A novel mutation in LEPRE1 that eliminates only the KDEL ER- retrieval sequence causes non-lethal osteogenesis imperfecta.

Masaki Takagi, Tomohiro Ishii, Aileen M. Barnes, Maryann Weis, Naoko Amano, Mamoru Tanaka, Ryuji Fukuzawa, Gen Nishimura, David R. Eyre, Joan C. Marini, Tomonobu Hasegawa

研究成果: Article

19 引用 (Scopus)

抄録

Prolyl 3-hydroxylase 1 (P3H1), encoded by the LEPRE1 gene, forms a molecular complex with cartilage-associated protein (CRTAP) and cyclophilin B (encoded by PPIB) in the endoplasmic reticulum (ER). This complex is responsible for one step in collagen post-translational modification, the prolyl 3-hydroxylation of specific proline residues, specifically α1(I) Pro986. P3H1 provides the enzymatic activity of the complex and has a Lys-Asp-Glu-Leu (KDEL) ER-retrieval sequence at the carboxyl terminus. Loss of function mutations in LEPRE1 lead to the Pro986 residue remaining unmodified and lead to slow folding and excessive helical post-translational modification of type I collagen, which is seen in both dominant and recessive osteogenesis imperfecta (OI). Here, we present the case of siblings with non-lethal OI due to novel compound heterozygous mutations in LEPRE1 (c.484delG and c.2155dupC). The results of RNA analysis and real-time PCR suggest that mRNA with c.2155dupC escapes from nonsense-mediated RNA decay. Without the KDEL ER- retrieval sequence, the product of the c.2155dupC variant cannot be retained in the ER. This is the first report of a mutation in LEPRE1 that eliminates only the KDEL ER-retrieval sequence, whereas other functional domains remain intact. Our study shows, for the first time, that the KDEL ER- retrieval sequence is essential for P3H1 functionality and that a defect in KDEL is sufficient for disease onset.

元の言語English
ジャーナルPLoS One
7
発行部数5
DOI
出版物ステータスPublished - 2012
外部発表Yes

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Osteogenesis Imperfecta
bone formation
Endoplasmic Reticulum
endoplasmic reticulum
mutation
Mutation
RNA
Hydroxylation
post-translational modification
Cartilage
Post Translational Protein Processing
Collagen Type I
Proline
lysyl-aspartyl-glutamyl-leucine
collagen
Collagen
Genes
cyclophilins
Messenger RNA
Defects

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

これを引用

A novel mutation in LEPRE1 that eliminates only the KDEL ER- retrieval sequence causes non-lethal osteogenesis imperfecta. / Takagi, Masaki; Ishii, Tomohiro; Barnes, Aileen M.; Weis, Maryann; Amano, Naoko; Tanaka, Mamoru; Fukuzawa, Ryuji; Nishimura, Gen; Eyre, David R.; Marini, Joan C.; Hasegawa, Tomonobu.

:: PLoS One, 巻 7, 番号 5, 2012.

研究成果: Article

Takagi, Masaki ; Ishii, Tomohiro ; Barnes, Aileen M. ; Weis, Maryann ; Amano, Naoko ; Tanaka, Mamoru ; Fukuzawa, Ryuji ; Nishimura, Gen ; Eyre, David R. ; Marini, Joan C. ; Hasegawa, Tomonobu. / A novel mutation in LEPRE1 that eliminates only the KDEL ER- retrieval sequence causes non-lethal osteogenesis imperfecta. :: PLoS One. 2012 ; 巻 7, 番号 5.
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AU - Weis, Maryann

AU - Amano, Naoko

AU - Tanaka, Mamoru

AU - Fukuzawa, Ryuji

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AU - Marini, Joan C.

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