A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis.
KLICK syndrome is a rare autosomal-recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic papules, and ichthyosiform scaling. In order to establish the genetic cause of this disorder, we collected DNA samples from eight European probands. 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.
Dahlqvist
Johanna
J
Department of Genetics and Pathology, Uppsala University and University Hospital, 75185 Uppsala, Sweden.
Klar
Joakim
J
Tiwari
Neha
N
Schuster
Jens
J
Törmä
Hans
H
Badhai
Jitendra
J
Pujol
Ramon
R
van Steensel
Maurice A M
MA
Brinkhuizen
Tjinta
T
Brinkhuijzen
Tjinta
T
Gijezen
Lieke
L
Chaves
Antonio
A
Tadini
Gianluca
G
Vahlquist
Anders
A
Dahl
Niklas
N
D020121:5' Untranslated Regions / Q000235:genetics*; D000328:Adult; D001483:Base Sequence; D016022:Case-Control Studies; D002478:Cells, Cultured; D004817:Epidermis / Q000378:metabolism / Q000473:pathology*; D005190:Family; D017353:Gene Deletion; D006720:Homozygote; D006801:Humans; D007057:Ichthyosis / Q000235:genetics* / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D007642:Keratosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012594:Scleroderma, Localized / Q000235:genetics* / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D013577:Syndrome; D014158:Transcription, Genetic
D020121:5' Untranslated Regions; D018832:Molecular Chaperones; C110856:proteasome maturation protein; D046988:Proteasome Endopeptidase Complex