Alternative titles; symbols
ORPHA: 667; DO: 0110944;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.3 | Osteopetrosis, autosomal recessive 4 | 611490 | Autosomal recessive | 3 | CLCN7 | 602727 |
A number sign (#) is used with this entry because of evidence that autosomal recessive osteopetrosis-4 (OPTB4) is caused by homozygous or compound heterozygous mutation in the CLCN7 gene (602727) on chromosome 16p13.
An autosomal dominant form of osteopetrosis (OPTA2; 166600) is also caused by mutation in CLCN7.
Autosomal recessive osteopetrosis-4 (OPTB4) is characterized by severe osteosclerosis, pathologic fractures, hepatosplenomegaly, and pancytopenia. Increased bone density and early signs of optic nerve atrophy are apparent in infancy (Cleiren et al., 2001, Lam et al., 2007).
For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive osteopetrosis, see OPTB1 (259700).
Cleiren et al. (2001) reported a girl, born to second-cousin parents of Chinese ancestry, who presented at 3 months of age with Bell palsy. Radiographic skeletal survey revealed severe osteopetrosis and several nondisplaced oblique fractures. She had anemia, reticulocytosis, hepatosplenomegaly, and mild optic nerve atrophy. The child underwent a mismatched allogeneic marrow transplant but died at age 18 months from sepsis and respiratory failure.
The transmission pattern of OPTB4 in the family reported by Cleiren et al. (2001) was consistent with autosomal recessive inheritance.
Based on the similarity between the phenotype of patients with infantile malignant osteopetrosis and that of mice with targeted disruption of the Clcn7 gene (see 602727), which develop severe osteopetrosis and retinal degeneration, Kornak et al. (2001) searched for mutations in the human CLCN7 gene in 12 patients with infantile osteopetrosis. They identified compound heterozygosity for a nonsense (Q555X; 602727.0001) and a missense (R762Q; 602727.0002) mutation in the CLCN7 gene in 1 patient with infantile malignant osteopetrosis who had early visual impairment. No retinal histology was available.
In a girl with severe autosomal recessive infantile osteopetrosis born to consanguineous parents of Chinese ancestry, Cleiren et al. (2001) identified homozygosity for a missense mutation (L766P; 602727.0003) in the CLCN7 gene. Her parents, who were heterozygous for the mutation, were asymptomatic, but radiographic skeletal survey was unavailable. Because OPTB4 patients are homozygous whereas patients with autosomal dominant osteopetrosis-2 (OPTA2; 166600) are heterozygous for mutations in CLCN7, the 2 disorders appear to be allelic. Cleiren et al. (2001) hypothesized that OPTA2 reflects a dominant-negative effect, since loss-of-function mutations in CLCN7 do not cause abnormalities in heterozygous individuals.
Using whole-genome scans based on high density single-nucleotide polymorphism (SNP) microarray for homozygosity mapping, Lam et al. (2007) investigated a consanguineous Chinese family in which a sister and brother had malignant osteopetrosis. Mapping revealed that among the 3 possible causal loci, only the CLCN7 gene was located in an autozygous region. Sequencing of CLCN7 showed that the proband and her affected brother were homozygous for a novel missense mutation (I261F; 602727.0006). Their unaffected first-cousin parents and an unaffected brother were heterozygous for the mutation, which was not found in 50 Chinese controls.
Cleiren, E., Benichou, O., Van Hul, E., Gram, J., Bollerslav, J., Singer, F. R., Beaverson, K., Aledo, A., Whyte, M. P., Yoneyama, T., deVernejou, M.-C., Van Hul, W. Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum. Molec. Genet. 10: 2861-2867, 2001. [PubMed: 11741829] [Full Text: https://doi.org/10.1093/hmg/10.25.2861]
Kornak, U., Kasper, D., Bosl, M. R., Kaiser, E., Schweizer, M., Schulz, A., Friedrich, W., Delling, G., Jentsch, T. J. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell 104: 205-215, 2001. [PubMed: 11207362] [Full Text: https://doi.org/10.1016/s0092-8674(01)00206-9]
Lam, C.-W., Tong, S.-F., Wong, K., Luo, Y. F., Tang, H.-Y., Ha, S.-Y., Chan, M. H.-M. DNA-based diagnosis of malignant osteopetrosis by whole-genome scan using a single-nucleotide polymorphism microarray: standardization of molecular investigations of genetic diseases due to consanguinity. J. Hum. Genet. 52: 98-101, 2007. [PubMed: 17033731] [Full Text: https://doi.org/10.1007/s10038-006-0075-4]