TY - JOUR
T1 - Cystatin M/E Variant Causes Autosomal Dominant Keratosis Follicularis Spinulosa Decalvans by Dysregulating Cathepsins L and V
AU - Eckl, Katja Martina
AU - Gruber, Robert
AU - Brennan, Luise
AU - Marriott, Andrew
AU - Plank, Roswitha
AU - Moosbrugger-Martinz, Verena
AU - Blunder, Stephan
AU - Schossig, A. S.
AU - Altmüller, Janine
AU - Thiele, Holger
AU - Nürnberg, Peter
AU - Zschocke, Johannes
AU - Hennies, Hans
AU - Schmuth, Matthias
N1 - Funding Information:
The project was supported in part by grants from the Austrian National Bank (OeNB 15620), Austrian Science Fund (I 2259-B26), Köln Fortune Program of the Faculty of Medicine, University of Cologne (HH), Walter Schaar, Hans Gröber Foundations, University of Damman (MS), and Edge Hill University Research Fund – RIF (KE).
Funding Information:
We are grateful to the probands for providing samples. We would like to thank Viktoria Migschitz for excellent editorial assistance, and Christian Ploner for providing skin samples. Funding. The project was supported in part by grants from the Austrian National Bank (OeNB 15620), Austrian Science Fund (I 2259-B26), K?ln Fortune Program of the Faculty of Medicine, University of Cologne (HH), Walter Schaar, Hans Gr?ber Foundations, University of Damman (MS), and Edge Hill University Research Fund ? RIF (KE).
Publisher Copyright:
© Copyright © 2021 Eckl, Gruber, Brennan, Marriott, Plank, Moosbrugger-Martinz, Blunder, Schossig, Altmüller, Thiele, Nürnberg, Zschocke, Hennies and Schmuth.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/7/12
Y1 - 2021/7/12
N2 - Keratosis follicularis spinulosa decalvans (KFSD) is a rare cornification disorder with an X-linked recessive inheritance in most cases. Pathogenic variants causing X-linked KFSD have been described in MBTPS2, the gene for a membrane-bound zinc metalloprotease that is involved in the cleavage of sterol regulatory element binding proteins important for the control of transcription. Few families have been identified with an autosomal dominant inheritance of KFSD. We present two members of an Austrian family with a phenotype of KFSD, a mother and her son. The disease was not observed in her parents, pointing to a dominant inheritance with a de novo mutation in the index patient. Using whole-exome sequencing, we identified a heterozygous missense variant in CST6 in DNA samples from the index patient and her affected son. In line with family history, the variant was not present in samples from her parents. CST6 codes for cystatin M/E, a cysteine protease inhibitor. Patient keratinocytes showed increased expression of cathepsin genes CTSL and CTSV and reduced expression of transglutaminase genes TGM1 and TGM3. A relative gain of active, cleaved transglutaminases was found in patient keratinocytes compared to control cells. The variant found in CST6 is expected to affect protein targeting and results in marked disruption of the balance between cystatin M/E activity and its target proteases and eventually transglutaminases 1 and 3. This disturbance leads to an impairment of terminal epidermal differentiation and proper hair shaft formation seen in KFSD.
AB - Keratosis follicularis spinulosa decalvans (KFSD) is a rare cornification disorder with an X-linked recessive inheritance in most cases. Pathogenic variants causing X-linked KFSD have been described in MBTPS2, the gene for a membrane-bound zinc metalloprotease that is involved in the cleavage of sterol regulatory element binding proteins important for the control of transcription. Few families have been identified with an autosomal dominant inheritance of KFSD. We present two members of an Austrian family with a phenotype of KFSD, a mother and her son. The disease was not observed in her parents, pointing to a dominant inheritance with a de novo mutation in the index patient. Using whole-exome sequencing, we identified a heterozygous missense variant in CST6 in DNA samples from the index patient and her affected son. In line with family history, the variant was not present in samples from her parents. CST6 codes for cystatin M/E, a cysteine protease inhibitor. Patient keratinocytes showed increased expression of cathepsin genes CTSL and CTSV and reduced expression of transglutaminase genes TGM1 and TGM3. A relative gain of active, cleaved transglutaminases was found in patient keratinocytes compared to control cells. The variant found in CST6 is expected to affect protein targeting and results in marked disruption of the balance between cystatin M/E activity and its target proteases and eventually transglutaminases 1 and 3. This disturbance leads to an impairment of terminal epidermal differentiation and proper hair shaft formation seen in KFSD.
KW - Keratosis follicularis spinulosa decalvans
KW - Congenital disorder of cornification
KW - Cicatricial alopecia
KW - Cystatin
KW - Transglutaminase
KW - Epidermal differentiation
KW - Cathepsin
KW - transglutaminase
KW - cathepsin
KW - keratosis follicularis spinulosa decalvans
KW - congenital disorder of cornification
KW - epidermal differentiation
KW - cystatin
KW - cicatricial alopecia
UR - http://www.scopus.com/inward/record.url?scp=85111612735&partnerID=8YFLogxK
U2 - 10.3389/fgene.2021.689940
DO - 10.3389/fgene.2021.689940
M3 - Article
VL - 12
JO - Frontiers in Genetics
JF - Frontiers in Genetics
SN - 1664-8021
M1 - 689940
ER -