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

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.

• Authors: 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, French clinical and genetic research network on FTLD/FTLD-ALS
• Journal: Neurogenetics (Neurogenetics) Vol. 15 Issue 2 Pg. 95-100 (May 2014) ISSN: 1364-6753 [Electronic] United States
• PMID: 24469240 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GRN protein, human
• Intercellular Signaling Peptides and Proteins
• Progranulins

Topics

• Frontotemporal Lobar Degeneration (genetics)
• Gene Deletion
• Humans
• Intercellular Signaling Peptides and Proteins (genetics)
• Loss of Heterozygosity
• Middle Aged
• Pedigree
• Progranulins