The mutational spectrum of human malignant autosomal recessive osteopetrosis

Abstract

Human malignant infantile osteopetrosis (arOP; MIM 259700) is a genetically heterogeneous autosomal recessive disorder of bone metabolism, which, if untreated, has a fatal outcome. Our group, as well as others, have recently identified mutations in the ATP6i (TCIRG1) gene, encoding the a3 subunit of the vacuolar proton pump, which mediates the acidification of the bone/osteoclast interface, are responsible for a subset of this condition. By sequencing the ATP6i gene in arOP patients from 44 unrelated families with a worldwide distribution we have now established that ATP6i mutations are responsible for approximately 50% of patients affected by this disease. The vast majority of these mutations (40 out of 42 alleles, including seven deletions, two insertions, 10 nonsense substitutions and 21 mutations in splice sites) are predicted to cause severe abnormalities in the protein product and are likely to represent null alleles. In addition, we have also analysed nine unrelated arOP patients from Costa Rica, where this disease is apparently much more frequent than elsewhere. All nine Costa Rican patients bore either or both of two missense mutations (G405R and R444L) in amino acid residues which are evolutionarily conserved from yeast to humans. The identification of ATP6i gene mutations in two families allowed us for the first time to perform prenatal diagnosis: both fetuses were predicted not to be affected and two healthy babies were born. This study contributes to the determination of genetic heterogeneity of arOP and allows further delineation of the other genetic defects causing this severe condition.

Human V-ATPase gene can protect or predispose the host to pulmonary tuberculosis

“…[8][9][10][11][12][13][14][15] The study was extended to six SNPs (rs36027301, rs4147779, rs2471829, rs4147778, rs4147780 and rs2075609), which are not found in patients affected with osteopetrosis. 4 The corresponding alleles were therefore expected to be present in the population at a reasonable frequency. Genetic association studies suffer from low reproducibility.…”

“…In humans, the 'a' subunit has four different isoforms (a1-a4), expressed in a tissue-and organelle-specific manner. 3 V-ATPase is also involved in the pathological processes; mutations in the a3 subunit cause osteopetrosis 4 and in the a4 subunit, distal renal tubule acidosis. 5 Mycobacterium tuberculosis has the unique ability to survive within macrophages by inhibiting the fusion of phagosomes with lysosomes.…”

SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity

“…(1,(5)(6)(7)(8)(9)(10) The SNX10 gene was amplified using primers and conditions kindly provided by Aker and colleagues (Hebrew University Medical Center, Jerusalem). The mutation nomenclature conforms to www.hgvs.org/mutnomen.…”

“…The disease is usually early lethal unless treated with hematopoietic stem cell transplantation (HSCT). The estimated incidence is 1 in 250,000 newborns, although it is much higher in specific geographic areas with a consanguineous population, such as Costa Rica, (1) the Chuvash Republic of Russia, (2) and the Province of Västerbotten in Northern Sweden. (3) Current knowledge on the molecular bases of human ARO has identified the gene responsible for the disease in the Costa Rican and the Chuvashian subgroups, whereas the Västerbottenian cluster represents a somewhat less severe form (3) of yet unknown etiology.…”

Long-term outcome of haematopoietic stem cell transplantation in autosomal recessive osteopetrosis: an EBMT report

“…2 This defect is estimated to cause half of the cases of AR-OP. 3 A different small subgroup with a milder phenotype is known to have carbonic anhydrase II deficiency. 4 Also a defect in the CIC-7 chloride channel has been demonstrated to cause osteopetrosis in a minority of cases.…”