A direct link between Prss53, hair curvature, and skeletal dysplasia
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ABSTRACT:
PROVIDER: PRJNA593251 | ENA |
REPOSITORIES: ENA
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Project description:PRSS53, a member of the membrane-anchored serine proteases, hydrolyzes peptide bonds and is highly expressed in the hair follicle IRS, medulla, precortex and some melanocytes1. Previous studies reported that Prss53 is a psoriasis susceptibility locus and is linked to systemic lupus erythematosus, suggesting its potential roles in skin function2. The Q30R SNP in Prss53 may influence hair shape and is involved in the human variation of head hair shape among different continental groups1. In addition, ENaC activity is regulated by the activity of a channel-activating protease of Prss8 (a homologous gene of Prss53), implying the Prss53 may have an indispensable role in ion channel activity3.The triggering of hair curvature is clearly related to symmetry or asymmetry axis formation in follicles and includes Wnt, TGFβ, BMP, Shh and FGFs, etc. In particular, the Wnt/Ca2+ and Wnt/planar cell polarity (PCP) pathways are additional novel mechanisms that affect hair shape4. Furthermore, disruptions in calcium metabolism may contribute to a wide variety of clinical symptoms, including osteoporosis, osteolysis, nephrocalcinosis and adynamie5.Here, we successfully generated Prss53-deficient rabbits. These rabbits exhibited curved hair, severe skeletal malformation and disrupted calcium metabolism. Altogether, these data suggest that Prss53 play an important role in calcium metabolism and provide the first direct evidence that Prss53 functions in hair curvature shape and skeletal dysplasia.
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Project description:MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Heterozygous loss-of-function point mutations of miRNA genes are associated with several human congenital disorders, but neomorphic (gain-of-new-function) mutations in miRNAs due to nucleotide substitutions have not been reported. Here we describe a neomorphic seed region mutation in the chondrocyte-specific, super-enhancer-associated MIR140 gene encoding microRNA-140 (miR-140) in a novel autosomal dominant human skeletal dysplasia. Mice with the corresponding single nucleotide substitution show skeletal abnormalities similar to those of the patients but distinct from those of miR-140-null mice. This mutant miRNA gene yields abundant mutant miR-140-5p expression without miRNA-processing defects. In chondrocytes, the mutation causes widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, indicating that the mutation produces both loss-of-function and gain-of-function effects. Furthermore, the mutant miR-140-5p seed competes with the conserved RNA-binding protein Ybx1 for overlapping binding sites. This finding may explain the potent target repression and robust in vivo effect by this mutant miRNA even in the absence of evolutionary selection of miRNA–target RNA interactions, which contributes to the strong regulatory effects of conserved miRNAs. Our study presents the first case of a pathogenic gain-of-function miRNA mutation and provides molecular insight into neomorphic actions of emerging and/or mutant miRNAs.
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