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PLoS Genetics Nov 2023Kinesin motor proteins transport intracellular cargo, including mRNA, proteins, and organelles. Pathogenic variants in kinesin-related genes have been implicated in...
BACKGROUND
Kinesin motor proteins transport intracellular cargo, including mRNA, proteins, and organelles. Pathogenic variants in kinesin-related genes have been implicated in neurodevelopmental disorders and skeletal dysplasias. We identified de novo, heterozygous variants in KIF5B, encoding a kinesin-1 subunit, in four individuals with osteogenesis imperfecta. The variants cluster within the highly conserved kinesin motor domain and are predicted to interfere with nucleotide binding, although the mechanistic consequences on cell signaling and function are unknown.
METHODS
To understand the in vivo genetic mechanism of KIF5B variants, we modeled the p.Thr87Ile variant that was found in two patients in the C. elegans ortholog, unc-116, at the corresponding position (Thr90Ile) by CRISPR/Cas9 editing and performed functional analysis. Next, we studied the cellular and molecular consequences of the recurrent p.Thr87Ile variant by microscopy, RNA and protein analysis in NIH3T3 cells, primary human fibroblasts and bone biopsy.
RESULTS
C. elegans heterozygous for the unc-116 Thr90Ile variant displayed abnormal body length and motility phenotypes that were suppressed by additional copies of the wild type allele, consistent with a dominant negative mechanism. Time-lapse imaging of GFP-tagged mitochondria showed defective mitochondria transport in unc-116 Thr90Ile neurons providing strong evidence for disrupted kinesin motor function. Microscopy studies in human cells showed dilated endoplasmic reticulum, multiple intracellular vacuoles, and abnormal distribution of the Golgi complex, supporting an intracellular trafficking defect. RNA sequencing, proteomic analysis, and bone immunohistochemistry demonstrated down regulation of the mTOR signaling pathway that was partially rescued with leucine supplementation in patient cells.
CONCLUSION
We report dominant negative variants in the KIF5B kinesin motor domain in individuals with osteogenesis imperfecta. This study expands the spectrum of kinesin-related disorders and identifies dysregulated signaling targets for KIF5B in skeletal development.
Topics: Animals; Humans; Mice; Caenorhabditis elegans; Carrier Proteins; Down-Regulation; Kinesins; NIH 3T3 Cells; Osteogenesis Imperfecta; Proteomics; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 37934770
DOI: 10.1371/journal.pgen.1011005 -
Frontiers in Endocrinology 2023
Topics: Animals; Zebrafish; Musculoskeletal Diseases
PubMed: 38053724
DOI: 10.3389/fendo.2023.1331690 -
Genes Sep 2023The formation and maintenance of the gross structure and microarchitecture of the human skeleton require the concerted functioning of a plethora of morphogenic signaling... (Review)
Review
The formation and maintenance of the gross structure and microarchitecture of the human skeleton require the concerted functioning of a plethora of morphogenic signaling processes. Through recent discoveries in the field of genetics, numerous genotypic variants have been implicated in pathologic skeletal phenotypes and disorders arising from the disturbance of one or more of these processes. For example, total loss-of-function variants of were found to be the cause of osteoporosis-pseudoglioma syndrome (OPPG). encodes for the low-density lipoprotein receptor-related protein 5, a co-receptor in the canonical WNT-β-catenin signaling pathway and a crucial protein involved in the formation and maintenance of homeostasis of the human skeleton. Beyond OPPG, other partial loss-of-function variants of have been found to be associated with other low bone mass phenotypes and disorders, while gain-of-function variants have been implicated in high bone mass phenotypes. This review introduces the roles that plays in skeletal morphogenesis and discusses some of the structural consequences that result from abnormalities in . A greater understanding of how the LRP5 receptor functions in bone and other body tissues could provide insights into a variety of pathologies and their potential treatments, from osteoporosis and a variety of skeletal abnormalities to congenital disorders that can lead to lifelong disabilities.
Topics: Humans; Bone Density; Osteoporosis; Osteogenesis Imperfecta; Bone and Bones; Low Density Lipoprotein Receptor-Related Protein-5
PubMed: 37895195
DOI: 10.3390/genes14101846 -
The Journal of Clinical Endocrinology... Jun 2024Denosumab is a potential therapeutic agent for osteogenesis imperfecta (OI), but its efficacy and safety remain unclear in children with OI. (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
CONTEXT
Denosumab is a potential therapeutic agent for osteogenesis imperfecta (OI), but its efficacy and safety remain unclear in children with OI.
OBJECTIVE
We aimed to investigate the effects of denosumab on bone mineral density (BMD), spinal morphometry, and safety in children with OI compared with zoledronic acid.
METHODS
In this prospective study, 84 children or adolescents with OI were randomized to receive denosumab subcutaneous injection every 6 months or zoledronic acid intravenous infusion once. Changes of BMD and its Z-score, vertebral shape, serum levels of calcium and bone turnover biomarkers were assessed during the 1-year treatment.
RESULTS
After 12 months of treatment, BMD at the lumbar spine, femoral neck, and total hip significantly increased by 29.3%, 27.8%, and 30.2% in the denosumab group, and by 32.2%, 47.1%, and 41.1% in the zoledronic acid group (all P < .001 vs baseline). Vertebral height and projection area significantly increased after denosumab and zoledronic acid treatment. Rebound hypercalcemia was found to be a common and serious side effect of denosumab, of which 14.3% reached hypercalcemic crisis. Rebound hypercalcemia could be alleviated by switching to zoledronic acid treatment.
CONCLUSION
Treatment with denosumab or zoledronic acid is beneficial in increasing BMD and improving the spinal morphometry of children with OI. However, denosumab should be used with caution in pediatric patients with OI because of its common and dangerous side effect of rebound hypercalcemia. The appropriate dosage and dosing interval of denosumab need to be further explored in children with OI.
Topics: Humans; Denosumab; Osteogenesis Imperfecta; Child; Female; Male; Bone Density; Bone Density Conservation Agents; Zoledronic Acid; Child, Preschool; Adolescent; Prospective Studies; Treatment Outcome; Bone Remodeling
PubMed: 38198649
DOI: 10.1210/clinem/dgad732 -
European Journal of Medical Genetics Nov 2023Osteogenesis imperfecta (OI) type VI is an extremely rare form of OI caused by biallelic variants in the SERPINF1 gene, which codes for the pigment-epithelium derived...
Osteogenesis imperfecta (OI) type VI is an extremely rare form of OI caused by biallelic variants in the SERPINF1 gene, which codes for the pigment-epithelium derived factor (PEDF). We report on four patients (three adults and one adolescent) with a severe deforming form of OI. All patients presented no abnormalities at birth, frequent long bone and vertebrae fractures (mainly during childhood), marked short stature, severe bone deformities, chronic mild to moderate pain, and severe limitation of mobility, with three being completely wheelchair bound. Blue sclera and dentinogenesis imperfecta were absent, although some patients presented tooth, ophthalmological, and/or cardiac features. Radiographic findings included, among others, thin diaphysis and popcorn calcifications, both of which are non-specific to this type of OI. The novel homozygous variants c.816_819del (p.Met272Ilefs*8) and c.283+2T > G in SERPINF1 were identified in three and one patient, respectively. The three patients carrying the frameshift variant were born in nearby regions suggesting a founder effect. Describing the long-term outcomes of four patients with OI type VI, this cohort adds relevant data on the clinical features and prognosis of this type of OI.
Topics: Adolescent; Adult; Humans; Infant, Newborn; Collagen Type I; Frameshift Mutation; Homozygote; Osteogenesis Imperfecta; Serpins
PubMed: 37839784
DOI: 10.1016/j.ejmg.2023.104867 -
Disability and Rehabilitation Jun 2024The aim of this qualitative study was to investigate resilience among adults with Osteogenesis Imperfecta (OI).
PURPOSE
The aim of this qualitative study was to investigate resilience among adults with Osteogenesis Imperfecta (OI).
MATERIALS AND METHODS
Semi-structured interviews were conducted with 15 adults with OI. Transcripts were coded and subsequently abstracted, yielding themes specific to resilience and coping. Interview guides covered broad topics including pain challenges specific to OI, mental health issues related to OI, and priorities for future interventions for individuals with OI.
RESULTS
Participants described resilience in the context of OI as the ability to grow from adversity, adapt to challenges resulting from OI-related injuries, and find identities apart from their condition. Psychological coping strategies included acceptance, self-efficacy, cognitive reframing, perspective-taking, and positivity. Behavioral factors that helped participants develop resilience included developing new skills, pursuing meaningful goals, practicing spirituality, and seeking external resources such as psychotherapy, education, and connection with community.
CONCLUSION
Having identified how adults with OI define resilience and the strategies they use to cope, we can now develop interventions and guide healthcare providers in improving psychological wellbeing in this population.
PubMed: 38841844
DOI: 10.1080/09638288.2024.2358903 -
Frontiers in Pediatrics 2023Children with skeletal dysplasia are frequently referred to pediatric endocrinologists due to short stature. These children may present with disproportionate growth or... (Review)
Review
Children with skeletal dysplasia are frequently referred to pediatric endocrinologists due to short stature. These children may present with disproportionate growth or medical histories that point to a skeletal dysplasia. This primer will discuss when to be concerned about skeletal dysplasia, the initial steps in evaluation for a skeletal dysplasia, and new therapies that are either recently approved or in development.
PubMed: 37675393
DOI: 10.3389/fped.2023.1229666 -
Ceskoslovenska Patologie 2023We present a comprehensive review dealing with rare genetic skeletal disorders. More than 400 entities are included in the latest classification. The most severe or... (Review)
Review
We present a comprehensive review dealing with rare genetic skeletal disorders. More than 400 entities are included in the latest classification. The most severe or lethal phenotypes are identifiable in the prenatal period and the pregnancy can be terminated. Perinatal autopsy and posmortem X-rays are crucial in providing a definitive diagnosis. The number of cases confirmed by genetic testing is increasing. We report our own experience with genetic skeletal disorders based on 41 illustrative fetal and neonatal cases which we encountered over a 10-year period. Thanatophoric dysplasia and osteogenesis imperfecta represent approximately half of the cases coming to autopsy. Achondrogenesis type 2 and hypochondrogenesis, short-rib dysplasia, chondrodysplasia punctata, campomelic dysplasia and achondroplasia are less common. Skeletal dysplasias with autosomal recessive inheritance are the least frequent, e.g. perinatally lethal hypophophatasia, achondrogenesis type 1A, diastrophic dysplasia/atelosteogenesis type 2 or mucolipidosis type 2 (I cell disease).
Topics: Pregnancy; Female; Humans; Osteochondrodysplasias; Thanatophoric Dysplasia; Campomelic Dysplasia; Receptor, Fibroblast Growth Factor, Type 3; Fetus
PubMed: 37468326
DOI: No ID Found -
JBMR Plus Jul 2023Mutations in the COL1A1 and COL1A2 genes, which encode type I collagen, are present in around 85%-90% of osteogenesis imperfecta (OI) patients. Because type I collagen...
Mutations in the COL1A1 and COL1A2 genes, which encode type I collagen, are present in around 85%-90% of osteogenesis imperfecta (OI) patients. Because type I collagen is the principal protein composition of bones, any changes in its gene sequences or synthesis can severely affect bone structure. As a result, skeletal deformity and bone frailty are defining characteristics of OI. Homozygous mice are utilized as models of severe progressive type III OI. Bone adapts to external forces by altering its mass and architecture. Previous attempts to leverage the relationship between muscle and bone involved using a soluble activin receptor type IIB-mFc (sActRIIB-mFc) fusion protein to lower circulating concentrations of activin A and myostatin. These two proteins are part of the TGF-β superfamily that regulate muscle and bone function. While this approach resulted in increased muscle masses and enhanced bone properties, adverse effects emerged due to ligand promiscuity, limiting clinical efficacy and obscuring the precise contributions of myostatin and activin A. In this study, we investigated the musculoskeletal and whole-body metabolism effect of treating 5-week-old wildtype (Wt) and / mice for 11 weeks with either control antibody (Ctrl-Ab) or monoclonal anti-activin A antibody (ActA-Ab), anti-myostatin antibody (Mstn-Ab), or a combination of ActA-Ab and Mstn-Ab (Combo). We demonstrated that ActA-Ab treatment minimally impacts muscle mass in / mice, whereas Mstn-Ab and Combo treatments substantially increased muscle mass and overall lean mass regardless of genotype and sex. Further, while no improvements in cortical bone microarchitecture were observed with all treatments, minimal improvements in trabecular bone microarchitecture were observed with the Combo treatment in / mice. Our findings suggest that individual or combinatorial inhibition of myostatin and activin A alone is insufficient to robustly improve femoral biomechanical and microarchitectural properties in severely affected OI mice. © 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
PubMed: 37457877
DOI: 10.1002/jbm4.10753 -
Graefe's Archive For Clinical and... Sep 2023Osteogenesis imperfecta (OI) is a rare inherited disease affecting collagen-rich tissues. Ocular complications have been reported such as thin corneas, low ocular...
PURPOSE
Osteogenesis imperfecta (OI) is a rare inherited disease affecting collagen-rich tissues. Ocular complications have been reported such as thin corneas, low ocular rigidity, keratoconus, among others. The purpose of this study is to characterize corneal tomographic features in OI patients compared to unaffected patients, with particular focus on commonly studied keratoconus indices.
METHODS
Cross-sectional case-control study including 37 OI patients and 37 age-matched controls. Patients and controls underwent comprehensive ophthalmological examination including corneal Scheimpflug tomography with a Pentacam HR device (Oculus Optikgeräte GmbH, Wetzlar, Germany) to analyse and compare topometric, tomographic, pachymetric and Belin-Ambrósio Enhanced Ectasia Display III (BAD-D) data of both eyes of each patient.
RESULTS
Most OI patients had type I disease (n = 24; 65%) but type III-VII patients were also included. Two patients had clinically overt bilateral keratoconus. OI patients had significantly higher maximum keratometry (45.2 ± 2.1 vs. 43.7 ± 1.2; p = 0.0416), front and back elevation (3.0 ± 3.3 vs. 2.1 ± 1.3, p = 0.0201; 11.1 ± 8.2 vs. 5.0 ± 3.7, p < 0.0001), index of surface variance (25.5 ± 13 vs. 17.4 ± 8.3; p = 0.0016), index of vertical asymmetry (0.21 ± 0.14 vs. 0.15 ± 0.06; p = 0.0215), index of height asymmetry (9.2 ± 14 vs. 6.0 ± 4.5; p = 0.0421), index of height decentration (0.02 ± 0.01 vs. 0.01 ± 0.01; p < 0.0001) and average pachymetric progression (1.01 ± 0.19 vs. 0.88 ± 0.14; p < 0.0001) readings. Thinnest corneal thickness and maximum Ambrósio relational thickness were significantly lower (477 ± 52 vs. 543 ± 26; 387 ± 95 vs. 509 ± 49; p < 0.0001). Two-thirds of OI patients had corneas with a minimum thickness < 500 µm. BAD-D value was significantly higher in OI patients (2.1 ± 1.4 vs. 0.9 ± 0.2; p < 0.0001).
CONCLUSION
OI patients showed significant changes in corneal profiles compared with healthy subjects. A high proportion of patients had tomographically suspect corneas when using keratoconus diagnostic indices. Further studies are warranted to assess the true risk of corneal ectasia in OI patients.
Topics: Humans; Keratoconus; Corneal Topography; Case-Control Studies; Corneal Pachymetry; Osteogenesis Imperfecta; Dilatation, Pathologic; Cross-Sectional Studies; ROC Curve; Cornea; Tomography; Retrospective Studies
PubMed: 37074408
DOI: 10.1007/s00417-023-06059-4