Metabolic and Pathologic Profiles of Human LSS Deficiency Recapitulated in Mice

February 2020 in “ PLOS genetics ”

Yoichi Wada, Atsuo Kikuchi, Akimune Kaga, Naoki Shimizu, Junya Ito, Ryo Onuma, Fumiyoshi Fujishima, Eriko Totsune, Ryo Sato, Tetsuya Niihori, Matsuyuki Shirota, Ryo Funayama, Kota Sato, Toru Nakazawa, Keiko Nakayama, Yoko Aoki, Setsuya Aiba, Kiyotaka Nakagawa, Shigeo Kure

Lanosterol synthase LSS deficiency congenital hypotrichosis hair loss cholesterol synthesis biallelic LSS mutations epoxysqualene lanosterol forehead sebum epidermis-specific Lss knockout tamoxifen-induced epidermal Lss knockout skin barrier integrity LSS skin barrier

Studysummary This study found that biallelic LSS mutations lead to congenital hypotrichosis and cataracts, with each tissue-specific loss of function observed in mouse models. Our plain-language summary of this paper — not a Tressless recommendation.

The study investigated the effects of Lanosterol synthase (LSS) deficiency, which is known to be associated with skin lesions, cataracts, and congenital anomalies due to its role in cholesterol synthesis. Researchers identified two patients with novel biallelic LSS mutations presenting with congenital hypotrichosis (hair loss) and midline anomalies but without cataracts. They confirmed LSS enzyme blockade in these patients by measuring the (S)-2,3-epoxysqualene/lanosterol ratio in forehead sebum, suggesting its potential as a diagnostic biomarker for LSS deficiency. Mouse models with tissue-specific Lss knockouts were created; epidermis-specific Lss knockout mice exhibited neonatal lethality due to dehydration, indicating LSS's role in skin barrier integrity, while tamoxifen-induced epidermal Lss knockout in adult mice led to hypotrichosis. Lens-specific Lss knockout mice developed cataracts. These findings confirmed that LSS deficiency leads to hypotrichosis and cataracts due to loss-of-function mutations in specific tissues, and the mouse models will help in understanding the pathophysiology of LSS disruption and in developing treatments for LSS deficiency.

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Research cited in this study

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

55 citations , November 2018 in “American journal of human genetics”

This study identified five mutations in the gene LSS in individuals with unexplained hypotrichosis simplex, highlighting a potential role of mislocalized LSS proteins in disrupting hair follicle biology.

research Hair Growth Defects in Insig-Deficient Mice Caused by Cholesterol Precursor Accumulation and Reversed by Simvastatin

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This study found that Insig deficiency in the skin of mice causes cholesterol precursors to accumulate, leading to defective hair development and skin abnormalities, which were alleviated by simvastatin treatment.

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427 citations , April 2008 in “Nature Protocols”