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

被引:53
|
作者
Romano, Maria-Teresa [1 ,2 ]
Tafazzoli, Aylar [1 ,2 ]
Mattern, Maximilian [1 ,2 ]
Sivalingam, Sugirthan [1 ,2 ]
Wolf, Sabrina [1 ,2 ]
Rupp, Alexander [3 ]
Thiele, Holger [4 ]
Altmueller, Janine [4 ,5 ]
Nuernberg, Peter [4 ,5 ,6 ]
Ellwanger, Juergen
Gambon, Reto [7 ]
Baumer, Alessandra [8 ]
Kohlschmidt, Nicolai [9 ]
Metze, Dieter [10 ]
Holdenrieder, Stefan [3 ]
Paus, Ralf [11 ,12 ]
Luetjohann, Dieter [13 ]
Frank, Jorge [14 ]
Geyer, Matthias [15 ]
Bertolini, Marta [10 ,16 ]
Kokordelis, Pavlos [1 ,2 ]
Betz, Regina C. [1 ,2 ]
机构
[1] Univ Bonn, Inst Human Genet, Sch Med, D-53127 Bonn, Germany
[2] Univ Hosp Bonn, D-53127 Bonn, Germany
[3] Tech Univ Munich, Inst Lab Med, German Heart Ctr, D-80636 Munich, Germany
[4] Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany
[5] Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany
[6] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany
[7] Feldstr, CH-7430 Thusis, Switzerland
[8] Univ Zurich, Inst Med Genet, CH-8092 Schlieren, Switzerland
[9] Inst Clin Genet, D-53111 Bonn, Germany
[10] Univ Munster, Dept Dermatol, D-48149 Munster, Germany
[11] Univ Miami, Miller Sch Med, Dept Dermatol & Cutaneous Surg, Miami, FL 33136 USA
[12] Univ Manchester, Ctr Dermatol Res, Manchester, Lancs, England
[13] Univ Bonn, Inst Clin Chem & Clin Pharmacol, D-53127 Bonn, Germany
[14] Univ Med Ctr Gottingen, Dept Dermatol Venereol & Allergol, D-37075 Gottingen, Germany
[15] Univ Bonn, Inst Innate Immun, D-53175 Bonn, Germany
[16] Skin & Hair Res Solut GmbH, Monasterium Lab, D-48149 Munster, Germany
关键词
GLAND TUMOR STEROLS; OXIDOSQUALENE CYCLASE; HAIR; CHOLESTEROL; PROTEIN; INHIBITORS; LIPIDS; DHCR7;
D O I
10.1016/j.ajhg.2018.09.011
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:777 / 785
页数:9
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