Novel mutations in the TCIRG1 gene encoding the a3 subunit of the vacuolar proton pump in patients affected by infantile malignant osteopetrosis

Fifty percent of the infantile malignant osteopetrosis (IMO) cases reported in the literature present mutations in the TCIRG1 gene encoding the 116‐kDa osteoclast specific subunit of the vacuolar proton ATPase (ATP6I). In this study, we identified four novel mutations in a series of six IMO patients. All of these mutations correspond to single nucleotide changes and affect splice acceptor or donor sites, resulting in aberrant transcription products. We report also a missense mutation, G405R, previously described in several Costa Rican patients. This independent finding suggests that the highly conserved residue at amino acid 405 plays a critical role in the a3 subunit function. Finally, the results of this study were used to provide a prenatal diagnosis to one of the families. Hum Mutat 21:151–157, 2003 © 2003 Wiley‐Liss, Inc.