Infantile Malignant Osteopetrosis is a severe form of osteopetrosis most commonly caused by a genetic mutation of the TCIRG1
gene which leads to ineffective osteoclast function.
Clinical features include bone marrow failure resulting in pancytopenia, hepatosplenomegaly, blindness secondary to optic nerve compression, hydrocephalus, and other neurological complications. T-cell immune regulator 1 (TCIRG1, Gene ID: 10312) is one of the main genes that are responsible for the majority of IMO cases.
Mutation analysis of the TCIRG1 gene was performed using direct DNA sequencing of polymerase chain reaction-amplified exons.
Several genes have been revealed to be involved in ARO pathology, TCIRG1
mutated in approximately 50% of cases, CLCN7 in 10-15% of all ARO patients (1), OSTM1 in 4%, five other genes in 5% of patients, and the remaining with unknown molecular pathology (3).
The main genes are the osteoclast-specific proton pump subunit, T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 sub-unit A3 (TCIRG1
) (encodes the a3 subunit of vacuolar ATPase), CLCN7 (encodes the osteoclast-specific chloride channel), and carbonic anhydrase II (CA2) (1-3).
This rare genetic disease is associated with four genes TCIRG1
, CICN7, OSTM1, PLEKHM1.
ARO can result from mutations in the TCIRG1
gene (T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 protein a isoform 3) (3) the CLCN7 gene (chloride channel 7) (4) the OSTM1 gene (osteopetrosis-associated transmembrane protein 1) (5) the TNFSF11 gene (tumour necrosis factor ligand superfamily, member 11 encoding receptor activator for nuclear factor kappa b ligand, RANKL) (6), the TNFRSF11A gene (tumour necrosis factor ligand superfamily, member 11A encoding receptor activator of nuclear factor-kappa B, RANK) (7) or PLEKHM1 gene (pleckstrin homology domain-containing protein, family M, member) (8) and CA2 gene (carbonic anhydrase II) (9).
(6) Two genes have been shown to be associated with osteopetrosis: Atp6a3 (TCIRG1
) associated with type 1 (autosomal recessive) and ClCN7 associated with type 2 (autosomal dominant).