Background/Introduction: Using whole exome sequencing we identified a truncating mutation in the KIAA2022 gene in a child with mental retardation and antibody-negative diabetes. The KIAA2022 gene encodes a large protein of 1516 amino acids, which has no significant homology with other known proteins. KIAA2022 has already been associated to X-linked mental retardation. In this study we analyze the potential contribution of KIAA2022 to diabetes.

Methods: Whole exome capture sequencing was performed using the Illumina HiSeq instrument. We performed qRT-PCR and immunohistochemistry. We used the INS-1E cell line for in vitro and zebrafish and mice for in vivo knock down studies.

Results: We confirmed mRNA and protein expression of KIAA2022 in murine and human islets by qRT-PCR and immunohistochemistry. KIAA2022 partially co-stained with insulin in pancreatic sections. In vitro experiments with INS-1E cells showed that KIAA2022 is highly expressed during cell division and after stress induction by H202. To characterize KIAA2022 function in vivo, we performed knock down studies in zebrafish and found a decrease of the beta cell mass by 40% compared to wild type. The beta cell expansion rate, assessed by culturing zebrafish embryos with and without glucose, lead to a 30% decrease of the expansion rate in the knock-down animals in comparison to the control group. We further used the CRISPR Cas9 technology to disrupt the KIAA2022 gene in mice. The knockout mice showed smaller islets and DNA damage signals in islets in comparison to the control mice. The i.p. glucose tolerance tests at twelve weeks of age showed glucose intolerance in mutant in comparison to wild type mice.

Conclusion: In vitro experiments using INS-1E cells suggest that KIAA2022 may play a role in cell division and in DNA damage signaling or repair. The KIAA2022 knock down experiments lead to a decrease of the beta cell mass and glucose-induced expansion rate in zebrafish and DNA damage signals in beta cells of mutant mice as well as glucose intolerance.


C. Stekelenburg: None. J. Blouin: None. F. Santoni: None. E.A. O'Hare: None. N.A. Zaghloul: None. V. Schwitzgebel: None.

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