Disease-associated KIF3A variants alter gene methylation and expression impacting skin barrier and atopic dermatitis risk

Mariana L. Stevens, Zhonghua Zhang, Elisabet Johansson, Samriddha Ray, Amrita Jagpal, Brandy P. Ruff, Arjun Kothari, Hua He, Lisa J. Martin, Hong Ji, Kathryn Wikenheiser-Brokamp, Matthew T. Weirauch, Dorothy M. Supp, Jocelyn M. Biagini Myers and Gurjit K. Khurana Hershey ()
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Mariana L. Stevens: Cincinnati Children’s Hospital Medical Center
Zhonghua Zhang: Cincinnati Children’s Hospital Medical Center
Elisabet Johansson: Cincinnati Children’s Hospital Medical Center
Samriddha Ray: Cincinnati Children’s Hospital Medical Center
Amrita Jagpal: Cincinnati Children’s Hospital Medical Center
Brandy P. Ruff: Cincinnati Children’s Hospital Medical Center
Arjun Kothari: Cincinnati Children’s Hospital Medical Center
Hua He: Cincinnati Children’s Hospital Medical Center
Lisa J. Martin: Cincinnati Children’s Hospital Medical Center
Hong Ji: Cincinnati Children’s Hospital Medical Center
Kathryn Wikenheiser-Brokamp: University of Cincinnati College of Medicine
Matthew T. Weirauch: University of Cincinnati College of Medicine
Dorothy M. Supp: Shriners Hospitals for Children
Jocelyn M. Biagini Myers: Cincinnati Children’s Hospital Medical Center
Gurjit K. Khurana Hershey: Cincinnati Children’s Hospital Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract Single nucleotide polymorphisms (SNPs) in the gene encoding kinesin family member 3A, KIF3A, have been associated with atopic dermatitis (AD), a chronic inflammatory skin disorder. We find that KIF3A SNP rs11740584 and rs2299007 risk alleles create cytosine-phosphate-guanine sites, which are highly methylated and result in lower KIF3A expression, and this methylation is associated with increased transepidermal water loss (TEWL) in risk allele carriers. Kif3aK14∆/∆ mice have increased TEWL, disrupted junctional proteins, and increased susceptibility to develop AD. Thus, KIF3A is required for skin barrier homeostasis whereby decreased KIF3A skin expression causes disrupted skin barrier function and promotes development of AD.

Date: 2020
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DOI: 10.1038/s41467-020-17895-x

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