Partial deletions of the GRN gene are a cause of frontotemporal lobar degeneration.
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.
Département de Génétique, Cytogénétique et Embryologie, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Assistance Publique-Hôpitaux de Paris, Paris, France, fabienne.clot@psl.aphp.fr.
Fabienne
F
Clot
Anne
A
Rovelet-Lecrux
Foudil
F
Lamari
Sandrine
S
Noël
Boris
B
Keren
Agnès
A
Camuzat
Agnès
A
Michon
Ludmila
L
Jornea
Béatrice
B
Laudier
Anne
A
de Septenville
Paola
P
Caroppo
Dominique
D
Campion
Cécile
C
Cazeneuve
Alexis
A
Brice
Eric
E
LeGuern
Isabelle
I
Le Ber
D057174:Frontotemporal Lobar Degeneration / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D019656:Loss of Heterozygosity; D008875:Middle Aged; D010375:Pedigree; D000077153:Progranulins
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins