Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice
| Autor: | Kota Sato, Setsuya Aiba, Matsuyuki Shirota, Naoki Shimizu, Ryo Onuma, Ryo Sato, Akimune Kaga, Tetsuya Niihori, Eriko Totsune, Junya Ito, Ryo Funayama, Atsuo Kikuchi, Yoko Aoki, Toru Nakazawa, Yoichi Wada, Fumiyoshi Fujishima, Keiko Nakayama, Shigeo Kure, Kiyotaka Nakagawa |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Cancer Research Pathology DNA Mutational Analysis Enzyme Metabolism QH426-470 Hypotrichosis medicine.disease_cause Biochemistry Mice chemistry.chemical_compound 0302 clinical medicine Medicine and Health Sciences Enzyme Chemistry Intramolecular Transferases Genetics (clinical) Skin Mice Knockout 0303 health sciences Mutation Lanosterol Animal Models Congenital Anomalies Lipids Pathophysiology Pedigree Enzymes Cholesterol Experimental Organism Systems Knockout mouse Congenital cataracts Anatomy Integumentary System Research Article medicine.medical_specialty Adolescent Mouse Models Holistic Health Biology Research and Analysis Methods Cataract 03 medical and health sciences Model Organisms Cataracts Lens Crystalline Exome Sequencing Congenital Disorders Genetics medicine Animals Humans Molecular Biology Ecology Evolution Behavior and Systematics 030304 developmental biology Biology and Life Sciences Proteins medicine.disease Sebum Disease Models Animal Ophthalmology chemistry Lens Disorders Animal Studies Enzymology biology.protein Epidermis 030217 neurology & neurosurgery Hair Lanosterol synthase |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 16, Iss 2, p e1008628 (2020) |
| ISSN: | 1553-7404 |
| Popis: | 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. Author summary Skin lesions, cataracts, and congenital anomalies have been frequently associated with inherited deficiencies of cholesterol synthetic enzymes. LSS encodes lanosterol synthase, an enzyme in the cholesterol biosynthesis pathway, and biallelic mutations in LSS have been reported in families with congenital cataracts and hypotrichosis. However, it remains to be clarified whether these phenotypes are caused by LSS enzymatic deficiency in each tissue, and disruption of LSS enzymatic activity in vivo has not yet been validated. We showed that LSS metabolic inhibition in patients with biallelic LSS mutations and congenital hypotrichosis in vivo by measuring metabolites of the LSS enzyme in the forehead sebum, which would be good biomarkers for the diagnosis of LSS deficiency. We recapitulated hypotrichosis and cataracts by creating tissue-specific Lss knockout mice. Our mouse studies confirmed that LSS deficiency causes hypotrichosis and cataracts due to loss-of-function mutations in LSS in each tissue. These mice will lead to the elucidation of the pathophysiological mechanisms associated with disrupted LSS and to the development of therapeutic treatments for LSS deficiency. |
| Databáze: | OpenAIRE |
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