Autosomal Dominant Osteopetrosis (ADO) Caused by a Missense Variant in the TCIRG1 Gene

dc.contributor.authorJodeh, Wade
dc.contributor.authorKatz, Amy J.
dc.contributor.authorHart, Marian
dc.contributor.authorWarden, Stuart J.
dc.contributor.authorNiziolek, Paul
dc.contributor.authorAlam, Imranul
dc.contributor.authorIng, Steven
dc.contributor.authorPolgreen, Lynda E.
dc.contributor.authorImel, Erik A.
dc.contributor.authorEcons, Michael J.
dc.contributor.departmentMedicine, School of Medicine
dc.date.accessioned2025-02-18T08:22:52Z
dc.date.available2025-02-18T08:22:52Z
dc.date.issued2024
dc.description.abstractContext: 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.
dc.identifier.citationJodeh W, Katz AJ, Hart M, et al. Autosomal Dominant Osteopetrosis (ADO) Caused by a Missense Variant in the TCIRG1 Gene. J Clin Endocrinol Metab. 2024;109(7):1726-1732. doi:10.1210/clinem/dgae040
dc.identifier.urihttps://hdl.handle.net/1805/45764
dc.language.isoen_US
dc.publisherOxford University Press
dc.relation.isversionof10.1210/clinem/dgae040
dc.relation.journalThe Journal of Clinical Endocrinology and Metabolism
dc.rightsPublisher Policy
dc.sourcePMC
dc.subjectAutosomal dominant osteopetrosis
dc.subjectTCIRG1
dc.subjectMissense
dc.subjectVariant
dc.titleAutosomal Dominant Osteopetrosis (ADO) Caused by a Missense Variant in the TCIRG1 Gene
dc.typeArticle
ul.alternative.fulltexthttps://pmc.ncbi.nlm.nih.gov/articles/PMC11180502/
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