Nonsense mutation in ADAM10 (p.tyr167*) associated with familial Alzheimer's disease: a clinical correlate of alfa-secretase haploinsufficiency

Trabajo presentado al 6th Congress of the European Academy of Neurology, celebrado de forma virtual del 23 al 26 de mayo de 2020.
[Background and aims]: The disintegrin metalloproteinase 10 (ADAM 10) us the main α-secretase acting in the non-amyloidogenic processing of the amyloid precursor protein. Some ADAM10 gene variants have been associated with higher susceptibility to develop late-onset disease, though a clear clinical-genetic correlate has not been reported yet. We present a family in whom development of AD was associated with a nonsense ADAM10 prodomain mutation (p.Tyr167*) causing haploinsufficiency
[Methods]: Clinical-genetic and CSF biomarker study of a family with AD.
[Results]: The p.Tyr167* mutation was absent from public databases and segregated with the disease. Age at onset for 3 affected siblings ranged from 58 to 68 years, and their clinical phenotypes have been noteworthy for the slow disease evolution. CSF Ab42, total tau, and phosphorylated tau biomarkers were consistent with AD. Haploinsufficiency was demonstrated by: a) ADAM10 isoforms in CSF decreased around 50%, and b) 70% reduction of CSF sAPPα peptide, both compared to controls. Sporadic AD cases had a similar decrease in CSF ADAM10 levels to that of mutants, though their sAPPα levels resembled those of controls.
[Conclusion]: This family provides the first example of a deleterious coding variant in ADAM10 associated with familial AD, and further implicates the amyloidogenic process in the development of the disease. Similarities between clinical and biomarker findings suggest that this family could represent a genetic model of sporadic late-onset AD due to an age-related down-regulation of α-secretase.