Armstrong J, Boada M, Rey MJ, Vidal N, Ferrer I.
Familial Alzheimer disease associated with A713T mutation in APP.
Neurosci Lett. 2004 Nov 11;370(2-3):241-3.
PubMed.
We found that the A713T mutation segregated with disease in a large Italian family, strongly supporting the pathogenicity of this rare variant (Conidi et al., 2015). However, this mutation did not segregate with disease in a previously described family (Carter et al., 1992). Although we can only speculate, it may be that the four “healthy” A713T carriers in that family were, in fact, presymptomatic at age 62 and older (and in one case at age 88). Other studies have shown that carriers of this mutation exhibit a particularly variable age of symptom onset , ranging from 52 to 82 years (Rossi et al., 2004; Bernardi et al., 2009). It is also possible, as Carter and colleagues suggested, that genetic, epigenetic or environmental modifiers influence the penetrance of the A713T mutation.
Of particular note, in the A713T family they studied, Carter and colleagues also detected a G>A transition in the codon for the nearby amino acid 715. This is a synonymous change and may simply be a rare polymorphism. It was not present in the Italian family we studied, nor reported in any of the other known A713T carriers. Given the apparent lack of segregation of A713T in the family studied by Carter, it is possible that the accompanying G>A transition at codon 715 may reduce the penetrance of the A713T mutation. It is increasingly recognized that “silent” mutations can have significant biological effects, and that synonymous codons are not necessarily equivalent (Berleant et al., 2009).
We observed that APP A713T increases the Aβ42/Aβ40 ratio in plasma (Conidi et al., 2015). Studies in cell culture may elucidate the effects of the mutation on APP processing, and whether the presence of the nearby silent mutation affects this.
For reasons that are currently unclear, human carriers of A713T present with either classic Alzheimer’s pathology or prominent CAA with significant vascular lesions. It would be interesting to determine the pattern of amyloid pathology in a mouse model and to explore potential modifiers of that pathology.
References:
Conidi ME, Bernardi L, Puccio G, Smirne N, Muraca MG, Curcio SA, Colao R, Piscopo P, Gallo M, Anfossi M, Frangipane F, Clodomiro A, Mirabelli M, Vasso F, Cupidi C, Torchia G, Di Lorenzo R, Mandich P, Confaloni A, Maletta RG, Bruni AC.
Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family.
Neurology. 2015 Jun 2;84(22):2266-73. Epub 2015 May 6
PubMed.
Carter DA, Desmarais E, Bellis M, Campion D, Clerget-Darpoux F, Brice A, Agid Y, Jaillard-Serradt A, Mallet J.
More missense in amyloid gene.
Nat Genet. 1992 Dec;2(4):255-6.
PubMed.
Rossi G, Giaccone G, Maletta R, Morbin M, Capobianco R, Mangieri M, Giovagnoli AR, Bizzi A, Tomaino C, Perri M, Di Natale M, Tagliavini F, Bugiani O, Bruni AC.
A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene.
Neurology. 2004 Sep 14;63(5):910-2.
PubMed.
Bernardi L, Geracitano S, Colao R, Puccio G, Gallo M, Anfossi M, Frangipane F, Curcio SA, Mirabelli M, Tomaino C, Vasso F, Smirne N, Maletta R, Bruni AC.
AbetaPP A713T mutation in late onset Alzheimer's disease with cerebrovascular lesions.
J Alzheimers Dis. 2009;17(2):383-9.
PubMed.
Berleant D, White M, Pierce E, Tudoreanu E, Boeszoermenyi A, Shtridelman Y, Macosko JC.
The genetic code--more than just a table.
Cell Biochem Biophys. 2009;55(2):107-16. Epub 2009 Jul 29
PubMed.
Comments
Azienda Sanitaria Provinciale Catanzaro
Regional Neurogenetic Centre
Regional Neurogenetic Centre
We found that the A713T mutation segregated with disease in a large Italian family, strongly supporting the pathogenicity of this rare variant (Conidi et al., 2015). However, this mutation did not segregate with disease in a previously described family (Carter et al., 1992). Although we can only speculate, it may be that the four “healthy” A713T carriers in that family were, in fact, presymptomatic at age 62 and older (and in one case at age 88). Other studies have shown that carriers of this mutation exhibit a particularly variable age of symptom onset , ranging from 52 to 82 years (Rossi et al., 2004; Bernardi et al., 2009). It is also possible, as Carter and colleagues suggested, that genetic, epigenetic or environmental modifiers influence the penetrance of the A713T mutation.
Of particular note, in the A713T family they studied, Carter and colleagues also detected a G>A transition in the codon for the nearby amino acid 715. This is a synonymous change and may simply be a rare polymorphism. It was not present in the Italian family we studied, nor reported in any of the other known A713T carriers. Given the apparent lack of segregation of A713T in the family studied by Carter, it is possible that the accompanying G>A transition at codon 715 may reduce the penetrance of the A713T mutation. It is increasingly recognized that “silent” mutations can have significant biological effects, and that synonymous codons are not necessarily equivalent (Berleant et al., 2009).
We observed that APP A713T increases the Aβ42/Aβ40 ratio in plasma (Conidi et al., 2015). Studies in cell culture may elucidate the effects of the mutation on APP processing, and whether the presence of the nearby silent mutation affects this.
For reasons that are currently unclear, human carriers of A713T present with either classic Alzheimer’s pathology or prominent CAA with significant vascular lesions. It would be interesting to determine the pattern of amyloid pathology in a mouse model and to explore potential modifiers of that pathology.
References:
Conidi ME, Bernardi L, Puccio G, Smirne N, Muraca MG, Curcio SA, Colao R, Piscopo P, Gallo M, Anfossi M, Frangipane F, Clodomiro A, Mirabelli M, Vasso F, Cupidi C, Torchia G, Di Lorenzo R, Mandich P, Confaloni A, Maletta RG, Bruni AC. Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family. Neurology. 2015 Jun 2;84(22):2266-73. Epub 2015 May 6 PubMed.
Carter DA, Desmarais E, Bellis M, Campion D, Clerget-Darpoux F, Brice A, Agid Y, Jaillard-Serradt A, Mallet J. More missense in amyloid gene. Nat Genet. 1992 Dec;2(4):255-6. PubMed.
Rossi G, Giaccone G, Maletta R, Morbin M, Capobianco R, Mangieri M, Giovagnoli AR, Bizzi A, Tomaino C, Perri M, Di Natale M, Tagliavini F, Bugiani O, Bruni AC. A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene. Neurology. 2004 Sep 14;63(5):910-2. PubMed.
Bernardi L, Geracitano S, Colao R, Puccio G, Gallo M, Anfossi M, Frangipane F, Curcio SA, Mirabelli M, Tomaino C, Vasso F, Smirne N, Maletta R, Bruni AC. AbetaPP A713T mutation in late onset Alzheimer's disease with cerebrovascular lesions. J Alzheimers Dis. 2009;17(2):383-9. PubMed.
Berleant D, White M, Pierce E, Tudoreanu E, Boeszoermenyi A, Shtridelman Y, Macosko JC. The genetic code--more than just a table. Cell Biochem Biophys. 2009;55(2):107-16. Epub 2009 Jul 29 PubMed.
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