ABSTRACT
Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80-90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.
Subject(s)
Cell Cycle Proteins/genetics , Chromosomal Proteins, Non-Histone/genetics , Holoprosencephaly/diagnosis , Holoprosencephaly/genetics , Adolescent , Animals , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Mice , Mice, Inbred C57BL , CohesinsABSTRACT
The aim of this study was to identify ultrasound parameters reflecting subchondral porosity (Po), subchondral plate thickness (Tpl) and bone volume fraction at the trabecular bone region (BV/TVTb). Sixteen osteoarthritic human lateral femoral condyles were evaluated ex vivo using a 15-MHz pulsed-echo ultrasound 3-D scanning system. The cartilage-subchondral bone (C-B) surface region (layer 1) and inner subchondral bone region (layer 2) were analyzed; we newly introduced entropy (ENT) and correlation (COR) of ultrasound texture parameters of the parallel (x) or perpendicular (z) direction to the C-B interface for this analysis. Po, Tpl and BV/TVTb were evaluated as reference measurements using micro-computed tomography. ENTL1x (ENT of layer 1, x-direction) and ENTL1z were significantly correlated with Po (both r valuesâ¯=â¯0.58), CORL2x with Tpl (râ¯=â¯-0.73) and CORL2z with BV/TVTb (râ¯=â¯-0.66). These are efficient indicators of the characteristics of osteoarthritis-related subchondral bone; the other texture parameters were not significant.
Subject(s)
Imaging, Three-Dimensional/methods , Osteoarthritis, Knee/diagnostic imaging , Ultrasonography/methods , X-Ray Microtomography/methods , Aged , Cancellous Bone/diagnostic imaging , Cancellous Bone/pathology , Cancellous Bone/surgery , Female , Humans , Knee Joint/diagnostic imaging , Knee Joint/pathology , Knee Joint/surgery , Male , Osteoarthritis, Knee/pathology , Osteoarthritis, Knee/surgery , Reproducibility of ResultsABSTRACT
BACKGROUND: Osteochondral autologous transfer is one of the repair techniques for cartilage defects of knee with promising knee function recovery. There are no reports including histopathological images concerning human osteochondral tissue after osteochondral autologous transfer. This is the first report to present pathohistological findings of transplanted plugs and host tissues extracted from the human body 3 years after osteochondral autologous transfer. This study aimed to explore the cause factor of chronic pain using histological techniques. CASE PRESENTATION: A 67-year-old Japanese man presented with adjusted total knee arthroplasty 3 years after osteochondral autologous transfer. Although in pain, arthroscopic assessment was not severe. The specimens which was gained during total knee arthroplasty were investigated in gross and microscopically using immunohistochemical staining technic. Histological examination revealed that the gap between grafted plugs and host osteochondral tissues was filled with fibrous tissue that stained positive for type I collagen. A degenerative change and some neovascularity were observed in the regenerated tissue and host trabecular bone. Furthermore, cysts and bone marrow edema were observed. CONCLUSION: Our data suggests that the host osteochondral morbidity around grafted plugs might be related to chronical pain and revision surgery.
