Human Molecular Genetics Advance Access originally published online on September 12, 2006
Human Molecular Genetics 2006 15(21):3083-3097; doi:10.1093/hmg/ddl249
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Bathing suit ichthyosis is caused by transglutaminase-1 deficiency: evidence for a temperature-sensitive phenotype
1 Department of Dermatology, University of Muenster, Von-Esmarch-Str. 58 D-48149, Münster, Germany, 2 Dermatology Department, Rangueil Hospital, Toulouse, France, 3 X-ray Crystallography Facility/Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA, 4 Department of Dermatology, University of Heidelberg, Heidelberg, Germany, 5 Department of Dermatology, University of Maastricht, Maastricht, The, Netherlands, 6 TOMESA Clinic of Dermatology, Bad Salzschlirf, Germany, 7 INSERM, U.563, Toulouse, 31300, France, 8 University Paul Sabatier, Toulouse, 31400, France and 9 Cologne Center for Genomics, Division of Dermatogenetics, University of Cologne, Cologne, Germany
* To whom correspondence should be addressed. Tel: +49 2518352685; Fax: +49 2518357279; Email: ojiv{at}uni-muenster.de , ojiv{at}mednet.uni-muenster.de
Received June 30, 2006; Revised August 31, 2006; Accepted September 7, 2006
Bathing suit ichthyosis (BSI) is a striking and unique clinical form of autosomal recessive congenital ichthyosis characterized by pronounced scaling on the bathing suit areas but sparing of the extremities and the central face. Here we report on a series of 10 BSI patients. Our genetic, ultrastructural and biochemical investigations show that BSI is caused by transglutaminase-1 (TGase-1) deficiency. Altogether, we identified 13 mutations in TGM1—among them seven novel missense mutations and one novel nonsense mutation. Structural modeling for the Tyr276Asn mutation reveals that the residue is buried in the hydrophobic interior of the enzyme and that the hydroxyl side chain of Tyr276 is exposed to solvent in a cavity of the enzyme. Cryosections of healthy skin areas demonstrated an almost normal TGase activity, in contrast to the affected BSI skin, which only showed a cytoplasmic and clearly reduced TGase-1 activity. The distribution of TGase-1 substrates in the epidermis of affected skin corresponded to the situation in TGase-1 deficiency. Interestingly, the expression of TGase-3 and cathepsin D was reduced. Digital thermography validated a striking correlation between warmer body areas and presence of scaling in patients suggesting a decisive influence of the skin temperature. In situ TGase testing in skin of BSI patients demonstrated a marked decrease of enzyme activity when the temperature was increased from 25 to 37°C. We conclude that BSI is caused by TGase-1 deficiency and suggest that it is a temperature-sensitive phenotype.
Deceased July, 24 2006.