TCIRG1 – Osteopetrosis

Autosomal recessive osteopetrosis (ARO) is a severe skeletal disorder characterized by impaired osteoclast‐mediated bone resorption and early mortality. The TCIRG1 gene (HGNC:11647) encodes the a3 subunit of the vacuolar H⁺‐ATPase essential for osteoclast acidification. Biallelic TCIRG1 mutations account for over 50% of ARO cases, presenting as infantile malignant osteopetrosis with failure of hematopoiesis and neurovascular complications (PMID:22280207; PMID:24535484).

Genetic evidence includes analysis of 55 unrelated ARO patients revealing nine novel TCIRG1 mutations, among them splice‐site variants and protein‐truncating alleles in 30% of mutant alleles (PMID:15300850). In silico and segregation studies in consanguineous Pakistani families identified a homozygous frameshift deletion c.624delC (p.Val209_Cys238del) in exon 6, confirming loss‐of‐function in affected individuals (PMID:29237407).

The variant spectrum spans missense substitutions, canonical splice‐site mutations, frameshift indels, and deep intronic changes. Recurrent mutations include c.909C>A (p.Tyr303Ter) and c.2008C>T (p.Arg670Ter), observed as compound heterozygotes with CLCN7 in complex phenotypes (PMID:24535484). No common founder alleles have been reported.

Phenotypic features extend beyond dense brittle bones to include anemia, thrombocytopenia, hypophosphatemia, pulmonary arterial hypertension, optic atrophy, and failure to thrive, reflecting bone marrow failure and abnormal monocyte/macrophage function (PMID:22280207; PMID:23412864). Hematopoietic stem cell transplantation remains the only curative intervention.

Functional studies demonstrate that splice‐site mutations (e.g., c.117+4A>T, c.1673+5G>A) disrupt TCIRG1 pre‐mRNA processing in hybrid minigene assays, partially rescued by U1 snRNA complementation (PMID:15300850). Missense mutations such as p.Arg444Leu cause ER retention and misprocessing of a3, abrogating lysosomal trafficking and acidification (PMID:22685294), while intronic variants in intron 15 reduce normal transcript levels, correlating with milder intermediate phenotypes (PMID:25829125).

Integration of genetic and functional data supports a Strong gene‐disease association: over 55 probands with biallelic LoF variants, consistent segregation in multiple families, and concordant in vitro and in vivo loss‐of‐function assays. The ClinGen genetic evidence is Strong (ClinGen cap reached) and functional evidence is Moderate. Genetic testing for TCIRG1 is recommended in infants with high bone density and marrow failure to guide early stem cell therapy. Key take-home: TCIRG1 loss‐of‐function mutations cause autosomal recessive osteopetrosis with a robust genetic and functional evidence base, enabling accurate diagnosis and timely intervention.

References

• Pediatric and developmental pathology • 2012 • A novel TCIRG1 gene mutation leads to severe osteopetrosis with altered content of monocytes/macrophages in several organs. PMID:22280207
• Molecular medicine reports • 2014 • Identification of TCIRG1 and CLCN7 gene mutations in a patient with autosomal recessive osteopetrosis. PMID:24535484
• BMC medical genetics • 2017 • Identification and in silico characterization of a novel p.P208PfsX1 mutation in V-ATPase a3 subunit associated with autosomal recessive osteopetrosis in a Pakistani family. PMID:29237407
• Human mutation • 2004 • TCIRG1-dependent recessive osteopetrosis: mutation analysis, functional identification of the splicing defects, and in vitro rescue by U1 snRNA. PMID:15300850
• The Journal of biological chemistry • 2012 • Osteopetrosis mutation R444L causes endoplasmic reticulum retention and misprocessing of vacuolar H+-ATPase a3 subunit. PMID:22685294
• Journal of bone and mineral research • 2015 • Buried in the Middle but Guilty: Intronic Mutations in the TCIRG1 Gene Cause Human Autosomal Recessive Osteopetrosis. PMID:25829125
• Journal of pediatric endocrinology & metabolism • 2013 • A case of autosomal dominant osteopetrosis type II with a novel TCIRG1 gene mutation. PMID:23412864

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