Fig. 2: Variant location on NSRP1 schematic and impact on protein sequence. | Genetics in Medicine

Fig. 2: Variant location on NSRP1 schematic and impact on protein sequence.

From: Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy

Fig. 2

(a) Schematic diagram of NSRP1 and the position of pathogenic variants identified in this study. 5’UTR and 3’UTR are labeled (white). Exons are indicated in gray. The structure of the main transcript NM_032141.4 (ENST00000247026.9) and the alternate transcript ENST00000612959.4 are provided. (b) Structure of Nuclear Speckle Splicing Regulatory Protein 1 and the position of pathogenic variants identified in this study. NSRP1 contains two RNA recognition motif (RRM) domains (blue), an RS-like domain (orange), two coiled-coil domains that overlap with the RRM and RS-like domains (black bars), and a C-terminal nuclear localization signal (black). The two predicted truncated proteins (p.Glu455AlafsTer20 and p.Lys425GlufsTer5) are depicted. Novel amino acids following the frameshifts are indicated in red. All diagrams are approximately to scale. (c) Model of splicing dysfunction caused by last exon frameshift variants. As previously demonstrated, wild type (WT) NSRP1 is found within the nucleus where it promotes exon inclusion or exclusion by antagonizing the activity of serine/arginine-rich splicing factors 1 and 2 (SRSF1, SRSF2) [8, 9]. Truncated variants of NSRP1 lacking the C-terminal nuclear localization signal (amino acids 531–540) show abnormal cytoplasmic localization and lack splicing activity.

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