Moosa, Shahida ORCID: 0000-0002-4463-3067, Yamamoto, Guilherme L., Garbes, Lutz, Keupp, Katharina, Beleza-Meireles, Ana, Moreno, Carolina Araujo, Valadares, Eugenia Ribeiro, de Sousa, Sergio B., Maia, Sofia, Saraiva, Jorge, Honjo, Rachel S., Kim, Chong Ae, de Menezes, Hamilton Cabral, Lausch, Ekkehart, Lorini, Pablo Villavicencio, Lamounier, Arsonval, Jr., Bezerra Carniero, Tulio Canella, Giunta, Cecilia ORCID: 0000-0002-9313-8257, Rohrbach, Marianne ORCID: 0000-0002-4013-6012, Janner, Marco, Semler, Oliver, Beleggia, Filippo ORCID: 0000-0003-0234-7094, Li, Yun, Yigit, Goekhan, Reintjes, Nadine, Altmueller, Janine, Nuernberg, Peter, Cavalcanti, Denise P., Zabel, Bernhard, Warman, Matthew L., Bertola, Debora R., Wollnik, Bernd and Netzer, Christian (2019). Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta. Am. J. Hum. Genet., 105 (4). S. 836 - 844. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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Abstract

Osteogenesis imperfecta (OI) comprises a genetically heterogeneous group of skeletal fragility diseases. Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD. Affected individuals had recurrent fractures and at least one had oligodontia. MESD encodes an endoplasmic reticulum (ER) chaperone protein for the canonical Wingless-related integration site (WNT) signaling receptors LRP5 and LRP6. Because complete absence of MESD causes embryonic lethality in mice, we hypothesized that the OI-associated mutations are hypomorphic alleles since these mutations occur downstream of the chaperone activity domain but upstream of ER-retention domain. This would be consistent with the clinical phenotypes of skeletal fragility and oligodontia in persons deficient for LRP5 and LRP6, respectively. When we expressed wild-type (WT) and mutant MESD in HEK293T cells, we detected WT MESD in cell lysate but not in conditioned medium, whereas the converse was true for mutant MESD. We observed that both WT and mutant MESD retained the ability to chaperone LRP5. Thus, 01-associated MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Since these individuals have no eye abnormalities (which occur in individuals completely lacking LRP5) and have neither limb nor brain patterning defects (both of which occur in mice completely lacking LRP6), we infer that bone mass accrual and dental patterning are more sensitive to reduced canonical WNT signaling than are other developmental processes. Biologic agents that can increase LRP5 and LRP6-mediated WNT signaling could benefit individuals with MESD-associated OI.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Moosa, ShahidaUNSPECIFIEDorcid.org/0000-0002-4463-3067UNSPECIFIED
Yamamoto, Guilherme L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garbes, LutzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keupp, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beleza-Meireles, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moreno, Carolina AraujoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Valadares, Eugenia RibeiroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Sousa, Sergio B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maia, SofiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saraiva, JorgeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Honjo, Rachel S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, Chong AeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Menezes, Hamilton CabralUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lausch, EkkehartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorini, Pablo VillavicencioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lamounier, Arsonval, Jr.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bezerra Carniero, Tulio CanellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giunta, CeciliaUNSPECIFIEDorcid.org/0000-0002-9313-8257UNSPECIFIED
Rohrbach, MarianneUNSPECIFIEDorcid.org/0000-0002-4013-6012UNSPECIFIED
Janner, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Semler, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beleggia, FilippoUNSPECIFIEDorcid.org/0000-0003-0234-7094UNSPECIFIED
Li, YunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yigit, GoekhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reintjes, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cavalcanti, Denise P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zabel, BernhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Warman, Matthew L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bertola, Debora R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Netzer, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-131406
DOI: 10.1016/j.ajhg.2019.08.008
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 105
Number: 4
Page Range: S. 836 - 844
Date: 2019
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RECEPTOR-RELATED PROTEIN-6; LRP5; WNT1; OSTEOPOROSIS; TRAFFICKING; OSTEOBLASTS; BOCAMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/13140

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