Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121514245 G>T
Position: (GRCh37/hg19):Chr11:121384954 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GGG to TGG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 8

Findings

The heterozygous G379W variant was identified in five affected individuals from an extended family from Greece (Xiromerisiou et al., 2021). Three of the carriers were clinically diagnosed with Parkinson’s disease (PD) that progressed to PD dementia; these carriers had normal levels of Alzheimer’s CSF core biomarkers. The other two carriers were clinically diagnosed with Alzheimer’s disease, a diagnosis confirmed by CSF biomarker studies and supported by imaging studies—structural MRI showed hippocampal and cortical atrophy, as well as evidence of vascular damage. Perhaps coincidentally, but perhaps not, the carriers affected with PD are all male, while the two AD carriers are female. Importantly, the variant segregated with the disease in this family: In addition to the five affected carriers, DNA was available from three unaffected relatives, none of whom carried the variant.

Subsequently, an additional 650 Greek PD patients and 650 Greek controls were screened for the G379W mutation—among them 50 PD patients and 50 controls from the same village as the family described above. One more carrier was identified, a PD patient, 46 years old at symptom onset, who was from the same village as the described family but not believed to be closely related to them.

The variant was not seen in 5,000 in-house controls or in the gnomAD database.

Functional Consequences

Glycine-379 is part of a conserved motif within the propellers of the VPS10p domain called the “Asp-box.” While the function of this motif is not known, it has been suggested that it stabilizes the propeller. Andersen and colleagues have predicted that mutations at this position are highly likely to associate with AD risk (Andersen et al., 2023).

The G379W variant was predicted to be deleterious by SIFT, Mutation Taster, and PolyPhen-2.

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References

Paper Citations

1. Xiromerisiou G, Bourinaris T, Houlden H, Lewis PA, Senkevich K, Hammer M, Federoff M, Khan A, Spanaki C, Hadjigeorgiou GM, Bonstanjopoulou S, Fidani L, Ermolaev A, Gan-Or Z, Singleton A, Vandrovcova J, Hardy J. SORL1 mutation in a Greek family with Parkinson's disease and dementia. Ann Clin Transl Neurol. 2021 Oct;8(10):1961-1969. Epub 2021 Sep 10 PubMed.
2. Andersen OM, Monti G, Jensen AM, deWaal M, Hulsman M, Olsen JG, Holstege H. Relying on the relationship with known disease-causing variants in homologous proteins to predict pathogenicity of SORL1 variants in Alzheimer's disease. 2023 Feb 27 10.1101/2023.02.27.524103 (version 1) bioRxiv.

Further Reading

No Available Further Reading