Strikingly Different Clinicopathological Phenotypes Determined by Progranulin-Mutation Dosage

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• 作者：Katherine  ; R. Smith¹ ; ² ; John Damiano³ ; Silvana Franceschetti⁴ ; Stirling Carpenter⁵ ; Laura Canafoglia⁴ ; Michela Morbin⁶ ; Giacomina Rossi⁶ ; Davide Pareyson⁷ ; Sara  ; E. Mole⁸ ; John  ; F. Staropoli⁹ ; Katherine  ; B. Sims⁹ ; Jada Lewis¹⁰ ; Wen-Lang Lin¹¹ ; Dennis  ; W. Dickson¹¹ ; Hans-Henrik Dahl³ ; Melanie Bahlo¹ ; ¹² ; ^{bahlo@wehi.edu.au} ; Samuel  ; F. Berkovic³ ; ^{s.berkovic@unimelb.edu.au}
• 刊名：The American Journal of Human Genetics
• 出版年：2012
• 期刊代码：P22_00029297
• 类别：bio
• 出版时间：8 June, 2012
• 卷：90
• 期：6
• 页码：1102-1107
• 文件大小：425 K

摘要

We performed hypothesis-free linkage analysis and exome sequencing in a family with two siblings who had neuronal ceroid lipofuscinosis (NCL). Two linkage peaks with maximum LOD scores of 3.07 and 2.97 were found on chromosomes 7 and 17, respectively. Unexpectedly, we found these siblings to be homozygous for a c.813_816del (p.Thr272Serfs^{鈭?/sup>10) mutation in the progranulin gene (GRN, granulin precursor) in the latter peak. Heterozygous mutations in GRN are a major cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), the second most common early-onset dementia. Reexamination of progranulin-deficient mice revealed rectilinear profiles typical of NCL. The age-at-onset and neuropathology of FTLD-TDP and NCL are markedly different. Our findings reveal an unanticipated link between a rare and a common neurological disorder and illustrate pleiotropic effects of a mutation in the heterozygous or homozygous states.}