Browsing by Author "Niziolek, Paul"

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    Autosomal Dominant Osteopetrosis (ADO) Caused by a Missense Variant in the TCIRG1 Gene
    (Oxford University Press, 2024) Jodeh, Wade; Katz, Amy J.; Hart, Marian; Warden, Stuart J.; Niziolek, Paul; Alam, Imranul; Ing, Steven; Polgreen, Lynda E.; Imel, Erik A.; Econs, Michael J.; Medicine, School of Medicine
    Context: Autosomal dominant osteopetrosis (ADO) is a rare genetic disorder resulting from impaired osteoclastic bone resorption. Clinical manifestations frequently include fractures, osteonecrosis (particularly of the jaw or maxilla), osteomyelitis, blindness, and/or bone marrow failure. ADO usually results from heterozygous missense variants in the Chloride Channel 7 gene (CLCN7) that cause disease by a dominant negative mechanism. Variants in the T-cell immune regulator 1 gene (TCIRG1) are commonly identified in autosomal recessive osteopetrosis but have only been reported in 1 patient with ADO. Case description: Here, we report 3 family members with a single heterozygous missense variant (p.Gly579Arg) in TCIRG1 who have a phenotype consistent with ADO. Three of 5 protein prediction programs suggest this variant likely inhibits the function of TCIRG1. Conclusion: This is the first description of adult presentation of ADO caused by a TCIRG1 variant. Similar to families with ADO from CLCN7 mutations, this variant in TCIRG1 results in marked phenotype variability, with 2 subjects having severe disease and the third having very mild disease. This family report implicates TCIRG1 missense mutations as a cause of ADO and demonstrates that the marked phenotypic variability in ADO may extend to disease caused by TCIRG1 missense mutations.
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    Suppression of sost/sclerostin and dikkopf-1 augment intervertebral disc structure in mice
    (Wiley, 2022) Kroon, Tori; Bhadouria, Neharika; Niziolek, Paul; Edwards, Daniel; Clinkenbeard, Erica L.; Robling, Alexander; Holguin, Nilsson; Biomedical Engineering, School of Engineering and Technology
    Intervertebral disc (IVD) degeneration is a leading cause of low back pain, characterized by accelerated extracellular matrix breakdown and IVD height loss but there is no approved pharmacological therapeutic. Deletion of Wnt ligand competitor Lrp5 induces IVD degeneration, suggesting that Wnt signaling is essential for IVD homeostasis. Therefore, the IVD may respond to neutralization of Wnt ligand competitors sost(gene)/sclerostin(protein) and/or dikkopf-1 (dkk1). Anti-sclerostin antibody (scl-Ab) is an FDA-approved bone therapeutic that activates Wnt signaling. We (1) determined if pharmacological neutralization of sclerostin, dkk1 or their combination would stimulate Wnt signaling and augment IVD structure and (2) determined the prolonged adaptation of the IVD to global, persistent deletion of sost. Nine-week-old C57Bl/6J female mice (n = 6-7/grp) were subcutaneously injected 2x/wk for 5.5 wk with scl-Ab (25 mg/kg), dkk1-Ab (25 mg/kg), 3:1 scl-Ab/dkk1-Ab (18.75:6.25 mg/kg) or vehicle (veh). Separately, IVD of sost KO and wildtype (WT) mice (n = 8/grp) were harvested at 16 weeks of age. First, compared to vehicle, injection of scl-Ab, dkk1-Ab and 3:1 scl-Ab/dkk1-Ab similarly increased lumbar IVD height and β-catenin gene expression. Despite these similarities, only injection of scl-Ab alone strengthened IVD mechanical properties and decreased heat shock protein gene expressions. Genetically and compared to WT, sost KO enlarged IVD height, increased proteoglycan staining and imbibed IVD hydration. Notably, persistent deletion of sost was compensated by upregulation of dkk1, which consequently reduced the cell nuclear fraction for Wnt signaling co-transcription factor β-catenin in the IVD. Lastly, RNA-sequencing pathway analysis confirmed the compensatory suppression of Wnt signaling and revealed a reduction of cellular stress-related pathways. Together, suppression of sost/sclerostin or dkk1 each augmented IVD structure by stimulating Wnt signaling, but scl-Ab outperformed dkk1-Ab in strengthening the IVD. Ultimately, postmenopausal women prescribed scl-Ab injections to prevent vertebral fracture may also benefit from a restoration of IVD height and health.
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    Unusual Cortical Phenotype After Hematopoietic Stem Cell Transplantation in a Patient With Osteopetrosis
    (Wiley, 2022-04-29) Afshariyamchlou, Sonia; Ng, Michelle; Ferdjallah, Asmaa; Warden, Stuart J.; Niziolek, Paul; Alam, Imranul; Polgreen, Lynda E.; Imel, Erik A.; Orchard, Paul; Econs, Michael J.; Medicine, School of Medicine
    The osteopetroses are a group of rare genetic diseases caused by osteoclast dysfunction or absence. The hallmark of osteopetrosis is generalized increased bone mineral density (BMD). However, the bone is fragile and fractures are common. Autosomal recessive osteopetrosis is usually a severe disorder and often life-threatening in childhood. We present male siblings with autosomal recessive osteopetrosis due to biallelic variants in TCIRG1 who survived childhood and underwent hematopoietic stem cell transplant (HSCT) in adulthood. One sibling died of posttransplant complications. After transplant, the other sibling had improvement of multiple clinical parameters, including some decline in BMD Z-scores by dual-energy X-ray absorptiometry (DXA) and cessation of fractures. However, spine quantitative computed tomography 11 years after transplant demonstrated an anvil pattern of sclerosis with BMD Z-score of +18.3. High-resolution peripheral quantitative computed tomography (HR-pQCT) of the tibia demonstrated near complete obliteration of the marrow space combined with an unusual cortical phenotype, suggesting extensive cortical porosity at the distal tibia. This case highlights that despite successful transplantation and subsequent improvement in clinical parameters, this patient continued to have significantly elevated bone density and decreased marrow space. Transplant-associated increased cortical porosity is multifactorial and occurs in two-thirds of non-osteopetrotic patients undergoing HSCT. This finding after transplant in osteopetrosis may suggest particular sensitivity of the cortical bone to resorptive activity of transplanted osteoclasts. The case also suggests HR-pQCT may be a useful modality for imaging and assessing the therapeutic effects on bone in individuals with osteopetrosis.