Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta.

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, 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.

Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement.

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.

Genotype-phenotype study in type V osteogenesis imperfecta.

Type V osteogenesis imperfecta (OI) presents with moderate-to-severe skeletal deformity and is characterized by hyperplastic callus formation at fracture sites and calcification of the interosseous membranes of the forearm and lower leg. The facial dysmorphism is not well characterized and has not been described in previous reports. Inheritance is autosomal dominant, although the genetic aetiology remained unknown until very recently. The aims of this study were to establish the genetic aetiology in patients with type V OI and further characterize patients with this condition, and to ascertain whether they have a similar clinical phenotype and facial dysmorphism. Three families (one mother-daughter pair and two singletons) were identified with the above features and further investigations (molecular genetic analysis and skin biopsy including electron microscopy, histology and collagen species analysis) were performed. Accurate phenotyping of patients with type V OI was performed. PCR amplification was performed using the Sheffield Diagnostic Genetics Service pyrosequencing assay for the interferon-induced transmembrane protein-5 (IFITM5) gene. All the patients had been confirmed to have a heterozygous variant, c.[-14C>T];[=], in the 5'-UTR of the IFITM5 gene, which is located in the transcribed region of this gene. This recurrent mutation, in IFITM5, also known as bone-restricted interferon-induced transmembrane protein-like protein or BRIL, encodes a protein with a function in bone formation and plays an important role in osteoblast formation. All four patients in this study appear to have similar clinical features and facial dysmorphism, including a short, up-turned nose, a small mouth, a prominent chin and greyish-blue sclerae. Skin biopsy in one patient showed clumping of elastic fibres and normal biochemical analysis of collagen. We have been able to characterize patients with type V OI further and confirm the genetic aetiology in this distinct form of OI. Accurate phenotyping (including describing the common facial features) before investigations is important to enable the useful interpretation of genetic results and/or target-specific gene testing.