Ichthyosis, follicular atrophoderma, and hypotrichosis caused by mutations in ST14 is associated with impaired profilaggrin processing.
Congenital ichthyosis encompasses a heterogeneous group of disorders of cornification. Isolated forms and syndromic ichthyosis can be differentiated. We have analyzed two consanguineous families from the United Arab Emirates and Turkey with an autosomal recessive syndrome of diffuse congenital ichthyosis, patchy follicular atrophoderma, generalized and diffuse nonscarring hypotrichosis, marked hypohidrosis, and woolly hair (OMIM 602400). By genome-wide analysis, we found a homozygous interval on chromosome 11q24-q25 and obtained a LOD score of 4.0 at D11S910. We identified a homozygous splice-site mutation in the Arab patients and a frame-shift deletion in the Turkish patient in the gene suppression of tumorigenicity-14 (ST14). The product of ST14, matriptase, is a type II transmembrane serine protease synthesized in most human epithelia. Two missense mutations in ST14 were recently described in patients with a phenotype of ichthyosis and hypotrichosis, indicating diverse activities of matriptase in the epidermis and hair follicles. Here we have further demonstrated the loss of matriptase in differentiated patient keratinocytes, reduced proteolytic activation of prostasin, and disturbed processing of profilaggrin. As filaggrin monomers play a pivotal role in epidermal barrier formation, these findings reveal the link between congenital disorders of keratinization and filaggrin processing in the human skin.
Alef
Thomas
T
Division of Dermatogenetics, Cologne Center for Genomics, University of Cologne, Cologne, Germany.
Torres
Serena
S
Hausser
Ingrid
I
Metze
Dieter
D
Türsen
Umit
U
Lestringant
Gilles G
GG
Hennies
Hans Christian
HC
D000293:Adolescent; D001284:Atrophy; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D005260:Female; D000091344:Filaggrin Proteins; D006801:Humans; D007039:Hypotrichosis / Q000235:genetics*; D007057:Ichthyosis / Q000235:genetics*; D007223:Infant; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D008297:Male; D009154:Mutation; D012697:Serine Endopeptidases / Q000235:genetics*; D012867:Skin / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure
C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D012697:Serine Endopeptidases; C485596:ST14 protein, human