PMC6074827_01
Brain structural neuroimaging data and family pedigree of the proband at diagnosis.. Note: (A) Axial FLAIR, coronal, and sagittal T1 images of brain MRI, arrows pointing at left-dominant bilateral temporal lobe atrophy, (B) FDG-PET, arrows pointing at hypometabolism in left temporal cortex, right anterior temporal cortex and bilateral frontal cortex and (C) family tree identifying the proband (II-4) with the PSEN2 p.His169Asn.. Abbreviations: FDG-PET, 18 F-fludeoxyglucose positron emission tomography; FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; PSEN, presenilin.
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Her brain magnetic resonance imaging at 1 year after symptom onset revealed atrophy of left-dominant bilateral temporal lobe (Figure 1A). 18 F-fludeoxyglucose positron emission tomography (FDG-PET) at 2 years after symptom onset showed hypometabolism in the left temporal lobe, right anterior temporal lobe, and bilateral frontal cortex (Figure 1B). AD. All living family members declined genetic testing (Figure 1C).
Identification and in silico analysis of function the mutation in the patient.. Notes: (A) NGS and Sanger sequencing data identifying the PSEN2 H169N mutation in the proband. (B) Bulkiness profile of wild-type and H169N mutant PSEN2 proteins. Dotted line represents the shift in the bulkiness around the mutant site. X-axis represents amino acid sequence from N- to C-terminal. Y-axis represents scores computed by each algorithm. The prediction was done using the ProtScale program at Expasy server. (C) Differences of normal and mutant PSEN2 have been highlighted with a black circle, and histidine was labeled yellow, while asparagine was labeled pink. (D) ClueGO model on the putative pathways on proteins which carried mutations.. Abbreviations: NGS, next-generations sequencing; PSEN, presenilin.
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A heterozygous C > A substitution was identified and was confirmed to occur in the PSEN2 coding region using both NGS and standard sequencing (Figure 2A). For example, scores of bulkiness were reduced slightly due to H169N (17.292 Dal) in comparison to normal PSEN2 (17.389 Dal), and several amino acids near the mutation site were also affected (Figure 2B). TM-III domain had an N-terminal loop structure disturb to residue 169 (Figure 2C), suggesting divergent structures between normal PSEN2 and its mutant p.His169Asn. ClueGO Ontology analyses (Figure 2D) revealed 2 important pathways in which the genes with missense variants could be involved: amyloid metabolism and regulation of mitochondrial fission.