Growth arrest in the ribosomopathy, Bowen–Conradi syndrome, is due to dramatically reduced cell proliferation and a defect in mitotic progression

Abstract

Bowen-Conradi syndrome (BCS) is a ribosomopathy characterized by severe developmental delay and growth failure that typically leads to death by one year of age. It is caused by a c.257A>G, p.D86G substitution in the ribosomal biogenesis protein, Essential for Mitotic Growth 1 (EMG1). We generated a knock-in of the D86G substitution in mice to characterize the effects of EMG1 deficiency, particularly in the brain, where EMG1 expression is high. Embryos homozygous for the mutation in Emg1 were small for gestational age with neural tube defects, and died between embryonic days 8.5 and 12.5. These embryos exhibited dramatically reduced cell proliferation, which we also detected in autopsy brain tissue and bone marrow of BCS patients, consistent with a requirement for high levels of EMG1 in tissues with rapid cell proliferation. In fibroblasts derived from the BCS mouse embryos, we detected a high proportion of binucleated cells, indicating that a mitotic defect underlies the growth arrest in BCS. These studies add to growing evidence of a link between ribosome biogenesis, mitotic progression, and brain development that is currently unexplored.

Hyaluronidase 2 Deficiency Causes Increased Mesenchymal Cells, Congenital Heart Defects, and Heart Failure

“… Hyaluronidase 2 (HYAL2) distribution in embryonic hearts. Sections of the embryonic heart at embryonic day (E) 8.5, from a previous study, 19 were used for the detection of HYAL2 using immunofluorescent and immunohistochemical approaches. A – C , Detection of HYAL2 (red) in the endocardial lining of the blood vessels of the E8.5 heart.…”

“…Wild-type embryos at E8.5, 11.5, and 12.5 were obtained as part of a previous study. 19 Morphology was examined by hematoxylin and eosin staining, and HA was detected using the HABP (HA-binding protein) following established procedures. 5 ECM components were visualized with Masson trichrome (Sigma) following the manufacturer’s instructions.…”

Effects of the Bowen-Conradi syndrome mutation in EMG1 on its nuclear import, stability and nucleolar recruitment

“…Due to the severity of the disorder, most of the BCS patients do not survive the first year of their life. Analysis of patient material (28,43), a knockin mouse model (44) and the results presented here show that the aspartate 86 to glycine mutation in EMG1 observed in BCS causes mislocalisation and degradation of the protein leading to defects in biogenesis of the small ribosomal subunit. Based on the findings that the catalytic activity of yeast Emg1 is not required for ribosome synthesis and that introduction of the BCS mutation in the Methanocaldococcus jannashii EMG1 homologue (45), yeast Emg1 (32) or human EMG1 (Supplementary Material, Fig.…”

Dysregulation of ribosome-related genes in ankylosing spondylitis: a systems biology approach and experimental method

“…The gene is required for the assembly of 40S ribosomal subunit and is involved in the modification of the 18S rRNA [ 60 ]. In that patients, skeletal dysmorphology is observed and serious prenatal and postnatal growth defect usually leads to death by 1 year of age [ 61 , 62 ].…”