Abstract
Keloids result from abnormal proliferative scar formation with scar tissue expanding beyond the margin of the original wound and are mostly found in individuals of sub-Saharan African descent. The etiology of keloids has not been resolved but previous studies suggest that keloids are a genetically heterogeneous disorder. Although possible candidate genes have been suggested by genome-wide association studies using common variants, by upregulation in keloids or their involvement in syndromes that include keloid formation, rare coding variants that contribute to susceptibility in non-syndromic keloid formation have not been previously identified. Through analysis of whole-genome data we mapped a locus to chromosome 8p23.3-p21.3 with a statistically significant maximum multipoint LOD score of 4.48. This finding was followed up using exome sequencing and led to the identification of a c.1202T>C (p.(Leu401Pro)) variant in the N-acylsphingosine amidohydrolase (ASAH1) gene that co-segregates with the keloid phenotype in a large Yoruba family. ASAH1 is an acid ceramidase known to be involved in tumor formation by controlling the ratio of ceramide and sphingosine. ASAH1 is also involved in cell proliferation and inflammation, and may affect the development of keloids via multiple mechanisms. Functional studies need to clarify the role of the ASAH1 variant in wound healing.
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Acknowledgements
We are indebted to the family members who participated in this study. We thank the recruitment teams in Nigeria (A Fatokun, E Josiah, E Atiba, P Adebayo, K Adefila, P Ilesanmi and M Olaleye) for their efforts. This study was supported by the National Institutes of Health (NIH) through the National Center for Research Resources grant M01RR006192 to the Clinical Research Center at UCHC, and National Institute of Arthritis and Musculoskeletal and Skin Diseases grant R01AR45286 to ER. Exome sequencing at the UWCMG was funded by NIH – National Human Genome Research Institute and National Heart, Lung and Blood Institute grant UM1-HG006493 to DAN, MJB and SML.
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Santos-Cortez, R., Hu, Y., Sun, F. et al. Identification of ASAH1 as a susceptibility gene for familial keloids. Eur J Hum Genet 25, 1155–1161 (2017). https://doi.org/10.1038/ejhg.2017.121
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DOI: https://doi.org/10.1038/ejhg.2017.121
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