Partial deletions of the GRN gene are a cause of frontotemporal lobar degeneration
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Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD). Most known GRN mutations are null mutations, such as nonsense and frameshift mutations, which create a premature stop codon resulting in loss of function of the progranulin protein. Complete or near-complete genomic GRN deletions have also been found in three families, but heterozygous partial deletions that remove only one or two exons have not been reported to date. In this study, we analysed three unrelated FTLD patients with low plasma progranulin levels but no point GRN mutations by multiplex ligation-dependent probe amplification (MLPA) and quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF). We detected two heterozygous partial GRN deletions in two patients. One deletion removed exon 1 and part of intron 1. The second deletion was complex: it removed 1,410 bp extending from the part of intron 1 to the part of exon 3, with a small 5-bp insertion at the breakpoint junction (c.-7-1121_159delinsGATCA). Our findings illustrate the usefulness of a quantitative analysis in addition to GRN gene sequencing for a comprehensive genetic diagnosis of FTLD, particularly in patients with low plasma progranulin levels.
KeywordsFTLD FTD PGRN/GRN Progranulin Deletion
This study was funded by the France Alzheimer Association contract R12091DD (to A.B..), the Programme Hospitalier de Recherche Clinique (PHRC) (to I.L.B.), the Neuromics FP7 contract E12009DD (to A.B..) and the programme “Investissements d’avenir” ANR-10-IAIHU-06. Dr. Paola Caroppo received a PhD Fellowship from the Carlo Besta Institute, Milano, Italy. Anne De Septenville was funded by the programme “Investissements d’avenir” ANR-10-IAIHU-06. We thank Dr. Merle Ruberg for her helpful suggestions on the manuscript and Ms Lydia Guennec, Isabelle Lagroua, Sylvie Forlani and Christelle Dussert (DNA and cell bank of CR-ICM, Hôpital de la Salpêtrière, Paris) for their excellent technical assistance.