BACKGROUND There are many factors that lead to dwarfism,and the mechanism has not yet been elucidated.Next-generation sequencing may identify candidate-related gene mutations,which may clarify the molecular cause.AIM ...BACKGROUND There are many factors that lead to dwarfism,and the mechanism has not yet been elucidated.Next-generation sequencing may identify candidate-related gene mutations,which may clarify the molecular cause.AIM To analyze genetic variation by using a constructed panel related to dwarfism by utilizing next-generation sequencing platform sequencing analysis to screen candidate-related gene mutations.METHODS Physical and laboratory characteristics,including clinical examination,growth hormone drug challenge test,serum insulin-like growth factor-1(IGF-1),IGF binding protein 3,other related tests,imaging examination,and chromosome karyotyping,were analyzed.Next-generation sequencing was performed to analyze pathogenicity variability.RESULTS In the 39 dwarfism patients,10 had pathogenicity variability.Gene variation was found in the OBSL1,SLC26A2,PTPN11,COL27AI,HDAC6,CUL7,FGFR3,DYNC2H1,GH1,and ATP7B genes.Of the 10 patients with pathogenicity variability,the related physical characteristics included double breast development and growth hormone deficiency,enuresis and indirect inguinal hernia on the left,two finger distance of 70.2 cm,head circumference of 49.2 cm,ischium/lower body length of 1.8 cm,weak limb muscles,and partial growth hormone deficiency.After 6 mo of growth hormone therapy,the concentrations of IGF-1 and IGF binding protein 3 increased from 215.2±170.3 to 285.0±166.0 and 3.9±1.4 to 4.2±1.1,respectively.CONCLUSION OBSL1,SLC26A2,PTPN11,COL27AI,HDAC6,CUL7,FGFR3,DYNC2H1,GH1,and ATP7B genes may be related to the incidence of dwarfism,and more research needs to be performed to elucidate the mechanism.展开更多
NF-κBp50/p52 double knockout(dKO)and RANK KO mice have no osteoclasts and develop severe osteopetrosis associated with dwarfism.In contrast,Op/Op mice,which form few osteoclasts,and Src KO mice,which have osteoclasts...NF-κBp50/p52 double knockout(dKO)and RANK KO mice have no osteoclasts and develop severe osteopetrosis associated with dwarfism.In contrast,Op/Op mice,which form few osteoclasts,and Src KO mice,which have osteoclasts with defective resorptive function,are osteopetrotic,but they are not dwarfed.Here,we compared the morphologic features of long bones from p50/p52 dKO,RANK KO,Op/Op and Src KO mice to attempt to explain the differences in their long bone lengths.We found that growth plates in p50/p52 dKO and RANK KO mice are significantly thicker than those in WT mice due to a 2-3-fold increase in the hypertrophic chondrocyte zone associated with normal a proliferative chondrocyte zone.This growth plate abnormality disappears when animals become older,but their dwarfism persists.Op/Op or Src KO mice have relatively normal growth plate morphology.In-situ hybridization study of long bones from p50/p52 dKO mice showed marked thickening of the growth plate region containing type 10 collagen-expressing chondrocytes.Treatment of micro-mass chondrocyte cultures with RANKL did not affect expression levels of type 2 collagen and Sox9,markers for proliferative chondrocytes,but RANKL reduced the number of type 10collagen-expressing hypertrophic chondrocytes.Thus,RANK/NF-κB signaling plays a regulatory role in post-natal endochondral ossification that maintains hypertrophic conversion and prevents dwarfism in normal mice.展开更多
基金Quanzhou Science and Technology Bureau,No.2018Z072。
文摘BACKGROUND There are many factors that lead to dwarfism,and the mechanism has not yet been elucidated.Next-generation sequencing may identify candidate-related gene mutations,which may clarify the molecular cause.AIM To analyze genetic variation by using a constructed panel related to dwarfism by utilizing next-generation sequencing platform sequencing analysis to screen candidate-related gene mutations.METHODS Physical and laboratory characteristics,including clinical examination,growth hormone drug challenge test,serum insulin-like growth factor-1(IGF-1),IGF binding protein 3,other related tests,imaging examination,and chromosome karyotyping,were analyzed.Next-generation sequencing was performed to analyze pathogenicity variability.RESULTS In the 39 dwarfism patients,10 had pathogenicity variability.Gene variation was found in the OBSL1,SLC26A2,PTPN11,COL27AI,HDAC6,CUL7,FGFR3,DYNC2H1,GH1,and ATP7B genes.Of the 10 patients with pathogenicity variability,the related physical characteristics included double breast development and growth hormone deficiency,enuresis and indirect inguinal hernia on the left,two finger distance of 70.2 cm,head circumference of 49.2 cm,ischium/lower body length of 1.8 cm,weak limb muscles,and partial growth hormone deficiency.After 6 mo of growth hormone therapy,the concentrations of IGF-1 and IGF binding protein 3 increased from 215.2±170.3 to 285.0±166.0 and 3.9±1.4 to 4.2±1.1,respectively.CONCLUSION OBSL1,SLC26A2,PTPN11,COL27AI,HDAC6,CUL7,FGFR3,DYNC2H1,GH1,and ATP7B genes may be related to the incidence of dwarfism,and more research needs to be performed to elucidate the mechanism.
基金supported by research grants from the National Institutes of Health PHS awards(AR48697 and AR63650 to LX,AR055915 to DC,and AR43510 and AR49305 to BFB)
文摘NF-κBp50/p52 double knockout(dKO)and RANK KO mice have no osteoclasts and develop severe osteopetrosis associated with dwarfism.In contrast,Op/Op mice,which form few osteoclasts,and Src KO mice,which have osteoclasts with defective resorptive function,are osteopetrotic,but they are not dwarfed.Here,we compared the morphologic features of long bones from p50/p52 dKO,RANK KO,Op/Op and Src KO mice to attempt to explain the differences in their long bone lengths.We found that growth plates in p50/p52 dKO and RANK KO mice are significantly thicker than those in WT mice due to a 2-3-fold increase in the hypertrophic chondrocyte zone associated with normal a proliferative chondrocyte zone.This growth plate abnormality disappears when animals become older,but their dwarfism persists.Op/Op or Src KO mice have relatively normal growth plate morphology.In-situ hybridization study of long bones from p50/p52 dKO mice showed marked thickening of the growth plate region containing type 10 collagen-expressing chondrocytes.Treatment of micro-mass chondrocyte cultures with RANKL did not affect expression levels of type 2 collagen and Sox9,markers for proliferative chondrocytes,but RANKL reduced the number of type 10collagen-expressing hypertrophic chondrocytes.Thus,RANK/NF-κB signaling plays a regulatory role in post-natal endochondral ossification that maintains hypertrophic conversion and prevents dwarfism in normal mice.