LSD1/KDM1A mutations associated to a newly described form of intellectual disability impair demethylase activity and binding to transcription factors.
Genetic diseases often lead to rare and severe syndromes and the identification of the genetic and protein alterations responsible for the pathogenesis is essential to understand both the physiological and pathological role of the gene product. Recently, de novo variants have been mapped on the gene encoding for the lysine-specific histone demethylase 1 (LSD1)/lysine(K)-specific histone demethylase 1A in three patients characterized by a new genetic disorder. We have analyzed the effects of these pathological mutations on the structure, stability and activity of LSD1 using both in vitro and cellular approaches. The three mutations (Glu403Lys, Asp580Gly and Tyr785His) affect active-site residues and lead to a partial impairment of catalytic activity. They also differentially perturb the ability of LSD1 to engage transcription factors that orchestrate key developmental programs. Moreover, cellular data indicate a decrease in the protein cellular half-life. Taken together, these results demonstrate the relevance of LSD1 in gene regulation and how even moderate alterations in its stability, catalytic activity and binding properties can strongly affect organism development. This depicts a perturbed interplay of catalytic and non-catalytic processes at the origin of the pathology.
Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
Simona
S
Pilotto
Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
Valentina
V
Speranzini
Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
Chiara
C
Marabelli
Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milano, Italy.
Francesco
F
Rusconi
Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milano, Italy.
Emanuela
E
Toffolo
Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milano, Italy.
Barbara
B
Grillo
Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milano, Italy elena.battaglioli@unimi.it andrea.mattevi@unipv.it.|CNR, Institute of Neuroscience, 20129 Milano, Italy.
Elena
E
Battaglioli
Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy elena.battaglioli@unimi.it andrea.mattevi@unipv.it.
Andrea
A
Mattevi
D002384:Catalysis; D020134:Catalytic Domain / Q000235:genetics; D005786:Gene Expression Regulation; D056466:Histone Demethylases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics; D014158:Transcription, Genetic
D014157:Transcription Factors; D056466:Histone Demethylases; C495195:KDM1A protein, human