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

• Published in: Nature communications Vol. 11; no. 1; p. 4092
• Main Authors: Stevens, Mariana L., Zhang, Zhonghua, Johansson, Elisabet, Ray, Samriddha, Jagpal, Amrita, Ruff, Brandy P., Kothari, Arjun, He, Hua, Martin, Lisa J., Ji, Hong, Wikenheiser-Brokamp, Kathryn, Weirauch, Matthew T., Supp, Dorothy M., Biagini Myers, Jocelyn M., Khurana Hershey, Gurjit K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-08-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 14/19; 38/77; 38/88; 38/90; 38/91; 45/23; 631/208/199; 631/208/721; 631/337/176/1988; 64/110; 692/699/4033; Adolescent; Adult; Alleles; Animals; Atopic dermatitis; Child; Cytosine; Dermatitis; Dermatitis, Atopic - genetics; Dermatitis, Atopic - metabolism; Dermatitis, Atopic - pathology; DNA methylation; Eczema; Epidermis; Female; Gene expression; Genetic diversity; Genetic variance; Guanine; High-Throughput Nucleotide Sequencing; Homeostasis; Humanities and Social Sciences; Humans; Kinesin; Kinesin - genetics; Kinesin - metabolism; Male; Methylation; Mice; multidisciplinary; Nucleotides; Real-Time Polymerase Chain Reaction; Risk; Science; Science (multidisciplinary); Single-nucleotide polymorphism; Skin - metabolism; Skin - pathology; Skin diseases; Water loss; Young Adult
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17895-x

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.
Kif3a
K14
∆
/
∆
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.
Genetic variants in
KIF3A
are associated with atopic dermatitis (AD). Here, the authors identify two AD-risk alleles that show high methylation resulting in lower
KIF3A
expression. Mice with epidermis-specific loss of
Kif3a
show disrupted skin barrier homeostasis and increased AD susceptibility.