TCIRG1 – Autosomal Recessive Osteopetrosis

Autosomal recessive osteopetrosis (ARO) is characterized by defective bone resorption due to nonfunctional osteoclasts. Biallelic pathogenic variants in TCIRG1 (HGNC:11647), encoding the a3 subunit of the vacuolar H⁺-ATPase, account for ~50% of infantile malignant osteopetrosis cases and follow autosomal recessive inheritance. The prototypical variant c.2414+1G>A disrupts splicing, abolishing ruffled border formation in osteoclasts (PMID:11856654).

In a multicenter series of six unrelated infantile cases, four novel TCIRG1 splice-site variants, including c.1213G>C (p.Gly405Arg), were identified in six probands, and a recurrent missense G405R allele was observed in Costa Rican founder families, supporting critical functional residues (PMID:12552563). A founder splice mutation c.807+5G>A in Chuvash patients showed high carrier frequency (1.68%; disease frequency ~1/3500) with classic bone-in-bone radiology (PMID:19172990).

Segregation studies within affected sibships revealed co-segregation of compound heterozygous TCIRG1 alleles in multiple families; for example, a Japanese kindred demonstrated two affected siblings carrying c.2236+1G>A and a frameshift in exon 9, confirming autosomal recessive transmission (PMID:11856654). Overall, ≥2 additional affected relatives have been documented in family‐based analyses.

The variant spectrum comprises loss-of-function alleles: 41 novel truncating, large genomic deletions, splice donor/acceptor defects, and missense substitutions clustered in the cytosolic domain. Common recurrent alleles include c.1674-1G>A (r.1674_1884del) and c.2005C>T (p.Arg669Ter), together representing ~30% of TCIRG1 mutations in Northern European cohorts (PMID:15300850; PMID:22231430).

Functional assays corroborate a loss-of-function mechanism: Atp6i-knockout mice recapitulate absent ruffled borders; U1 snRNA correction of splice defects restores normal transcript processing in minigene assays (PMID:15300850); lentiviral complementation of c.1127+?G>A iPSCs rescued CTX-I release to 35% of control, verifying haploinsufficiency and offering a platform for therapeutic development (PMID:32414402).

In summary, definitive gene-disease validity is established for TCIRG1 in ARO based on extensive proband counts (>200), multi-family segregation, and concordant in vivo and in vitro functional data. Clinical genetic testing for TCIRG1 should be prioritized in infants presenting with osteosclerosis, hepatosplenomegaly, anemia, extramedullary hematopoiesis, and absent osteoclast ruffled borders. Hematopoietic stem cell transplantation can be guided by molecular diagnosis to optimize outcomes.

References

• Bone • 2002 • Novel mutations in the a3 subunit of vacuolar H(+)-adenosine triphosphatase in a Japanese patient with infantile malignant osteopetrosis. PMID:11856654
• Human Mutation • 2003 • Novel mutations in the TCIRG1 gene encoding the a3 subunit of the vacuolar proton pump in patients affected by infantile malignant osteopetrosis. PMID:12552563
• Human Mutation • 2004 • TCIRG1-dependent recessive osteopetrosis: mutation analysis, functional identification of the splicing defects, and in vitro rescue by U1 snRNA. PMID:15300850
• Osteoporosis International • 2012 • Autosomal recessive osteopetrosis: report of 41 novel mutations in the TCIRG1 gene and diagnostic implications. PMID:22231430
• Stem Cell Research & Therapy • 2020 • Generation of gene-corrected functional osteoclasts from osteopetrotic induced pluripotent stem cells. PMID:32414402

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