Proteomics

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Genotyping, generation and lysine 2-hydroxyisobutyrylation identification of the first human autosomal dominant osteopetrosis type II specific induced pluripotent stem cells


ABSTRACT: Background: Autosomal dominant osteopetrosis type II (ADO2) is a rare human genetic disease that has been broadly studied as an important osteopetrosis model; however, there are no disease-specific induced pluripotent stem cells (ADO2-iPSCs) that may be valuable for understanding the pathogenesis and may be a potential source of cells for autologous cell therapy. Methods: To generate the first human ADO2-iPSCs from a Chinese family with ADO2 and to identify their characteristics, blood samples were collected from the proband and his parents and were used for genotyping by whole-exome sequencing (WES); the urine-derived cells of the proband were reprogrammed with episomal plasmids that contained transcription factors, such as KLF4, OCT4, c-MYC, and SOX2. The proteome-wide analysis of lysine 2-hydroxyisobutyrylation in the ADO2-iPSCs and control cell lines was performed by high-resolution LC-MS/MS and a bioinformatics analysis. Results: WES with filtering strategies identified a mutation in CLCN7 (R286W) in the proband and his father, which was absent in the proband’s mother and the healthy controls; this was confirmed by Sanger sequencing. The ADO2-iPSCs were successfully generated, which carried the normal male karyotype (46, XY) and carried the mutation of CLCN7 (R286W); the ADO2-iPSCs positively expressed alkaline phosphatase and other surface markers; and no vector and transgene was detected. The ADO2-iPSCs could differentiate into all three germ cell layers, both in vitro and in vivo. Our proteomic profiling detected 7, 405 proteins and revealed 3,684 2-hydroxyisobutyrylated sites in 1,036 proteins in the ADO2-iPSCs. Conclusions: Our data indicated that mutation CLCN7 (R286W) may be a cause of the osteopetrosis family. The generated vector-free and transgene-free ADO2-iPSCs with identified lysine 2-hydroxyisobutyrylation may be valuable for personalized and cell-based regenerative medicine in the future.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Donge Tang  

LAB HEAD: Yong Dai

PROVIDER: PXD014227 | Pride | 2022-02-15

REPOSITORIES: Pride

Dataset's files

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Z8207TP2O.raw Raw
Z8207TP2o_txt.zip Other
Z8207TQ_1.raw Raw
Z8207TQ_10.raw Raw
Z8207TQ_11.raw Raw
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Publications

Multiomics landscape of the autosomal dominant osteopetrosis type II disease-specific induced pluripotent stem cells.

Li Chunhong C   Shangguan Yu Y   Zhu Peng P   Dai Weier W   Tang Donge D   Ou Minglin M   Dai Yong Y  

Hereditas 20211027 1


<h4>Background</h4>Autosomal dominant osteopetrosis type II (ADO2) is a genetically and phenotypically metabolic bone disease, caused by osteoclast abnormalities. The pathways dysregulated in ADO2 could lead to the defects in osteoclast formation and function. However, the mechanism remains elusive.<h4>Materials and methods</h4>To systematically explore the molecular characterization of ADO2, we performed a multi-omics profiling from the autosomal dominant osteopetrosis type II iPSCs (ADO2-iPSCs  ...[more]

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