Mutations in OSTM1 (Grey Lethal) Define a Particularly Severe Form of Autosomal Recessive Osteopetrosis With Neural Involvement

Abstract

We report three novel osteopetrosis patients with OSTM1 mutations and review two that have been previously described. Our analysis suggests that OSTM1 defines a new subset of patients with severe central nervous system involvement. This defect is also present in the gl mouse, which could represent a good model to study the role of the gene in the pathogenesis of this disease.Introduction: Autosomal recessive osteopetrosis (ARO) is a severe hereditary bone disease whose cellular basis is in the osteoclast, but with heterogeneous molecular defects. In addition to the TCIRG1 and the ClCN7 genes, whose mutations account for ∼55% and 10% of cases, respectively, the OSTM1 gene has been described thus far in only two ARO patients. Materials and Methods:We report here three novel ARO patients presenting with severe primary central nervous system involvement in addition to the classical stigmata of severe bone sclerosis, growth failure, anemia, thrombocytopenia, and visual impairment with optic atrophy. In addition we analyzed the brain morphology and histology of the grey lethal mutant mouse. Results: The analysis of the OSTM1 gene in two patients, both from Kuwait, showed homozygous two nucleotide deletion in exon 2, leading to a frameshift and premature termination. The third (Lebanese) patient showed a single point mutation in exon 1, leading to a nonsense mutation. The clinical neurological evaluation of the two Kuwaiti patients by CT and MRI scans showed a defect in the white matter, with a specific diagnosis of severe cerebral atrophy. The gl brain showed a diffuse translucent appearance with loss of the normal demarcation between the white and the grey matter, features consistent with myelin loss or hypomyelination. Histological and myelin staining analysis evidenced an atrophy of the corpus callosum with loss of myelin fibers, and in cortical areas, loss of the normal lamination consistent with multiple foci of cortical dysplasia. Conclusions: These findings suggest that OSTM1-dependent ARO defines a new subset of patients with severe central nervous system involvement leading to a very poor prognosis. The fact that central nervous system involvement is also present in the gl mouse mutant suggests that this mouse is a good model to test possible therapies.

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.…”

Secretion of a Truncated Osteopetrosis-associated Transmembrane Protein 1 (OSTM1) Mutant Inhibits Osteoclastogenesis through Down-regulation of the B Lymphocyte-induced Maturation Protein 1 (BLIMP1)-Nuclear Factor of Activated T Cells c1 (NFATc1) Axis

“…However, the primary cell sources of the secreted form of the truncated OSTM1 remain unknown. Interestingly, the gray-lethal mutation leads not only to osteopetrosis but also to coat color defects and neurological damage (5). Furthermore, a recent study demonstrated that a loss of function of the Ostm1 gene results in the deregulation of multiple hematopoietic lineages, including Tand B-cells, in addition to OC lineage cells (34).…”

Prognostic potential of precise molecular diagnosis of Autosomal Recessive Osteopetrosis with respect to the outcome of bone marrow transplantation

“…The subset of patients (5% in our cohort) displaying mutations in OSTM1 gene, encoding for a protein involved in late endosomal-lysosomal trafficking, functionally and physically linked to ClCN7 (Lange et al 2006;Meadows et al 2007), is characterized by even more serious neurological defects (neurodegeneration, optic atrophy, microcephaly, cortical atrophy; in one case, bilateral atrial subependymal heterotopias) (Chalhoub et al 2003;Quarello et al 2004;Ramirez et al 2004;Pangrazio et al 2006;Castellano Chiodo et al 2007;Maranda et al 2008). These findings strongly discourage HSCT, because, even if the transplant engrafted, the patient would die due to the severe CNS defects; indeed, in our series no OSTM1-dependent patients have been transplanted.…”