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Abstract
Recently, epigenetic regulation of alternative APP pre-mRNA splicing in the Lesch-Nyhan syndrome (LNS) has been studied (see Ref. 7) and showed for the first time, the presence of several APP-mRNA isoforms encoding divers APP protein isoforms ranging from 120 to 770 amino acids (with or without mutations and/or deletions). Here, by continuing on this work, I identified, for the first time new APP-mRNA isoforms with a deletion followed by an insertion (INDELS) in LNS and LNVs patients:
c.19_2295delinsG166TT…GAGTCC…CTTAGTC…TCT489,p.Leu7Valfs*2;c.19_2295 delinsG169TT…GAGACC…CTTGGTC…TCT492,p.Leu7Valfs*2;and c.16_2313delinsG84CC…CAT616,p.Leu7Hisfs*45. A role of genomic rearrangements of APP gene via the Fork Stalling and Template Switching (FoSTeS) mechanism leading to INDELS was suggested. Epistasis between mutated HPRT1 and APP genes could be one of the factors of epigenetic modifications responsible for genomic rearrangements of APP gene. My findings accounted for epigenetic mechanism in the regulation of alternative APP pre-mRNA splicing as well as for epigenetic control of genomic rearrangements of APP gene may provide therefore new directions not only for investigating the role of APP in neuropathology associated with HGprt-deficiency in LNS and LNVs patients but also for the research in neurodevelopmental and neurodegenerative disorders by which APP gene involved in the pathogenesis of the diseases such as autism, fragile X syndrome (FXS), and Alzheimer's disease (AD) with its diversity and complexity, especially for sporadic form of AD (SAD). An accurate quantification of various APP-mRNA isoforms in brain tissues for detection of initial pathological changes or pathology development is needed and antisense drugs are the potential treatments.
ABBREVIATIONS USED:
| Aβ | = | beta-amyloid peptide |
| AD | = | Alzheimer's disease |
| APOE | = | apolipoprotein E |
| APP | = | beta-amyloid precursor protein |
| APPsα | = | soluble APP fragment released from APP following the cleavage by α-secretase |
| BLAST | = | basic local alignment search tool |
| CNV | = | copy number variation |
| EPB41L2 | = | erythrocyte membrane protein band 4.1-like 2 |
| FAD | = | familial Alzheimer's disease |
| FoSTeS | = | fork stalling and template switching |
| FXS | = | fragile X syndrome |
| GALNS | = | galactosamine (N-acetyl)-6-sulfatase gene |
| G6PD | = | glucose-6-phosphate dehydrogenase |
| HGMD | = | human gene mutation data base |
| HGprt | = | hypoxanthine–guanine phosphoribosyltransferase |
| HPRT1 gene | = | hypoxanthine phosphoribosyltransferase 1 gene |
| IDS | = | iduronate 2-sulfatase gene |
| INDELS | = | deletion followed by an insertion |
| LNS | = | Lesch-Nyhan syndrome |
| LNVs | = | Lesch-Nyhan variants |
| MECP2 | = | methyl CpG binding protein 2 gene |
| mGluR5 | = | type 5 metabotropic glutamate receptor |
| MIM | = | Mendelian inheritance in man |
| NAHR | = | non-allelic homologous recombination |
| NFTs | = | neurofibrillary tangles |
| NHE | = | non-homologous end-joining |
| OFD1 | = | oral-facial-digital syndrome 1 gene |
| PCR | = | polymerase chain reaction |
| PGD | = | phosphogluconate dehydrogenase |
| 6PGL | = | 6-phosphogluconolactonase |
| PS | = | presenilin |
| PS1 | = | presenilin-1 |
| PS2 | = | presenilin-2 |
| RT | = | reverse transcription |
| SAD | = | sporadic Alzheimer's disease |
| SALL1 | = | spalt-like transcription factor 1 gene |
| SPs | = | senile plaques |
| SRS | = | serial replication slippage. |