Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta

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 HEK293Tcells, 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, OI-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.

The evolution of the nosology of osteogenesis imperfecta

“…The PLOD2 and SEC24D genes have been removed as pathological variants involved in OI 3, although PLOD2 remains listed as a pathological variant in BS type 2. Two new genes, SPARC 34 and TENT5A 35 have been identified and included as causal genes in OI 3.…”

Management of Endocrine Disease: Osteogenesis imperfecta: an update on clinical features and therapies

“…Some play an important role in the bone anabolic function of the WNT canonical signaling pathway (e.g. LRP5, WNT1, and MESD) and, in addition to OI, can be associated with generalized osteoporosis (WNT1) or similar conditions (LRP5 in osteoporosis pseudoglioma syndrome) (1,5).…”

Mechanisms of Bone Fragility: From Osteogenesis Imperfecta to Secondary Osteoporosis

“…Thus far, 24+ genes have been identified to cause OI ( Table 1 ). These include IFITM5 [ 5 , 6 ] [MIM: 614757], SERPINF1 [ 7 ] [MIM: 172860], CRTAP [ 8 ] [MIM: 605497], LEPRE1 [ 9 ] [MIM: 610339], P3H1 [ 10 ] [MIM: 610339], PPIB [ 11 ] [MIM: 123841], SERPINH1 [ 12 ] [MIM: 600943], FKBP10 [ 13 ] [MIM: 607063], SP7 [ 14 ] [MIM: 606633], BMP1 [ 15 ] [MIM: 112264], TMEM38B [ 16 ] [MIM: 611236], WNT1 [ 17 , 18 ] [MIM: 164820], CREB3L1 [ 19 ] [MIM: 616215], SPARC [ 20 ] [MIM: 182120], FAM46A [ 21 ] [MIM: 611357], MBTPS2 [ 22 ] [MIM: 300294], MESD [ 23 ] [MIM: 607783], SEC24D [ 24 ] [MIM: 607186], CCDC134 [ 25 ] [MIM: 618788], P4HB [ 26 ] [MIM: 176790], PLOD2 [ 27 ] [MIM: 601865], PLS3 [ 28 ] [MIM: 300131] and KDELR2 [MIM: 609024] [ 29 ]. These genes play a critical role in the processing and post-translational modification of type I collagen, the control of osteoblast differentiation or function or the formation of F-actin bundles.…”