The missense p.Trp7Arg mutation in GRN gene leads to progranulin haploinsufficiency

NEUROBIOLOGY OF AGING

卷:85

Article

Saracino, Dario^1,2  Sellami, Leila^1,2  Clot, Fabienne³  Camuzat, Agnes^1,4  Lamari, Foudil⁵  Rucheton, Benoit⁵  Benyounes, Imen⁵  Roue-Jagot, Carole^6,7  Lagarde, Julien^6,7  Sarazin, Marie^6,7  Jornea, Ludmila¹  Forlani, Sylvie¹  LeGuern, Eric^1,3  Dubois, Bruno^1,2  Brice, Alexis^1,8  Le Ber, Isabelle^1,2 

[1] UPMC Univ Paris 06, Sorbonne Univ, Hop Pitie Salpetriere, AP HP,Inserm,U1127,CNRS,UMR 7225,Inst Cerveau & M, Paris, France

[2] Hop La Pitie Salpetriere, AP HP, Dept Neurol, Ctr Reference Demences Rares Precoces,IM2A, Paris, France

[3] Hop Univ La Pitie Salpetriere Charles Foix, AP HP, Dept Genet, UF Neurogenet Mol & Cellulaire, Paris, France

[4] PSL Res Univ, EPHE, Paris, France

[5] Hop La Pitie Salpetriere, AP HP, UF Biochim Malad Neurometab & Neurodegenerat, Serv Biochim Metab, Paris, France

[6] Univ Paris 05, Hop St Anne, GHU Paris Psychiat & Neurosci, Unit Neurol Memory & Language,Sorbonne Paris Cite, Paris, France

[7] Univ Paris Saclay, Univ Paris Sud, Serv Hosp Freder Joliot, UMR 1023 IMIV,CEA,CNRS, Orsay, France

[8] Hop La Pitie Salpetriere, APHP, Natl Reference Ctr Neurogenet, Paris, France

关键词: Frontotemporal dementia;    Frontotemporal lobar degeneration;    Progranulin;    GRN;    C9orf72;    TDP-43;    Missense mutation;   

DOI  :  10.1016/j.neurobiolaging.2019.06.002

来源: Elsevier

【 摘 要 】

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. (C) 2019 Elsevier Inc. All rights reserved.

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