China
Africa
Explore chapters and articles related to this topic
Precision medicine in myelodysplastic syndromes
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Mutations in other genes (e.g., DNMT3A and U2AF1) are not enriched in specific MDS subtypes. These mutations represent founder or ancestral mutations that initiate the early stage of MDS, rather than secondary mutations involved in MDS progression. Mutations of TP53, EZH2, RUNX1, ETV6, and ASXL1 are associated with greater risk than predicted by the IPSS and the IPSS-R (Bejar et al., 2011). Further studies found additional mutated genes (NRAS, CBL, PRPF8, PTPN11, and NF1) with adverse MDS prognosis independent of the IPSS-R (Papaemmanuil et al., 2013; Haferlach et al., 2014). One or more of these adverse mutations can be found in over one-third of MDS patients. Therefore, we routinely underestimate disease risk using conventional analysis (Bejar, 2017). Complex karyotype MDS patients have about 50% TP53 mutations and have the worst overall outcomes, even after treatment.
Macular maldevelopment in ATF6-mediated retinal dysfunction
Published in Ophthalmic Genetics, 2019
Markus Ritter, Gavin Arno, Rola Ba-Abbad, Graham E. Holder, Andrew R. Webster
The variant associated with the severe macular abnormality, a frameshift insertion on exon 5, is expected to act as a true null allele since the transcript is likely to undergo NMD. However, since the loss of function mutations has also been reported in less severe ATF6 phenotypes (4,28), this patient may represent a broader spectrum of ATF6 disease or other modifiers may play a role. That there is a common electrophysiological phenotype between the two patients in the present report suggests a crucial role of ATF6A in human foveal development and cone function. This is surprising as ATF6 encodes the ubiquitously expressed activating transcription factor 6, a key regulator of the unfolded protein response (UPR), and a key component of cellular endoplasmic reticulum (ER) homeostasis. It, therefore, adds ATF6 to the list of genes that, despite ubiquitous expression, when mutated can result in an isolated retinal phenotype such as splicing factor PRPF31, NMNAT1, PRPF8 or HK1 (29–32).
Severe retinitis pigmentosa with posterior staphyloma in a family with c.886C>A p.(Lys296Glu) RHO mutation
Published in Ophthalmic Genetics, 2019
Vasily M. Smirnov, Caroline Marks, Isabelle Drumare, Sabine Defoort-Dhellemmes, Claire-Marie Dhaenens
Informed consents were obtained for all patients before testing. Genomic DNAs were extracted from peripheral leukocytes using the DNA Blood 1k Kit on the automated workstation Chemagic Star (PerkinElmer, Waltham, Massachusetts, USA). Autosomal dominant retinitis pigmentosa molecular diagnosis was performed by Sanger sequencing of the coding exons and flanking regions of RHO gene (NM_000539.3) and PRPH2 gene (NM_000322.4), and of the mutational hot spots of eight other adRP genes (IMPDH1, NR2E3, NRL, RP1, PRPF3, PRPF8, PRPF31, snRNP200). In total, 26 fragments were amplified for analysis (available on request). PCR products were purified on P10 gel (Biorad, Hercules, CA, USA) and sequenced in sense and antisense directions using the BigDye® Terminator v3.1 Cycle Sequencing Kit on a 3730 DNA analyzer (Applied Biosystems, Carlsbad, CA) (PCR conditions and primers available under request).
Variability in clinical phenotypes of PRPF8-linked autosomal dominant retinitis pigmentosa correlates with differential PRPF8/SNRNP200 interactions
Published in Ophthalmic Genetics, 2018
Pascal Escher, Olga Passarin, Francis L. Munier, Viet H. Tran, Veronika Vaclavik
PRPF8 is a 220 kDa spliceosomal protein (2335 aa) encoded by a 43 exon-containing gene located on human chromosome 17 (17p13.3). It is the largest and most evolutionarily conserved protein of the spliceosome’s catalytic core, with an overall sequence identity of 61% between human and yeast proteins (9). PRPF8 is the only spliceosomal protein that contacts all three regions in the pre-mRNA required for splicing, i.e., the 5’ splice site, the 3’ splice site, and the branch point (10). The crystal structure revealed the active site cavity, where the noncoding intronic gene regions are removed (11). The SNRNP200 RNA helicase requires the C-terminal tail of the PRPF8 Jab1/MPN domain for ATP-dependent U4/U6 snRNA unwinding activity (12), and this C-terminal tail contacts the N-terminal helicase cassette of the SNRNP200 helicase domains only (13). The presence of adRP-linked PRPF8 mutations in the C-terminal extension disrupts PRPF8/SNRNP200 interactions and dramatically decreases U4/U6 unwinding activity (12,14,15). The PRPF8 C-terminal tail inserts into the RNA-binding tunnel of SNRNP200 (16), and this intermittent insertion is the structural basis of the reversible inhibition of splicing by SNRNP200 (17,18).