title: [Pathology and molecular pathogenesis of spondyloepiphyseal dysplasia tarda with progressive arthropathy caused by compound CCN6 heterogeneous gene mutations].
abstract: OBJECTIVE
  To characterize the clinical manifestations, features of roentgenography and MR imaging, and the pathology of articular cartilage and matrix of spondyloepiphyseal dysplasia tarda with progressive arthropathy (SEDT-PA), to screen the mutations of the disease-causing CCN6 gene, and try to elucidate the molecular pathogenesis of SEDT-PA.
  
  
  METHODS
  A questionnaire survey on the clinical manifestations and history was conducted among a pedigree of SEDT-PA with 57 persons (53 living members) in tolal, including 2 probands, a 19-year old female and a 9-year old male. Physical examination and roentgenography and MR imaging were used on the 2 probands to characterize the features of their joints and articular cartilage. The femoral head extracted during replacement of hip of the proband 1 underwent hematoxylin-eosin staining and toludine blue (TB) staining to observe the pathological changes and ultra-microstructure of the articular chondrocytes and cartilage matrix using electron microscopy. Peripheral blood samples were collected from these 53 living members and 100 healthy controls. PCR was used to examine and sequence the exons of CCN6. 3D-conformational illustration of mutant CCN6 proteins were predicted using the Prospect Software.
  
  
  RESULTS
  The clinical manifestations, radiology, and MR imaging established the diagnosis of SEDT-PA. Pathologic examination demonstrated that the articular cartilage chondrocytes became hyper-proliferative and immature, while the density and diameter of matrix collagens were dramatically decreased. Mutation studies showed the two probands carried a deletion (840delT) mutation in maternal allele, that caused the truncated CCN6 protein to miss 43 residues in C-terminus; and a substitution mutation (1000T-->C, Ser334Pro) in paternal allele, which was also inherited down to other 4 members in the SEDT-PA kindred. The predicted 3D-conformational changes of the truncated mutant and the Ser334Pro mutant CCN6 proteins demonstrated that in comparison with the wild CCN6 protein, the single long peptide loop in the region from signal peptide to the beginning 24 amino acid residues in the first domain (IGFBP) was subjected to folding into two smaller cross-loops accompanied with a much shorter C-terminus in 840 delT truncated mutant CCN6 protein, and no substantial 3D-conformational change of Ser334Pro mutant CCN6 protein was detected except for the C-terminal peptide towards the opposite direction.
  
  
  CONCLUSIONS
  Novel 840delT mutation of CCN6 gene is the leading cause of SEDT-PA though coexistence of T1000C substitution is necessary for the clinical onset of SEDT-PA, in which marked abnormalities of cartilage chondrocytes and matrix are morphologically and functionally presented.
authors.affiliation: Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, Changsha 410011, China. Email: eyliao2003@21cn.com.
authors.forename: Yi-qun
authors.initials: YQ
authors.lastname: Peng
authors.forename: Er-yuan
authors.initials: EY
authors.lastname: Liao
authors.forename: Hui-min
authors.initials: HM
authors.lastname: Gu
authors.forename: Qi-you
authors.initials: QY
authors.lastname: Wei
authors.forename: Hou-de
authors.initials: HD
authors.lastname: Zhou
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Xie
authors.forename: Mu-xu
authors.initials: MX
authors.lastname: Zhai
authors.forename: Li-hua
authors.initials: LH
authors.lastname: Tan
authors.forename: Xiang-hang
authors.initials: XH
authors.lastname: Luo
authors.forename: Xian-ping
authors.initials: XP
authors.lastname: Wu
authors.forename: Ping-an
authors.initials: PA
authors.lastname: Hu
authors.forename: Jiang-dong
authors.initials: JD
authors.lastname: Ni
authors.forename: Xin
authors.initials: X
authors.lastname: Su
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.forename: Ru-chun
authors.initials: RC
authors.lastname: Dai
authors.forename: Li-juan
authors.initials: LJ
authors.lastname: Guo
authors.forename: Ling-qing
authors.initials: LQ
authors.lastname: Yuan
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Ping-fang
authors.initials: PF
authors.lastname: Wang
authors.forename: Shi-ping
authors.initials: SP
authors.lastname: Liu
authors.forename: Ya
authors.initials: Y
authors.lastname: Yang
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.forename: Guo-liang
authors.initials: GL
authors.lastname: Sui
authors.forename: Tuan-yu
authors.initials: TY
authors.lastname: Fang
mesh_terms: D000328:Adult; D001483:Base Sequence; D055511:CCN Intercellular Signaling Proteins; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D010003:Osteoarthritis / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010375:Pedigree; D017354:Point Mutation
chemical_list: D055511:CCN Intercellular Signaling Proteins; C400081:CCN6 protein, human; D018969:Insulin-Like Growth Factor Binding Proteins; D009363:Neoplasm Proteins