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- Title
Autosomal Dominant Osteopetrosis (ADO) Caused by a Missense Variant in the TCIRG1 Gene.
- Authors
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
- Abstract
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.
- Subjects
MISSENSE mutation; OSTEOPETROSIS; GENETIC variation; RECESSIVE genes; PHENOTYPIC plasticity; CHLORIDE channels; FRACTURE healing; T cells
- Publication
Journal of Clinical Endocrinology & Metabolism, 2024, Vol 109, Issue 7, p1726
- ISSN
0021-972X
- Publication type
Article
- DOI
10.1210/clinem/dgae040