A Single-Nucleotide Deletion in the POMP 5 ' UTR Causes a Transcriptional Switch and Altered Epidermal Proteasome Distribution in KLICK Genodermatosis

Johanna Dahlqvist, Joakim Klar, Neha Tiwari, Jens Schuster, Hans Torma, Jitendra Badhai, Ramon Pujol, Maurice A. M. van Steensel, Tjinta Brinkhuizen, Lieke Gijezen, Antonio Chaves, Gianluca Tadini, Anders Vahlquist, Niklas Dahl*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

44 Citations (Web of Science)

Abstract

KLICK syndrome is a rare autosomal-recessive skin disorder characterized by palmoplantar keratoderrna, linear hyperkeratotic papules, and ichthyosiform scaling. In order to establish the genetic cause of this disorder, we collected DNA samples from eight European prohands. Using high-density genome-wide SNP analysis, we identified a 1.5 Mb homozygous candidate region on chromosome 13q. Sequence analysis of the ten annotated genes in the candidate region revealed homozygosity for a single-nucleotide deletion at position c.-95 in the proteasome maturation protein (POMP) gene, in all probands. The deletion is included in POMP transcript variants with long 5' untranslated regions (UTRs) and was associated with a marked increase of these transcript variants in keratinocytes from KLICK patients. POMP is a ubiquitously expressed protein and functions as a chaperone for proteasome maturation. Immunohistochemical analysis of skin biopsies from KLICK patients revealed an altered epidermal distribution of POMP, the proteasome subunit proteins alpha 7 and beta 5, and the ER stress marker CHOP. Our results suggest that KLICK syndrome is caused by a single-nucleotide deletion in the 5' UTR of POMP resulting in altered distribution of POMP in epidermis and a perturbed formation of the outermost layers of the skin. These findings imply that the proteasome has a prominent role in the terminal differentiation of human epidermis.
Original languageEnglish
Pages (from-to)596-603
JournalAmerican Journal of Human Genetics
Volume86
Issue number4
DOIs
Publication statusPublished - 9 Apr 2010

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