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New Gene for Frontotemporal Dementia Identified

Two landmark articles report the identification of mutations in the progranulin gene in familial frontotemporal dementia.

Many mutations have been identified in the gene that encodes microtubule-associated protein tau (MAPT) in familial frontotemporal dementia (FTD). However, several large FTD families have been identified that showed significant linkage to chromosome 17 (the location of the MAPT gene) but carried no MAPT mutations. This finding suggested several possibilities: that the mutations in these families are in a noncoding part of the MAPT gene deep within an intron, that a chromosomal rearrangement alters expression of MAPT, or that a second gene in this region also causes FTD. Previous research has excluded the first two possibilities.

To explore the third possibility, Baker and colleagues systematically sequenced more than 80 candidate genes in the linked region in a large Canadian FTD family and identified a heterozygous mutation in the progranulin (PGRN) gene that segregated with FTD but was absent in 550 people without FTD (controls). Sequencing of the PGRN gene in 41 families revealed seven additional mutations. In most cases, the mutations resulted in a premature termination codon and, thus, a truncated protein. Both protein and mRNA levels of PGRN were reduced by 50% in affected individuals compared with unaffected individuals, suggesting that the mutant mRNA is rapidly degraded and that this form of FTD is caused by haploinsufficiency.

Using a similar strategy, Cruts and colleagues identified PGRN mutations in two FTD families previously linked to chromosome 17. Screening of 103 FTD patients identified three additional mutations. PGRN mutations accounted for a higher proportion of FTD cases than did MAPT mutations in this FTD series. In one patient, a mutation in the Kozak consensus sequence was observed that resulted in a null allele with respect to the PGRN protein, confirming that the mutant alleles result in a loss of function.

Comment: These studies resolve a decade-old conundrum regarding FTD families linked to chromosome 17 but with no mutation in the MAPT gene. They demonstrate that mutations in two unrelated genes (MAPT and PGRN), located within two million base pairs of one another, can each cause familial FTD. Mutations in PGRN may be a more common cause of FTD than MAPT mutations, although confirmation requires additional screening. PGRN mutations are associated with a wide range in age of onset, even within a single family (45–70 years), which suggests that other factors can modulate disease onset. PGRN is a multifunctional growth factor that is clearly necessary for neuronal survival, but little is known about its regulation or normal function in the brain. Because an excess of PGRN has been shown to cause tumor formation and a deficiency causes neurodegeneration, PGRN expression must be very tightly regulated.

— Alison Goate, DPhil

Dr. Goate is Samuel & Mae S. Ludwig Professor of Genetics in Psychiatry, Professor of Neurology, and Professor of Genetics, Washington University School of Medicine, St. Louis, MO.

Published in Journal Watch Neurology September 26, 2006

Citation(s):

Baker M et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006 Aug 24; 442:916-9.

• Medline abstract (Free)

Cruts M et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006 Aug 24; 442:920-4.

• Medline abstract (Free)

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