title: 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.
  
  
  BACKGROUND
  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 approximately 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.
authors.affiliation: Institute for Biomedical Technologies, CNR, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pangrazio
authors.forename: Pietro Luigi
authors.initials: PL
authors.lastname: Poliani
authors.forename: André
authors.initials: A
authors.lastname: Megarbane
authors.forename: Gérard
authors.initials: G
authors.lastname: Lefranc
authors.forename: Edoardo
authors.initials: E
authors.lastname: Lanino
authors.forename: Maja
authors.initials: M
authors.lastname: Di Rocco
authors.forename: Francesca
authors.initials: F
authors.lastname: Rucci
authors.forename: Franco
authors.initials: F
authors.lastname: Lucchini
authors.forename: Maria
authors.initials: M
authors.lastname: Ravanini
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.forename: Mario
authors.initials: M
authors.lastname: Abinun
authors.forename: Paolo
authors.initials: P
authors.lastname: Vezzoni
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.forename: Annalisa
authors.initials: A
authors.lastname: Frattini
mesh_terms: D000818:Animals; D002526:Cerebellar Diseases / Q000000981:diagnostic imaging / Q000235:genetics* / Q000628:therapy; D018389:Codon, Nonsense / Q000235:genetics*; D004195:Disease Models, Animal; D016368:Frameshift Mutation; D030342:Genetic Diseases, Inborn / Q000000981:diagnostic imaging / Q000235:genetics* / Q000628:therapy; D006801:Humans; D008279:Magnetic Resonance Imaging; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D010022:Osteopetrosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000628:therapy; D014057:Tomography, X-Ray Computed; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D008565:Membrane Proteins; C489946:OSTM1 protein, human; D044767:Ubiquitin-Protein Ligases