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:
CreatorsEmailORCIDORCID Put Code
Romano, Maria-TeresaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tafazzoli, AylarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mattern, MaximilianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sivalingam, SugirthanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, SabrinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rupp, AlexanderUNSPECIFIEDorcid.org/0000-0002-2131-4581UNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ellwanger, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gambon, RetoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumer, AlessandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kohlschmidt, NicolaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Metze, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holdenrieder, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paus, RalfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luetjohann, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frank, JorgeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geyer, MatthiasUNSPECIFIEDorcid.org/0000-0002-7718-5002UNSPECIFIED
Bertolini, MartaUNSPECIFIEDorcid.org/0000-0002-5927-6998UNSPECIFIED
Kokordelis, PavlosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Betz, Regina C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
GLAND TUMOR STEROLS; OXIDOSQUALENE CYCLASE; HAIR; CHOLESTEROL; PROTEIN; INHIBITORS; LIPIDS; DHCR7Multiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/16663

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