Careful analysis of the chromosomal region shared by patients in each family with FTLDU-17 revealed that the minimum region harboring the gene for FTLDU-17 was 6.2 million base pairs (bp), as delimited by a centromeric recombinant in Dutch family 1083 and by a telomeric recombinant in Canadian family UBC-17.4Next, all genes within the shared region needed to be identified before they could be screened for mutations. Whereas this used to be an elaborate laboratory procedure, the completion of the draft sequence of the human genome via the Human Genome Project has greatly facilitated this process, allowing computer-assisted assembly and annotation of the DNA sequence in the candidate region based on genetic information in public databases (Figure 2B). Assembly and annotation of the minimal FTLDU-17 genomic sequence revealed 165 known genes, including MAPT. Although simple mutations in MAPThad been excluded after extensive DNA sequence analysis of a 138 500-bp MAPTgenomic region,6more complex mutations such as genomic rearrangements (inversion of a chromosomal region) or copy number variations (duplication or deletion of the MAPTlocus) might cause disease. With fluorescence in situ hybridization, a technique using fluorescently labeled DNA probes to visualize a given DNA sequence, it was proven that an inversion of the chromosomal region containing MAPTexists but that this inversion is not associated with affection status (ie, also occurs in healthy individuals).7In addition, the presence of copy number variations causing disease was excluded via oligo-based array comparative genome hybridization, a fluorescence in situ hybridization–based technique used to detect chromosomal regions that are amplified (eg, duplicated) or deleted.8In parallel with the exclusion of complex mutations in MAPT, other genes located in the shared region underwent a mutation screening through direct sequence analysis, comparing base by base the DNA sequence of protein coding and regulatory parts of the genes between patients and healthy individuals (Figure 2B). After sequencing approximately 100 genes in the region, progranulin (GRNor PGRN[OMIM 138945]; 1.7 million bp centromeric of MAPT) was identified as the gene causing FTLDU-17 through the discovery of PGRNmutations in UBC-17, family 1083, and newly identified Belgian founder family DR8.8,9PGRNencodes a growth factor involved in multiple processes, including development, wound repair, and inflammation. Although widely expressed in neurons, its function in brain is as yet unknown, but upregulation of PGRNin neurodegenerative diseases such as amyotrophic lateral sclerosis and Creutzfeldt-Jakob disease suggests a role in neuronal survival.