necessary for the proper protein conformation. Therefore,
his substitution with the His residue may also change
PGRN 3D structure with consequences at functional level.
The effect of the Thr182Met mutation is less clear since it
is just outside the granulin motif. This amino acid is
conserved between mammals and was not detected in
Consistent with other PGRN studies, the clinical pre-
sentation in patients carrying the pathogenic mutations is
characterized by a large variation in age at onset and by
occurrence of symptoms of nonfluent aphasia, whereas
semantic deficits were more often seen in patients with
missense and intronic MAPT mutations within the same
The HTFD3 family, in particular, shows a large
variation in age at onset. The high variability is further
confirmed by the presence of a 72-year-old healthy carrier.
Our and other findings show that a significant proportion
of patients remain unaffected until old age suggesting
therefore an interplay of several genetic and/or environ-
mental factors in the disease development.
The percentage of PGRN mutations detected in our
familial FTLD cohort (up to B7% by including the two
highly conserved missense mutations) is lower compared
to the much higher frequency observed in other studies
where PGRN mutations explain up to B25% of familial
The lower frequency of PGRN mutations in
our group might reflect differences in patients recruit-
ment methods, as the MAPT mutations in the Belgian
cohort account for only to 7% of all familial cases
compared to 14% detected in this cohort.
addition, in the studies by Cruts et al.
and Baker et al.
a strong founder effect among probands carrying
the IVS0 þ 5G4C and Arg493X was observed, whereas
we restricted our estimation of mutation frequency to
independent patients only.
In addition, geographical differences in frequencies may
also play a role, as seen in MAPT studies, and they cannot
be ruled out until more reports will allow a better estimate
of PGRN mutation frequency in familial FTLD.
In summary, mutations in PGRN explain only part
of FTLD in our cohort and they are absent in B80% of
cases including familial FTLD þ MND as well as FTLD-U
without MND strongly suggesting that we are only
beginning to unravel the molecular pathways leading to
FTLD and that additional genes contribute to the disease
This study was supported by the Centre for Medical Systems Biology
(CMSB), a centre of excellence approved by the Netherlands Genomics
Initiative/Netherlands Organization for Scientific Research (NWO)
and by the ‘Hersenstichting Nederland’ Project-Number 13F05(2).14
and ‘Stichting Dioraphte’.
1 Neary D, Snowden JS, Gustafson L et al: Frontotemporal lobar
degeneration – a consensus on clinical diagnostic criteria.
Neurology 1998; 51: 1546 –1554.
2 Forman MS, Farmer J, Johnson JK et al: Frontotemporal
dementia: clinicopathological correlations. Ann Neurol 2006; 59:
952 – 962.
3 McKhann GM, Albert MS, Grossman M, Miller B, Dickson D,
Trojanowski JQ: Clinical and pathological diagnosis of fronto-
temporal dementia: report of the Work Group on Frontotemporal
Dementia and Pick’s Disease. Arch Neurol 2001; 58: 1803 –1809.
4 Rosso SM, Kamphorst W, de Graaf B et al: Familial frontotemporal
dementia with ubiquitin-positive inclusions is linked to chromo-
some 17q2l-22. Brain 2001; 124: 1948 – 1957.
5 Skibinski G, Parkinson NJ, Brown JM et al: Mutations in the
endosomal ESCRTIII-complex subunit CHMP2B in fronto-
temporal dementia. Nat Genet 2005; 37: 806 –808.
6 Vance C, Al-Chalabi A, Ruddy D et al: Familial amyotrophic
lateral sclerosis with frontotemporal dementia is linked to a locus
on chromosome 9p13.2-21.3. Brain 2006; 129: 868 – 876.
7 Hosler BA, Siddique T, Sapp PC et al: Linkage of familial
amyotrophic lateral sclerosis with frontotemporal dementia to
chromosome 9q21-q22. JAMA 2000; 284: 1664 – 1669.
8 Hutton M, Lendon CL, Rizzu P et al: Association of missense
-splice-site mutations in tau with the inherited dementia
FTDP-17. Nature 1998; 393: 702 –705.
9 Baker M, Mackenzie IR, Pickering-Brown SM et al: Mutations in
progranulin cause tau-negative frontotemporal dementia linked
to chromosome 17. Nature 2006; 442: 916 – 919.
10 Cruts M, Gijselinck I, van der Zee J et al: Null mutations in
progranulin cause ubiquitin-positive frontotemporal dementia
linked to chromosome 17q21. Nature 2006; 442: 920 – 924.
11 He Z, Bateman A: Progranulin (granulin –epithelin precursor,
PC-cell-derived growth factor, acrogranin) mediates tissue repair
and tumorigenesis. J Mol Med 2003; 81: 600 – 612.
12 The Lund and Manchester Groups: Clinical and neuropatho-
logical criteria for frontotemporal dementia. J Neurol Neurosurg
Psychiatry 1994; 57: 416 – 418.
13 Rizzu P, van Mil SE, Anar B et al: CHMP2B mutations are not a
cause of dementia in Dutch patients with familial and sporadic
frontotemporal dementia. Am J Med Genet B Neuropsychiatr Genet
2006; 141: 944 – 946.
14 Rosso SM, Kaat LD, Baks T et al: Frontotemporal dementia in The
Netherlands: patient characteristics and prevalence estimates
from a population-based study. Brain 2003; 126: 2016 –2022.
15 Gass J, Cannon A, Mackenzie IR et al: Mutations in progranulin
are a major cause of ubiquitin-positive frontotemporal lobar
degeneration. Hum Mol Genet 2006; 15: 2988 – 3001.
16 Sampathu DM, Neumann M, Kwong LK et al: Pathological
heterogeneity of frontotemporal lobar degeneration with
Figure 2 (a) Progranulin motif alignment between species. Human progranulin sequence is given in blue. Only progranulin motifs containing
mutations are shown. Progranulin motifs are underlined. Conserved amino acids described by He and Bateman
are turquoise and nonconserved
amino acids are shown in yellow. The possible Thr182Met, Pro233His and Trp541Cis mutations are shown in red. The Gly414Val polymorphism is
given in green. (b) Conservation of amino acids between progranulin motifs. The longest human progranulin isoform is shown. All human progranulin
motifs are aligned. Conserved amino acids described by He and Bateman
are turquoise and non-conserved amino acids are shown in yellow.
Consensus depicts the consensus motif adapted from He and Bateman.
The possible Thr182Met, Pro233His and Trp541Cys mutations are shown in
red. The Gly414Val polymorphism is given in green.
PGRN mutations in FTLD
IF Bronner et al
European Journal of Human Genetics