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 molecular analysis of genes TCIRG1, CLCN7, OSTM1, that are responsible for approximately 70% of autosomal recessive osteopetrosis cases, was performed by amplification and sequencing of all exons and intron-exon boundaries.
Although genetic studies have not been performed, the biochemical changes with increased LD and AST are highly suggestive of a chloride channel, voltage-sensitive 7 (CLCN7) (8) mutation (5).
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).
A novel CLCN7
mutation resulting in a most severe form of autosomal recessive osteopetrosis.
Chloride Channel ClCN7
Mutations Are Responsible for Severe Recessive, Dominant, and Intermediate Osteopetrosis.
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).
Most ARO cases have been ascribed to mutations in the TCIRG1 gene and only a few cases have been ascribed to mutations in the CLCN7 gene (10).
The expression of Clcn7
and Ostm1 in osteoclasts is coregulated by microphthalmia transcription factor.
(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).
Other genes mutated in ARO are CLCN7
and OSTM1, that together form a chloride channel or chloride/proton-exchanger which also resides in the ruffled membrane and facilitates acidification (5,6).
ADO2 is caused by heterozygous mutations in the chloride channel 7 (ClCN7
) gene, located on chromosome 16p13.3 (6-8).