uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Congenital ichthyosis: mutations in ichthyin are associated with specific structural abnormalities in the granular layer of epidermis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Show others and affiliations
2007 (English)In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 44, no 10, 615-620 p.Article in journal (Refereed) Published
Abstract [en]

Background: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of skin disorders. Several mutant genes have been identified in ARCI, but the association between genotype and phenotype is poorly understood.

Methods: To investigate genotype–phenotype correlations in ARCI, we selected 27 patients from 18 families with specific ultrastructural features of the epidermis. The characteristic findings using electron microscopy (EM) were abnormal lamellar bodies and elongated membranes in the stratum granulosum, classified as ARCI EM type III. DNA samples from a subset of affected individuals were screened for homozygous genomic regions, and a candidate gene region was identified on chromosome 5q33. The region coincides with the ichthyin gene, previously reported as mutated in ARCI.

Results: Mutation screening of ichthyin revealed missense or splice-site mutations in affected members from 16 of 18 (89%) families with characteristics of ARCI EM type III. In a control group of 18 patients with ARCI without EM findings consistent with type III, we identified one patient homozygous for a missense mutation in ichthyin.

Discussion: Our findings indicate a strong association between ultrastructural abnormalities in the granular layer of epidermis and ichthyin mutations. The results also suggest that EM provides a tool for specific diagnosis in a genetically homogenous subgroup of patients with ARCI.

Place, publisher, year, edition, pages
2007. Vol. 44, no 10, 615-620 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-12690DOI: 10.1136/jmg.2007.050542ISI: 000249889300002OAI: oai:DiVA.org:uu-12690DiVA: diva2:40459
Available from: 2008-01-10 Created: 2008-01-10 Last updated: 2011-05-05Bibliographically approved
In thesis
1. Genetic and Molecular Studies of Two Hereditary Skin Disorders
Open this publication in new window or tab >>Genetic and Molecular Studies of Two Hereditary Skin Disorders
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Monogenic disorders, i.e., disorders caused by mutations in a single gene, are rare and clinically heterogeneous conditions. Identification of the genetic cause of monogenic traits can bring new insights into molecular pathways and disease mechanisms. The aims of the present study were to identify the mutant genes in two autosomal recessive skin disorders and to characterize the functions of the mutated genes.  In order to identify candidate genes for the two disorders whole-genome SNP analysis, homozygosity mapping and gene sequencing were used.

Autosomal recessive congenital ichthyosis (ARCI) is a group of disorders characterized by extensive scaling and redness of the skin.  A subgroup of ARCI patients (n=27) was selected based on specific ultrastructural aberrations in their skin, revealed by electron microscopy. Mutations were identified in the Ichthyin gene in 93% of the selected patients, indicating a strong association between mutant Ichthyin and the specific morphological abnormalities. Ichthyin mRNA levels were shown to increase during keratinocyte differentiation in cells from healthy and affected individuals. Electron microscopy revealed a localization of ichthyin protein to keratins and desmosomes in epidermis. Staining of epidermal lipids identified aberrant lipid aggregates in skin sections of patients with Ichthyin mutations, indicating a role for Ichthyin in epidermal lipid metabolism.

In twelve KLICK syndrome patients with ichthyosis, palmoplantar keratoderma and keratotic striae on joints, a single-nucleotide deletion was identified in the 5’ region of the proteasome maturation protein (POMP) gene.  The deletion caused an increase in the proportion of POMP transcripts with long 5’ UTR’s in patient keratinocytes.  Immunohistochemical analysis of differentiated skin cell layers revealed aberrant expression of POMP, proteasome subunits and the skin protein filaggrin in patients. CHOP expression, associated with endoplasmic reticulum stress, was increased in the same layers. siRNA silencing of POMP in cell cultures reduced proteasome subunit levels and induced expression of CHOP.  The results indicate that the mutation in KLICK patients causes POMP and proteasome insufficiency with subsequent cellular stress.

This study conclusively contributes to the understanding of epidermal physiology and the pathogenesis of two inherited skin diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 57 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 657
Monogenic disorder, autosomal recessive congenital ichthyosis, KLICK syndrome, Ichthyin, POMP, proteasome, epidermal differentiation
National Category
Medical Genetics
Research subject
Clinical Genetics
urn:nbn:se:uu:diva-149185 (URN)978-91-554-8038-7 (ISBN)
Public defence
2011-05-06, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskiölds väg 20, Uppsala, 09:00 (English)
Available from: 2011-04-14 Created: 2011-03-15 Last updated: 2011-05-05Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Dahlqvist, JohannaGånemo, AgnetaVahlquist, AndersDahl, Niklas
By organisation
Department of Genetics and PathologyDepartment of Medical Sciences
In the same journal
Journal of Medical Genetics
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 233 hits
ReferencesLink to record
Permanent link

Direct link