Abstract
Down syndrome (DS) is caused by trisomy of chromosome 21 and it is the most common genetic cause of intellectual disability (ID) in humans. Subjects with DS show a typical phenotype marked by facial dysmorphisms and ID. Partial trisomy 21 (PT21) is a rare genotype characterized by the duplication of a delimited chromosome 21 (Hsa21) portion and it may or may not be associated with DS diagnosis. The highly restricted Down syndrome critical region (HR-DSCR) is a region of Hsa21 present in three copies in all individuals with PT21 and a diagnosis of DS. This region, located on distal 21q22.13, is 34 kbp long and does not include characterized genes. The HR-DSCR is annotated as an intergenic region between KCNJ6-201 transcript encoding for potassium inwardly rectifying channel subfamily J member 6 and DSCR4-201 transcript encoding Down syndrome critical region 4. Two transcripts recently identified by massive RNA-sequencing (RNA-Seq) and automatically annotated on Ensembl database reveal that the HR-DSCR seems to be partially crossed by KCNJ6-202 and DSCR4-202 isoforms. KCNJ6-202 shares the coding sequence with KCNJ6-201 which is involved in many physiological processes, including heart rate in cardiac cells and circuit activity in neuronal cells. DSCR4-202 transcript has the first two exons in common with DSCR4-201, the only experimentally verified gene uniquely present in Hominidae. In this study, we performed in silico and in vitro analyses of the HR-DSCR. Bioinformatic data, obtained using Sequence Read Archive (SRA) and SRA-BLAST software, were confirmed by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Sanger sequencing on a panel of human tissues. Our data demonstrate that the HR-DSCR cannot be defined as an intergenic region. Further studies are needed to investigate the functional role of the new transcripts, likely involved in DS phenotypes.
Highlights
Human chromosome 21 (Hsa21) is the smallest human autosome, and it represents 1–1.5% of the human genome (Piovesan et al, 2019)
It was demonstrated that the presence of a highly restricted Down syndrome critical region (HRDSCR) of only 34 kb located on distal 21q22.13 from 37,929,229 to 37,963,130 shared by all subjects with partial trisomy 21 (PT21) and with diagnosis of DS (Pelleri et al, 2019)
DSCR4-201, the only DSCR4 isoform registered on National Center for Biotechnology Information (NCBI) Gene database, was discovered in 1997 via Expressed Sequence Tag (EST) (Nakamura et al, 1997) and it has three exons
Summary
Human chromosome 21 (Hsa21) is the smallest human autosome, and it represents 1–1.5% of the human genome (Piovesan et al, 2019). Hsa is the human chromosome with the lowest number of genes (Piovesan et al, 2016); it has 228 known protein-coding and 106 non-coding RNA (ncRNA) genes (http:// www.ncbi.nlm.nih.gov/gene) It is still unclear how the specific alterations of Hsa genes are linked to the phenotypic features of subjects with DS. The absence of the syndrome was reported in PT21 subjects where the short arm (21p) and the proximal part of the long arm (21q21) were present in three copies (Shapiro, 1999) These results indicate a relationship between the 21q22 region and DS phenotype, while 21p and 21q21 resulted not essential for the development of DS pathogenesis (Gustavson, 1964; Hamerton, 1971; Daniel, 1979; Eggermann and Schwanitz, 2011). It was demonstrated that the presence of a highly restricted Down syndrome critical region (HRDSCR) of only 34 kb located on distal 21q22.13 from 37,929,229 to 37,963,130 shared by all subjects with PT21 and with diagnosis of DS (Pelleri et al, 2019)
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