MicroRNAs (miRNA) are small-non coding RNAs endowed with great regulatory power, thus playing key roles not only in almost all physiological pathways, but also in the pathogenesis of several diseases. Surprisingly, genomic distribution analysis revealed the highest density of miRNA sequences on the X chromosome; this evolutionary conserved mammalian feature equips females with a larger miRNA machinery than males. However, miRNAs contribution to some X-related conditions, properties or functions is still poorly explored. With the aim to support and focus research in the field, this review analyzes the literature and databases about X-linked miRNAs, trying to understand how miRNAs could contribute to emerging gender-biased functions and pathological mechanisms, such as immunity and cancer. A fine map of miRNA sequences on the X chromosome is reported, and their known functions are discussed; in addition, bioinformatics functional analyses of the whole X-linked miRNA targetome (predicted and validated) were performed. The emerging scenario points to different gaps in the knowledge that should be filled with future experimental investigations, also in terms of possible implications and pathological perspectives for X chromosome aneuploidy syndromes, such as Turner and Klinefelter syndromes.
Nicoletta Potenza and Aniello Russo were supported by VALERE grants from University of Campania “Luigi Vanvitelli”. Claus H. Gravholt is a member of the European Reference Network on Rare Endocrine Conditions (ENDO-ERN), Project ID number 739543. Claus H. Gravholt was supported by Grants from the Lundbeck Foundation, the Aase og Einar Danielsen Foundation, the Novo Nordisk Foundation (NNF13OC0003234, NNF15OC0016474), “Fonden til lægevidenskabens fremme”, and the Familien Hede Nielsen foundation.