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J. Biol. Chem., Vol. 282, Issue 50, 36714-36723, December 14, 2007

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Autosomal Ichthyosis with Hypotrichosis Syndrome Displays Low Matriptase Proteolytic Activity and Is Phenocopied in ST14 Hypomorphic Mice^*

Karin List, Brooke Currie, Tiffany C. Scharschmidt^¶, Roman Szabo, Jessica Shireman^¶, Alfredo Molinolo, Benjamin F. Cravatt^||, Julia Segre, and Thomas H. Bugge¹

From the Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, the ^¶Howard Hughes Medical Institute-Research Scholars Program, Chevy Chase, Maryland 20815, and the ^||The Skaggs Institute for Chemical Biology, and Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037

Human autosomal recessive ichthyosis with hypotrichosis (ARIH) is an inherited disorder recently linked to homozygosity for a point mutation in the ST14 gene that causes a G827R mutation in the matriptase serine protease domain (G216 in chymotrypsin numbering). Here we show that human G827R matriptase has strongly reduced proteolytic activity toward small molecule substrates, as well as toward its candidate epidermal target, prostasin. To further investigate the possible contribution of low matriptase activity to ARIH, we generated an ST14 hypomorphic mouse strain that displays a 100-fold reduction in epidermal matriptase mRNA levels. Interestingly, unlike ST14 null mice, ST14 hypomorphic mice were viable and fertile but displayed a spectrum of abnormalities that strikingly resembled ARIH. Thus, ST14 hypomorphic mice developed hyperproliferative and retention ichthyosis with impaired desquamation, hypotrichosis with brittle, thin, uneven, and sparse hair, and tooth defects. Biochemical analysis of ST14 hypomorphic epidermis revealed reduced prostasin proteolytic activation and profilaggrin proteolytic processing, compatible with a primary role of matriptase in this process. This work strongly indicates that reduced activity of a matriptase-prostasin proteolytic cascade is the etiological origin of human ARIH and provides an important mouse model for the exploration of matriptase function in ARIH, as well as multiple other physiological and pathological processes.

Received for publication, July 5, 2007 , and in revised form, September 19, 2007.

^* This work was supported by the National Institutes of Health Intramural Program and by Department of Defense Grant DAMD-17-02-1-0693 (to T. H. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Proteases and Tissue Remodeling Unit, Oral and Pharyngeal Cancer Branch, NIDCR, NIH, 30 Convent Dr., Rm. 211, Bethesda, MD 20892. Tel.: 301-435-1840; Fax: 301-402-0823; E-mail: thomas.bugge{at}nih.gov.

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