neurogenetics

, Volume 15, Issue 2, pp 95–100 | Cite as

Partial deletions of the GRN gene are a cause of frontotemporal lobar degeneration

  • Fabienne Clot
  • Anne Rovelet-Lecrux
  • Foudil Lamari
  • Sandrine Noël
  • Boris Keren
  • Agnès Camuzat
  • Agnès Michon
  • Ludmila Jornea
  • Béatrice Laudier
  • Anne de Septenville
  • Paola Caroppo
  • Dominique Campion
  • Cécile Cazeneuve
  • Alexis Brice
  • Eric LeGuern
  • Isabelle Le Ber
  • The French clinical and genetic research network on FTLD/FTLD-ALS
Original Article
  • 322 Downloads

Abstract

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.

Keywords

FTLD FTD PGRN/GRN Progranulin Deletion 

Notes

Acknowledgments

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.

Supplementary material

10048_2014_389_MOESM1_ESM.doc (44 kb)
Supplementary Table 1 (DOC 44 kb)
10048_2014_389_MOESM2_ESM.doc (49 kb)
Supplementary Table 2 (DOC 49 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Fabienne Clot
    • 1
    • 2
    • 3
    • 13
  • Anne Rovelet-Lecrux
    • 4
  • Foudil Lamari
    • 5
  • Sandrine Noël
    • 1
    • 2
  • Boris Keren
    • 1
    • 6
  • Agnès Camuzat
    • 7
    • 8
    • 9
  • Agnès Michon
    • 3
    • 10
  • Ludmila Jornea
    • 7
    • 8
    • 9
    • 11
  • Béatrice Laudier
    • 12
  • Anne de Septenville
    • 7
    • 8
    • 9
  • Paola Caroppo
    • 7
    • 8
    • 9
  • Dominique Campion
    • 4
  • Cécile Cazeneuve
    • 1
    • 2
  • Alexis Brice
    • 1
    • 7
    • 8
    • 9
    • 10
    • 11
  • Eric LeGuern
    • 1
    • 2
    • 7
    • 8
    • 9
  • Isabelle Le Ber
    • 3
    • 7
    • 8
    • 9
    • 10
  • The French clinical and genetic research network on FTLD/FTLD-ALS
  1. 1.Département de Génétique, Cytogénétique et EmbryologieHôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Assistance Publique-Hôpitaux de ParisParisFrance
  2. 2.UF de Neurogénétique Moléculaire et CellulaireHôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Assistance Publique-Hôpitaux de ParisParisFrance
  3. 3.Centre national de Référence des Démences RaresHôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Assistance Publique-Hôpitaux de ParisParisFrance
  4. 4.Inserm U1079, Université de Rouen, Institut de Recherche et d’Innovation Biomédicale, CHU de RouenRouenFrance
  5. 5.Laboratoire de Biochimie MétaboliqueHôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Assistance Publique-Hôpitaux de ParisParisFrance
  6. 6.UF de Génétique ChromosomiqueHôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Assistance Publique-Hôpitaux de ParisParisFrance
  7. 7.Inserm, UMR_S975, CRICMParisFrance
  8. 8.UPMC Univ Paris 06, UMR_S975ParisFrance
  9. 9.CNRS UMR 7225ParisFrance
  10. 10.Département de NeurologieHôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Assistance Publique-Hôpitaux de ParisParisFrance
  11. 11.Banque d’ADN et de Cellules - CRICM UMR_S975ParisFrance
  12. 12.Centre Hospitalier Régional d’Orléans, Structure Interne de Génétique, Hôpital de la SourceOrléansFrance
  13. 13.Unité Fonctionnelle de Neurogénétique Moléculaire et CellulaireGroupe Hospitalier Pitié-SalpêtrièreParisFrance

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