The missense p.Trp7Arg mutation in GRN gene leads to progranulin haploinsufficiency.
GRN null mutations are among the main genetic causes of frontotemporal dementia through progranulin haploinsufficiency. Most missense mutations are considered not pathogenic. The p.Trp7Arg substitution is localized within the signal peptide domain and no formal evidence for its pathogenicity has yet been provided. We identified the p.Trp7Arg substitution in 3 carriers with low plasma progranulin levels. This evidences that this missense mutation leads to functional haploinsufficiency and should thus be considered pathogenic. Assessing the pathogenicity of variants of unknown significance has significant implications for clinical practice, genetic counseling, and future therapeutic interventions.
['Saracino|Dario|D|', 'Sellami|Leila|L|', 'Clot|Fabienne|F|', 'Camuzat|Agnès|A|', 'Lamari|Foudil|F|', 'Rucheton|Benoît|B|', 'Benyounes|Imen|I|', 'Roué-Jagot|Carole|C|', 'Lagarde|Julien|J|', 'Sarazin|Marie|M|', 'Jornea|Ludmila|L|', 'Forlani|Sylvie|S|', 'LeGuern|Eric|E|', 'Dubois|Bruno|B|', 'Brice|Alexis|A|', 'Le Ber|Isabelle|I|']
D000073885:C9orf72 Protein D004268:DNA-Binding Proteins D005260:Female D057180:Frontotemporal Dementia D057895:Haploinsufficiency D006801:Humans D008297:Male D008875:Middle Aged D020125:Mutation, Missense D000077153:Progranulins
GRN Progranulin Frontotemporal dementia Missense mutation C9orf72 Frontotemporal lobar degeneration TDP-43