Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2

被引：49

作者：

van Dijk, Fleur S. ^{[1
,2
,3
,4
]}

Semler, Oliver ^{[5
,6
,7
]}

Etich, Julia ^{[8
]}

Koehler, Anna ^{[6
,9
]}

Jimenez-Estrada, Juan A. ^{[10
]}

Bravenboer, Nathalie ^{[11
]}

Claeys, Lauria ^{[12
]}

Riesebos, Elise ^{[12
]}

Gegic, Sejla ^{[12
]}

Piersma, Sander R. ^{[13
]}

Jimenez, Connie R. ^{[13
]}

Waisfisz, Quinten ^{[12
]}

Flores, Carmen-Lisset ^{[10
]}

Nevado, Julian ^{[14
,15
]}

Harsevoort, Arjan J. ^{[1
]}

Janus, Guus J. M. ^{[1
]}

Franken, Anton A. M. ^{[1
]}

van der Sar, Astrid M. ^{[16
]}

Meijers-Heijboer, Hanne ^{[12
]}

Heath, Karen E. ^{[14
,15
,17
]}

Lapunzina, Pablo ^{[14
,15
]}

Nikkels, Peter G. J. ^{[18
]}

Santen, Gijs W. E. ^{[19
]}

Nuechel, Julian ^{[6
,9
]}

Plomann, Markus ^{[6
,9
]}

Wagener, Raimund ^{[6
,9
,20
]}

Rehberg, Mirko ^{[5
,6
]}

Hoyer-Kuhn, Heike ^{[5
,6
]}

Eekhoff, Elisabeth M. W. ^{[21
]}

Pals, Gerard ^{[12
]}

Morgelin, Matthias ^{[22
]}

Newstead, Simon ^{[23
]}

Wilson, Brian T. ^{[3
,24
]}

Ruiz-Perez, Victor L. ^{[10
,14
,15
]}

Maugeri, Alessandra ^{[12
]}

Netzer, Christian ^{[6
,7
,25
]}

Zaucke, Frank ^{[8
]}

Micha, Dimitra ^{[12
]}

机构：

[1] Isala Hosp, Expert Ctr Adults Osteogenesis Imperfecta, NL-10400 Zwolle, Netherlands

[2] Univ Med Ctr Groningen, Dept Clin Genet, NL-30001 Groningen, Netherlands

[3] London North West Hlth Care Univ NHS Trust, North West Thames Reg Genet Serv, Harrow HA1 3UJ, Middx, England

[4] Imperial Coll London, Dept Metab Digest & Reprod, Sect Genet & Genom, London, England

[5] Univ Cologne, Fac Med, Dept Paediat, D-50931 Cologne, Germany

[6] Univ Cologne, Univ Hosp Cologne, D-50931 Cologne, Germany

[7] Univ Cologne, Univ Hosp Cologne, Ctr Rare Dis, D-50931 Cologne, Germany

[8] Orthopaed Univ Hosp Friedrichsheim gGmbH, Dr Rolf M Schwiete Res Unit Osteoarthrit, D-60528 Frankfurt, Germany

[9] Univ Cologne, Fac Med, Ctr Biochem, D-50931 Cologne, Germany

[10] CSIC UAM, Inst Invest Biomed Alberto Sols IIBM, Madrid 28029, Spain

[11] Vrije Univ Amsterdam, Dept Clin Chem, Amsterdam UMC, Amsterdam Movement Sci, Amsterdam, Netherlands

[12] Vrije Univ Amsterdam, Dept Clin Genet, Amsterdam UMC, NL-1081 BT Amsterdam, Netherlands

[13] Vrije Univ Amsterdam, Canc Ctr Amsterdam, Dept Med Oncol, Amsterdam UMC, Amsterdam, Netherlands

[14] ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain

[15] Univ Autonoma Madrid, Inst Med & Mol Genet INGEMM, Hosp Univ La Paz IdiPaz, Madrid 28046, Spain

[16] Vrije Univ Amsterdam, Dept Med Microbiol & Infect Control, Amsterdam UMC, Amsterdam, Netherlands

[17] Univ Autonoma Madrid, Hosp Univ La Paz, Skeletal Dysplasia Multidisciplinary Unit UMDE, Madrid 28046, Spain

[18] Univ Med Ctr Utrecht, Dept Pathol, Utrecht, Netherlands

[19] Leiden Univ, Dept Clin Genet, Med Ctr, Leiden, Netherlands

[20] Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany

[21] Vrije Univ Amsterdam, Dept Internal Med, Amsterdam UMC, Amsterdam Movement Sci,Sect Endocrinol, Amsterdam, Netherlands

[22] Colzyx AB, S-22381 Lund, Sweden

[23] Univ Oxford, Dept Biochem, South Parks Rd, Oxford OX1 3QU, England

[24] Newcastle Univ, Int Ctr Life, Biosci Inst, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England

[25] Univ Cologne, Fac Med, Inst Human Genet, D-50931 Cologne, Germany

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2020年 / 107卷 / 05期

关键词：

GOLGI; COMPONENTS; MUTATIONS;

D O I：

10.1016/j.ajhg.2020.09.009

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Osteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation. OI is genetically heterogeneous: over 20 genetic causes are recognized. We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families. KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, which recycles ER-resident proteins with a KDEL-like peptide from the cis-Golgi to the ER through COPI retrograde transport. Analysis of patient primary fibroblasts showed intracellular decrease of HSP47 and FKBP65 along with reduced procollagen type I in culture media. Electron microscopy identified an abnormal quality of secreted collagen fibrils with increased amount of HSP47 bound to monomeric and multimeric collagen molecules. Mapping the identified KDELR2 variants onto the crystal structure of G. gallus KDELR2 indicated that these lead to an inactive receptor resulting in impaired KDELR2-mediated Golgi-ER transport. Therefore, in KDELR2-deficient individuals, OI most likely occurs because of the inability of HSP47 to bind KDELR2 and dissociate from collagen type I. Instead, HSP47 remains bound to collagen molecules extracellularly, disrupting fiber formation. This highlights the importance of intracellular recycling of ER-resident molecular chaperones for collagen type I and bone metabolism and a crucial role of HSP47 in the KDELR2-associated pathogenic mechanism leading to OI.

引用

页码：989 / 999

页数：11

共 25 条

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