle chloride channel CLCN1.

The expression and function of the skeletal muscle chloride channel CLCN1/ClC-1 is regulated by alternative splicing. Inclusion of the CLCN1 exon 7A is aberrantly elevated in myotonic dystrophy (DM), a genetic disorder caused by the expansion of a CTG or CCTG repeat. Increased exon 7A inclusion leads to a reduction in CLCN1 function, which can be causative of myotonia.

Expression of MBNL and CELF mRNA transcripts in muscles with myotonic dystrophy.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder that causes muscle wasting, myotonia, cardiac conduction abnormalities, and other multi-systemic symptoms. Current evidence supports a pathogenic mechanism involving aberrantly expanded CTG repeats in the 3'-untranslated region of the DM protein kinase (DMPK) gene. The repeats are thought to recruit various RNA-binding proteins such as muscleblind-like (MBNL) proteins into foci in the nuclei of DM cells, resulting in loss of function.