title: Al-Aqeel Sewairi syndrome, a new autosomal recessive disorder with multicentric osteolysis, nodulosis and arthropathy. The first genetic defect of matrix metalloproteinase 2 gene.
abstract: OBJECTIVE
  We report a distinctive autosomal recessive multicentric osteolysis in Saudi Arabian families with distal arthropathy of the metacarpal, metatarsal and interphalangeal joints, with ultimate progression to the proximal joints with decreased range of movements and deformities with ankylosis and generalized osteopenia. In addition, they had large, painful to touch palmar and plantar pads. Hirsutism and mild dysmorphic facial features including proptosis, a narrow nasal bridge, bulbous nose and micrognathia.
  
  
  METHODS
  Using a genome-wide search for microsatellite markers from 11 members of the family from the Armed Forces Hospital and King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia, localized the disease gene to chromosome 16q12-21. Haplotype analysis with additional markers narrowed the critical region to 1.2cM and identified the matrix metalloproteinase 2 (MMP-2), (gelatinase A, collagenase type IV, EC 3.4, 24,24) gene as a disease candidate at Mount Sinai School of Medicine, New York, United States of America in April 2000.
  
  
  RESULTS
  Some affected individuals were homoallelic for a nonsense mutation (TCA>TAA) in codon 244 of exon 5, predicting the replacement of a tyrosine residue by a stop codon in the first fibronectin type II domain (Y244X). Other affected members had a missense mutation in exon 2 arginine 101-histidine (R101H) leading to no MMP-2 enzyme activity in serum or fibroblast or both of affected individuals. In other affected members, a non-pathogenic homoallelic GT transversion resulted in the substitution of an aspartate with a tyrosine residue in codon 210 of exon 4 (D210Y). The MMP-2-null mouse has no developmental defects, but are small, which may reflect genetic redundancy.
  
  
  CONCLUSIONS
  The discovery that deficiency of this well-characterized gelatinase/collagenase results in an inherited form of an osteolytic and arthritic disorder provides an invaluable insights for the understanding of osteolysis and arthritis and is the first genetic evidence that MMP2 deficiency is important in growth and development.
authors.affiliation: Inborn Errors of Metabolism, Endocrinology and Genetics, Department of Pediatrics, Armed Forces Hospital, PO Box 7897, Riyadh 11159, Kingdom of Saudi Arabia. aidaibrahim@hotmail.com
authors.forename: Aida I
authors.initials: AI
authors.lastname: Al-Aqeel
mesh_terms: D002675:Child, Preschool; D005808:Genes, Recessive; D031845:Hajdu-Cheney Syndrome / Q000235:genetics*; D006801:Humans; D007592:Joint Diseases / Q000235:genetics*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D012529:Saudi Arabia; D013577:Syndrome
chemical_list: D020778:Matrix Metalloproteinase 2