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

• DOI: 10.1359/jbmr.060403
• Publication Date: 2006-07-04T05:47:20Z
• Authors: Alessandra Pangrazio; Pietro Luigi Poliani; André Megarbane; Gérard Lefranc; Edoardo Lanino; Maja Di Rocco; Francesca Rucci; Franco Lucchini; Maria Ravanini; Fabio Facchetti; Mario Abinun; Paolo Vezzoni; Anna Villa; Annalisa Frattini
• Keywords: 0303 health sciences; myelin defect; OSTM1; Ubiquitin-Protein Ligases; grey-lethal mouse model; Genetic Diseases, Inborn; Membrane Proteins; Magnetic Resonance Imaging; Mice, Mutant Strains; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Cerebellar Diseases; Codon, Nonsense; Osteopetrosis; [SDV.BDD] Life Sciences [q-bio]/Development Biology; Animals; Humans; osteopetrosis; neural defect; Frameshift Mutation; Tomography, X-Ray Computed; [SDV.BDD]Life Sciences [q-bio]/Development Biology

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.