Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice

Autoři: Yoichi Wada aff001;  Atsuo Kikuchi aff001;  Akimune Kaga aff002;  Naoki Shimizu aff003;  Junya Ito aff003;  Ryo Onuma aff003;  Fumiyoshi Fujishima aff004;  Eriko Totsune aff001;  Ryo Sato aff001;  Tetsuya Niihori aff005;  Matsuyuki Shirota aff006;  Ryo Funayama aff007;  Kota Sato aff008;  Toru Nakazawa aff008;  Keiko Nakayama aff007;  Yoko Aoki aff005;  Setsuya Aiba aff013;  Kiyotaka Nakagawa aff003;  Shigeo Kure aff001
Působiště autorů: Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff001;  Department of Pediatrics, Tohoku Kosai Hospital, Sendai, Miyagi, Japan aff002;  Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan aff003;  Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff004;  Department of Medical Genetics, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff005;  Division of Interdisciplinary Medical Sciences, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff006;  Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff007;  Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff008;  Collaborative Program for Ophthalmic Drug Discovery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff009;  Department of Retinal Disease Control, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff010;  Departments of Retinal Disease Control, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff010;  Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff011;  Department of Ophthalmic Imaging and Information Analytics, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff012;  Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan aff013
Vyšlo v časopise: Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice. PLoS Genet 16(2): e32767. doi:10.1371/journal.pgen.1008628
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008628


Skin lesions, cataracts, and congenital anomalies have been frequently associated with inherited deficiencies in enzymes that synthesize cholesterol. Lanosterol synthase (LSS) converts (S)-2,3-epoxysqualene to lanosterol in the cholesterol biosynthesis pathway. Biallelic mutations in LSS have been reported in families with congenital cataracts and, very recently, have been reported in cases of hypotrichosis. However, it remains to be clarified whether these phenotypes are caused by LSS enzymatic deficiencies in each tissue, and disruption of LSS enzymatic activity in vivo has not yet been validated. We identified two patients with novel biallelic LSS mutations who exhibited congenital hypotrichosis and midline anomalies but did not have cataracts. We showed that the blockade of the LSS enzyme reaction occurred in the patients by measuring the (S)-2,3-epoxysqualene/lanosterol ratio in the forehead sebum, which would be a good biomarker for the diagnosis of LSS deficiency. Epidermis-specific Lss knockout mice showed neonatal lethality due to dehydration, indicating that LSS could be involved in skin barrier integrity. Tamoxifen-induced knockout of Lss in the epidermis caused hypotrichosis in adult mice. Lens-specific Lss knockout mice had cataracts. These results confirmed that LSS deficiency causes hypotrichosis and cataracts due to loss-of-function mutations in LSS in each tissue. These mouse models will lead to the elucidation of the pathophysiological mechanisms associated with disrupted LSS and to the development of therapeutic treatments for LSS deficiency.

Klíčová slova:

Cataracts – Congenital anomalies – Enzyme metabolism – Enzymes – Epidermis – Hair – Cholesterol – Mouse models


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2020 Číslo 2

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