Novel mutation of TCIRG1 and clinical pictures of two infantile malignant osteopetrosis patients

Infantile malignant osteopetrosis (IMO) (OMIM 259700) is a lethal autosomal recessive disease. The underlying gene in most IMO patients is TCIRG1. This codes for the TCIRG1 protein involved in the cellular proton pump, which is highly expressed on surfaces of osteoclasts. We have characterized a family comprising two affected siblings born to healthy parents. The sister and her younger brother both presented classical X-ray images of IMO at 17 h and 16 weeks, respectively, after birth, and both died after the appearance of fever and flu-like symptoms months later. Radiographs revealed normal bone density in both parents. Mutation detection of the TCIRG1 gene was performed in the boy and the parents. The novel mutation c.242delC (p.Pro81ArgfsX85) and the known mutation c.1114C>T (p.Gln372X) were both identified in the boy. Both mutations are predicted to introduce premature stop codons, with deletion of 666 amino acids from the C terminus of the TCIRG1 protein of one allele and 459 from the other. Both mutations involve loss of part or the whole of the ATPase V0-complex domain of the protein. The father carries the c.242delC (p.Pro81ArgfsX85) mutation and the mother the c.1114C>T (p.Gln372X). Our findings provide new data for pre- and post-natal genetic diagnosis and identification of heterozygous carriers of the disease.