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Fazeli E, Child DD, Bucks SA, Stovarsky M, Edwards G, Yu C-E, Latimer C, Kitago Y, Bird T, Andersen O, Jayadev S, Young JE. A familial missense variant in the AD gene SORL1 impairs its maturation and endosomal sorting. 2023 Jul 05 10.1101/2023.07.01.547348 (version 2) bioRxiv.
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Rouen University Hospital
This is another example of a missense variant affecting shedding and maturation of SORL1 in a family, segregating incompletely with AD, and with large diversity of ages of onset. Such diversity, and putative inheritance from the father with dementia at the age of 83, suggests that additional factors may be required to result in AD, at least before the age of 70-75, knowing that LOAD is very common. In my opinion, this variant may be insufficient to cause AD, although it seems to be a strong determinant.
We also have the same variant as in this work, in one of our unpublished patients (R953C). It is a sporadic case with an age at onset of 56 years, APOE genotype 3/4, unaffected parents at 80, large family, no other case except a paternal grandmother with an age at onset of 80. Unless there is a de novo mutation, which we could not check yet, it is inconsistent with autosomal-dominant inheritance. I hope we can see if one of the parents is a carrier, as this will help us better understand the variant's penetrance.
This paper adds another variant to the increasing list of variants with a maturation defect. We reported 15 variants with a similar effect in Rovelet-Lecrux et al., 2021 after expression of 70 missense variants in HEK cells. We selected three variants with such an effect, and two without, to further evaluate them in IPSCs after Crispr/cas9 introduction. We found that all three selected missense variants showed a maturation defect, including one with a milder effect. The two variants with the strongest maturation defect showed significantly increased secreted Aβ levels, clearly linking these variants to AD pathophysiology.
It is, however, unclear why, in the current paper, the authors mention our own paper with the following sentence: "Furthermore, a larger screen of 70 SORL1 coding variants suggested that impaired maturation may be general for dysfunctional proteins although no correlation to AD was established." We only studied SORL1, and we showed a direct link with AD for these specific variants, with the above-mentioned mechanism. We discussed that maturation defect of the encoded protein by a missense variant is a known mechanism for other diseases, but here we studied SORL1 missense variants impairing the maturation of SORL1 protein (this resulting to increased secreted Aβ) and not any other protein. There must be a misunderstanding on this point.
References:
Rovelet-Lecrux A, Feuillette S, Miguel L, Schramm C, Pernet S, Quenez O, Ségalas-Milazzo I, Guilhaudis L, Rousseau S, Riou G, Frébourg T, Campion D, Nicolas G, Lecourtois M. Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease. Acta Neuropathol Commun. 2021 Dec 18;9(1):196. PubMed.
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