The novel function of miR-3195 in targeting mutant PROK2 to prevent Kallmann syndrome

Kallmann syndrome (KS) is a rare human genetic disorder characterized by hypogonadotropic hypogonadism with the reduction or absence of olfactory sense. Mutations in multiple genes, including chemokine prokineticin-2 (PROK2), are considered to contribute to the abnormal migration of gonadotropin-releasing hormone (GnRH) neurons in the embryonic stage. However, the mechanisms of the different inheritance modes of KS have not been comprehensively determined. In this article, we present the case of one KS patient with the same mutation in PROK2 (c.223-4C>A) as his mother. RNA-seq analysis of his leukocytes showed a new transcript of PROK2, which contained a partial intron (192 bp) compared to those of his parents. Furthermore, we observed that hsa-miRNA-3195 was expressed at low levels in his and his father’s sera compared to his mother’s. Unexpectedly, hsa-miRNA-3195 was also identified to specifically target the 192 bp intron of the aberrant PROK2 transcript of this patient. We determined that high expression of hsa-miRNA-3195 could efficiently target aberrant PROK2 and stabilize the normal function of PROK2 in vitro, which provided a probable explanation for the different phenotypes of the patient and his mother with the same genotype.