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The causative gene for AKE remains unidentified. This study aims to identify the causative gene of AKE and explore the underlying biological mechanisms. A large, three-generation Chinese family exhibiting classic AKE symptoms was identified. A genome-wide linkage analysis and whole-exome sequencing were employed to determine the causative gene. shRNA knockdown in human skin fibroblasts and CRISPR\/Cas9 knockout in HEK293T cells were utilized to assess gene functions in the progression of elastic fiber biosynthesis. The linkage analysis identified a susceptibility region between rs7296765 to rs10784618 on chromosome 12. Whole-exome sequencing confirmed a splicing mutation of 1101\u2009+\u20091\u2009<jats:italic>G<\/jats:italic>\u2009&gt;\u2009<jats:italic>A<\/jats:italic> in the <jats:italic>CCDC91<\/jats:italic> gene, resulting in exon 11 skipping and a subsequent 59-amino-acid-residue loss (residues L309-Q367del). Further functional analysis revealed distended Golgi cisternae, cytoplasmic vesicle accumulation, and lysosome presence. Immnunostaining of si-CCDC91-HSF cells demonstrated tropoelastin accumulation in the Golgi and abnormal extracellular aggregates. There are no significant changes in Fibrillin-1 microfibril assembly and lysyl oxidase activity. The findings strongly suggest that the protein product of the <jats:italic>CCDC91<\/jats:italic> gene plays a crucial role in elastin transport. This discovery enhances our understanding of <jats:italic>CCDC91<\/jats:italic>\u2019s function and broadens the known pathogenic mechanisms of AKE.<\/jats:p>","DOI":"10.1038\/s41431-024-01573-3","type":"journal-article","created":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T10:02:36Z","timestamp":1713261756000},"page":"647-655","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A mutation in CCDC91, Homo sapiens coiled-coil domain containing 91 protein, cause autosomal-dominant acrokeratoelastoidosis"],"prefix":"10.1038","volume":"32","author":[{"given":"Yunlu","family":"Zhu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wannian","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyuan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanhui","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"HongSong","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3758-1390","authenticated-orcid":false,"given":"Yeqiang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,16]]},"reference":[{"key":"1573_CR1","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1159\/000256794","volume":"107","author":"OG Costa","year":"1953","unstructured":"Costa OG. 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This study has been approved by the Ethics Committee of Shanghai Dermatology Hospital.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical"}}]}}