ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome

Abstract

Chromosomal abnormalities are implicated in a substantial number of human developmental syndromes, but for many such disorders little is known about the causative genes. The recently described 1q41q42 microdeletion syndrome is characterized by characteristic dysmorphic features, intellectual disability and brain morphological abnormalities, but the precise genetic basis for these abnormalities remains unknown. Here, our detailed analysis of the genetic abnormalities of 1q41q42 microdeletion cases identified TP53BP2, which encodes apoptosis-stimulating protein of p53 2 (ASPP2), as a candidate gene for brain abnormalities. Consistent with this, Trp53bp2-deficient mice show dilation of lateral ventricles resembling the phenotype of 1q41q42 microdeletion patients. Trp53bp2 deficiency causes 100% neonatal lethality in the C57BL/6 background associated with a high incidence of neural tube defects and a range of developmental abnormalities such as congenital heart defects, coloboma, microphthalmia, urogenital and craniofacial abnormalities. Interestingly, abnormalities show a high degree of overlap with 1q41q42 microdeletion-associated abnormalities. These findings identify TP53BP2 as a strong candidate causative gene for central nervous system (CNS) defects in 1q41q42 microdeletion syndrome, and open new avenues for investigation of the mechanisms underlying CNS abnormalities.

A novel FBXO28 frameshift mutation in a child with developmental delay, dysmorphic features, and intractable epilepsy: A second gene that may contribute to the 1q41‐q42 deletion phenotype

“…In addition, >75% of CR‐deleted patients have virtually absent speech, brain anomalies on MRI/CT, dentition/gingival anomalies, and distinct dysmorphic facial features. The most common anomaly on brain imaging in these patients is enlargement of the ventricles, seen in 73% of patients in a previous study wherein TP53BP2 was proposed as a gene candidate (Zak et al, ).…”

High-Resolution Episcopic Microscopy (HREM): Looking Back on 13 Years of Successful Generation of Digital Volume Data of Organic Material for 3D Visualisation and 3D Display

“…DMDD independent stand-alone studies researching genetic regulation of mouse development include the analysis of: normal and abnormal cardiovascular development [49][50][51][52][53][54][55][56][57][58][59][60][61]; the development of the limbs, cloaca and pancreas [42,[62][63][64]; ciliopathies [65]; and the characterisation of cardiac defects in Down syndrome mouse models [66,67]. Despite its value for analysing such processes in embryos between embryonic day E8.5 and E14.5, when organogenesis is already finished, HREM also proved its value for analysing developmental processes in very early embryos immediately after implantation [68].…”

Epigenetic dysregulation of ASPP2 accelerates trophoblasts autophagy of placentas in preeclampsia through Beclin-1

“…Apoptosis-stimulating protein of p53-2 (ASPP2) belonging to the ASPP family can directly interact with p53 or its family members (p63 and p73) through its C-terminus and selectively stimulate the transcriptional activity of pro-apoptosis gene promoter, which plays a key role in metastasis of cancer [4,5]. Surprisingly, a few ASPP2 binding partners that are involved in biological pathways other than apoptosis have also been identified, suggesting that ASPP2 function is far more complex than simply enhancing p53-mediated apoptosis [6].…”