Biallelic Variants in Lanosterol Synthase (LSS) Cause Palmoplantar Keratoderma-Congenital Alopecia Syndrome Type 2

Yang，Fang1,2,3,4,5; Jiang，Xingyuan1,2,3; Zhu，Yuhao6; Lee，Mingyang1,2,3; Xu，Zhengren6; Zhang，Jianglin4,5; Li，Qian7; Lin，Mao ying8; Wang，Huijun9; Lin，Zhimiao1,8,9

2022

10.1016/j.jid.2022.03.023

JOURNAL OF INVESTIGATIVE DERMATOLOGY   影响因子和分区

0022-202X

1523-1747

Palmoplantar keratoderma-congenital alopecia syndrome type 2 is an autosomal recessive disorder with an unknown genetic basis. In this study, we identified biallelic variants in the LSS gene in two unrelated palmoplantar keratoderma-congenital alopecia syndrome type 2 cases (c.3G>A, p.Met1? and c.1025T>G, p.Ile342Ser in patient 1; c.1522G>T, p.Gly508Trp and c.428+42T>A in patient 2) presenting with additional clinical features, including early-onset cataracts, pseudoainhum, and agenesis of the corpus callosum. LSS encodes lanosterol synthase (LSS), which functions in the cholesterol biosynthesis pathway by converting (S)-2,3-oxidosqualene to lanosterol. The c.3G>A variant resulted in an alternative translation initiation at residue Met81, producing an N-terminal truncated protein (LSS-ΔN80), as shown by immunoblotting. The c.428+42T>A variant introduced a potential splicing site, leading to a premature stop codon. Ex vivo studies revealed downregulation of LSS in both patients. Remarkably decreased lanosterol levels were found in vitro in three LSS variants, LSS-ΔN80, p.Ile342Ser, and p.Gly508Trp, suggesting a loss of enzymatic activity. Transmission electron microscopy and immunofluorescence showed abnormal cornified envelope formation in the stratum corneum of the patients. Taken together, our findings indicate LSS as a causative gene for palmoplantar keratoderma-congenital alopecia syndrome type 2, which emphasizes the importance of the cholesterol synthesis pathway in human skin cornification.

SCI

英语

其他

National Natural Science Foundation of China[81872515];National Natural Science Foundation of China[82003327];National Natural Science Foundation of China[82073423];

Dermatology

Dermatology

WOS:000862722900001

ELSEVIER SCIENCE INC

CLINICAL MEDICINE

2-s2.0-85133686322

Scopus

1.Department of Dermatology,Peking University First Hospital,Beijing,China
2.Beijing Key Laboratory of Molecular Diagnosis on Dermatoses,Beijing,China
3.National Clinical Research Center for Skin and Immune Diseases,Beijing,China
4.Department of Dermatology,Shenzhen People's Hospital,The Second Clinical Medical College,Jinan University;,The First Affiliated Hospital,Southern University of Science and Technology,Shenzhen,China
5.Candidate Branch of National Clinical Research Center for Skin Diseases,Shenzhen,China
6.State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing,China
7.National Research Institute for Family Planning,National Human Genetic Resources Center,Beijing,China
8.Department of Dermatology,Xiamen Chang Gung Hospital,Xiamen,China
9.Dermatology Hospital,Southern Medical University,Guangzhou,China

Yang，Fang,Jiang，Xingyuan,Zhu，Yuhao,et al. Biallelic Variants in Lanosterol Synthase (LSS) Cause Palmoplantar Keratoderma-Congenital Alopecia Syndrome Type 2[J]. JOURNAL OF INVESTIGATIVE DERMATOLOGY,2022,142(10).

Yang，Fang.,Jiang，Xingyuan.,Zhu，Yuhao.,Lee，Mingyang.,Xu，Zhengren.,...&Lin，Zhimiao.(2022).Biallelic Variants in Lanosterol Synthase (LSS) Cause Palmoplantar Keratoderma-Congenital Alopecia Syndrome Type 2.JOURNAL OF INVESTIGATIVE DERMATOLOGY,142(10).

Yang，Fang,et al."Biallelic Variants in Lanosterol Synthase (LSS) Cause Palmoplantar Keratoderma-Congenital Alopecia Syndrome Type 2".JOURNAL OF INVESTIGATIVE DERMATOLOGY 142.10(2022).