Bi-allelic Mutations in LSS, Encoding Lanosterol Synthase, Cause Autosomal-Recessive Hypotrichosis Simplex

Am J Hum Genet. 2018 Nov 1;103(5):777-785. doi: 10.1016/j.ajhg.2018.09.011.

Maria-Teresa Romano ¹, Aylar Tafazzoli ¹, Maximilian Mattern ¹, Sugirthan Sivalingam ¹, Sabrina Wolf ¹, Alexander Rupp ², Holger Thiele ³, Janine Altmüller ⁴, Peter Nürnberg ⁵, Jürgen Ellwanger ⁶, Reto Gambon ⁷, Alessandra Baumer ⁸, Nicolai Kohlschmidt ⁹, Dieter Metze ¹⁰, Stefan Holdenrieder ², Ralf Paus ¹¹, Dieter Lütjohann ¹², Jorge Frank ¹³, Matthias Geyer ¹⁴, Marta Bertolini ¹⁵, Pavlos Kokordelis ¹, Regina C Betz ¹⁶

Affiliations

1 Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, 53127 Bonn, Germany.
2 Institute of Laboratory Medicine, German Heart Center, Technical University Munich, 80636 Munich, Germany.
3 Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
4 Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
5 Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
6 Dermatological Practice, 80333 München, Germany.
7 Pediatric Practice Feldstrasse, 7430 Thusis, Switzerland.
8 Institute for Genetic Medicine, University of Zürich, 8952 Schlieren, Switzerland.
9 Institute of Clinical Genetics, 53111 Bonn, Germany.
10 Department of Dermatology, University of Münster, 48149 Münster, Germany.
11 Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Centre for Dermatology Research, University of Manchester, Manchester, UK.
12 Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53127 Bonn, Germany.
13 Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, 37075 Göttingen, Germany.
14 Institute of Innate Immunity, University of Bonn, 53175 Bonn, Germany.
15 Department of Dermatology, University of Münster, 48149 Münster, Germany; Monasterium Laboratory - Skin and Hair Research Solutions GmbH, 48149 Münster, Germany.
16 Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, 53127 Bonn, Germany. Electronic address: regina.betz@uni-bonn.de.

PMID: 30401459 DOI: 10.1016/j.ajhg.2018.09.011

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.

Keywords

LSS; alopecia; cholesterol biosynthetic pathway; hair; hypothrichosis; lanosterol synthase; whole-exome sequencing.

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