Among the genes responsible for ARO, the TCIRG1 gene, coding for the a3 subunit of the osteoclast proton pump, is mutated in more than 50% of the cases, increasing the importance of TCIRG1-iPSCs as disease model.
Transgenic overexpression of TCIRG1 was sufficient to restore osteoclast function in iPS cell-derived osteoclasts from a patient with infantile malignant autosomal-recessive osteopetrosis.
Mutations in the a3 subunit of the vacuolar-type H<sup>+</sup> -ATPase (encoded by T-cell immune regulator 1 [TCIRG1]) are responsible for ~50% of all ARO cases.
We generated a human induced pluripotent stem cell (hiPSC) line, BIHi002-A, from peripheral blood mononuclear cells of an ARO patient carrying the CLCN7 mutations c.875G>A and c.1208G>A using Sendai viral vectors.
Novel mutations of CLCN7 cause autosomal dominant osteopetrosis type II (ADOII) and intermediate autosomal recessive osteopetrosis (ARO) in seven Chinese families.
In the present study, we reported seven unrelated ADO-II patients and one IARO patient from Chinese population and elucidated the characteristics of CLCN7 gene mutations in these patients.
Autosomal recessive osteopetrosis is a human bone disease mainly caused by TCIRG1 gene mutations that prevent osteoclasts resorbing activity, recapitulated by the oc/oc mouse model.
Our data a) Demonstrate that the unusual clinical presentation observed in our patient with a mild clinical onset evolving towards a more serious clinical picture, is associated to two novel mutations on CLCN7 gene. b) Support the already described clinical and molecular heterogeneity of the malignant osteopetrosis c) Suggest that, performing a molecular diagnosis of osteopetrosis with inconsistent clinical presentation these two novel mutations have to be first considered.
These results confirm the involvement of the SNX10 gene in human ARO and identify a new subset with a relatively favorable prognosis as compared to TCIRG1-dependent cases.
The deletion involved other genes besides CLCN7, while the proband displayed a classic ARO phenotype; however, her early death did not allow more extensive clinical investigations.
We present the first Chinese IARO patient with a novel homozygous variant in CLCN7 gene (p. Pro470Leu) and an ADO II patient with a heterozygous variant in CLCN7 gene (p. Arg286Trp).
Patients with a clinical diagnosis of ARO have been collected for 7 years and mutation analysis of the TCIRG1 gene was performed using direct DNA sequencing of PCR-amplified exons according to both a standard protocol and a modified one.
Having assumed a founder effect, we performed linkage disequilibrium (LD) mapping of the OPTB locus at the TCIRG1 region and found a unique splice site mutation c.807+5G>A in all Chuvashian OPTB patients studied.
Using the oc/oc mutant mouse, a murine model whose osteopetrotic phenotype closely recapitulates human TCIRG1-dependent ARO, we report that in utero transplantation of adult bone marrow hematopoietic stem cells can correct the ARO phenotype in a limited number of mice.