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Hipk4 is a manchette-associated protein essential for spermiogenesis

ABSTRACT: Nonobstructive azoospermia (NOA) is one of the most severe forms of male infertility, characterized by the absence of spermatozoa in the ejaculate. The etiology and genetic mechanism(s) of this disease remain largely unclear. Using Sanger sequence, we identified 12 heterozygous missense mutations and 2 heterozygous nonsense mutations in the HIPK4, encoding a serine/threonine kinase. Moreover, K490* mutant cause HIPK4 unstable in 293T cells. In accord with these findings, we observed that homozygous Hipk4-/- male mice were infertility owing to malformed and immotile spermatozoa, which are characterized by a deformed nucleus and a detached acrosome. Furthermore, we performed a phosphoproteomic analysis of testis from Hipk4 wild type and knockout mice, revealing multiple targets regulated by Hipk4 during spermiogenesis. Notably, manchette-associated protein Rimbp3 has multiple phosphorylation sites regulated by Hipk4. Moreover, Hipk4 and Rimbp3 deficiency mice display several common phenotypes, in particular with regard to the ectopic positioning of the manchette within spermatids, a presumed cause of sperm head deformities. Thus, Hipk4 might regulate manchette function through phosphorylation of Rimbp3, thereby playing essential role for sperm head formation and male fertility.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Testis

SUBMITTER: Xiaofei Liu

LAB HEAD: Guo Xuejiang

PROVIDER: PXD019303 | Pride | 2022-08-02

REPOSITORIES: Pride

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