Back to Search
Start Over
A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis.
- Source :
-
American journal of human genetics [Am J Hum Genet] 2010 Apr 09; Vol. 86 (4), pp. 596-603. Date of Electronic Publication: 2010 Mar 11. - Publication Year :
- 2010
-
Abstract
- 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.<br /> ((c) 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adult
Base Sequence
Case-Control Studies
Cells, Cultured
Epidermis metabolism
Family
Gene Deletion
Homozygote
Humans
Ichthyosis metabolism
Keratinocytes cytology
Keratinocytes metabolism
Keratosis metabolism
Male
Molecular Sequence Data
Scleroderma, Localized metabolism
Sequence Homology, Nucleic Acid
Syndrome
5' Untranslated Regions genetics
Epidermis pathology
Ichthyosis genetics
Keratosis genetics
Molecular Chaperones genetics
Polymorphism, Single Nucleotide
Proteasome Endopeptidase Complex metabolism
Scleroderma, Localized genetics
Transcription, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6605
- Volume :
- 86
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 20226437
- Full Text :
- https://doi.org/10.1016/j.ajhg.2010.02.018