Universität zu Köln

Romano, Maria-Teresa, Tafazzoli, Aylar, Mattern, Maximilian, Sivalingam, Sugirthan, Wolf, Sabrina, Rupp, Alexander ORCID: 0000-0002-2131-4581, Thiele, Holger, Altmueller, Janine, Nuernberg, Peter, Ellwanger, Juergen, Gambon, Reto, Baumer, Alessandra, Kohlschmidt, Nicolai, Metze, Dieter, Holdenrieder, Stefan, Paus, Ralf, Luetjohann, Dieter, Frank, Jorge, Geyer, Matthias ORCID: 0000-0002-7718-5002, Bertolini, Marta ORCID: 0000-0002-5927-6998, Kokordelis, Pavlos and Betz, Regina C. (2018). Bi-allelic Mutations in LSS, Encoding Lanosterol Synthase, Cause Autosomal-Recessive Hypotrichosis Simplex. Am. J. Hum. Genet., 103 (5). S. 777 - 786. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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Abstract

Hypotrichosis simplex (HS) is a rare form of hereditary alopecia characterized by childhood onset of diffuse and progressive scalp and body hair loss. Although research has identified a number of causal genes, genetic etiology in about 50% of HS cases remains unknown. The present report describes the identification via whole-exome sequencing of five different mutations in the gene LSS in three unrelated families with unexplained, potentially autosomal-recessive HS. Affected individuals showed sparse to absent lanugo-like scalp hair, sparse and brittle eyebrows, and sparse eyelashes and body hair. LSS encodes lanosterol synthase (LSS), which is a key enzyme in the cholesterol biosynthetic pathway. This pathway plays an important role in hair follicle biology. After localizing LSS protein expression in the hair shaft and bulb of the hair follicle, the impact of the mutations on keratinocytes was analyzed using immunoblotting and immunofluorescence. Interestingly, wild-type LSS was localized in the endoplasmic reticulum (ER), whereas mutant LSS proteins were localized in part outside of the ER. A plausible hypothesis is that this mislocalization has potential deleterious implications for hair follicle cells. Immunoblotting revealed no differences in the overall level of wild-type and mutant protein. Analyses of blood cholesterol levels revealed no decrease in cholesterol or cholesterol intermediates, thus supporting the previously proposed hypothesis of an alternative cholesterol pathway. The identification of LSS as causal gene for autosomal-recessive HS highlights the importance of the cholesterol pathway in hair follicle biology and may facilitate novel therapeutic approaches for hair loss disorders in general.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Romano, Maria-Teresa UNSPECIFIED UNSPECIFIED UNSPECIFIED Tafazzoli, Aylar UNSPECIFIED UNSPECIFIED UNSPECIFIED Mattern, Maximilian UNSPECIFIED UNSPECIFIED UNSPECIFIED Sivalingam, Sugirthan UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolf, Sabrina UNSPECIFIED UNSPECIFIED UNSPECIFIED Rupp, Alexander UNSPECIFIED orcid.org/0000-0002-2131-4581 UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Ellwanger, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Gambon, Reto UNSPECIFIED UNSPECIFIED UNSPECIFIED Baumer, Alessandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Kohlschmidt, Nicolai UNSPECIFIED UNSPECIFIED UNSPECIFIED Metze, Dieter UNSPECIFIED UNSPECIFIED UNSPECIFIED Holdenrieder, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Paus, Ralf UNSPECIFIED UNSPECIFIED UNSPECIFIED Luetjohann, Dieter UNSPECIFIED UNSPECIFIED UNSPECIFIED Frank, Jorge UNSPECIFIED UNSPECIFIED UNSPECIFIED Geyer, Matthias UNSPECIFIED orcid.org/0000-0002-7718-5002 UNSPECIFIED Bertolini, Marta UNSPECIFIED orcid.org/0000-0002-5927-6998 UNSPECIFIED Kokordelis, Pavlos UNSPECIFIED UNSPECIFIED UNSPECIFIED Betz, Regina C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-166633
DOI:	10.1016/j.ajhg.2018.09.011
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	103
Number:	5
Page Range:	S. 777 - 786
Date:	2018
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GLAND TUMOR STEROLS; OXIDOSQUALENE CYCLASE; HAIR; CHOLESTEROL; PROTEIN; INHIBITORS; LIPIDS; DHCR7 Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16663