HDDD2 Is a Familial Frontotemporal Lobar
Degeneration with Ubiquitin-Positive, Tau-
Negative Inclusions Caused by a Missense
Mutation in the Signal Peptide of
Odity Mukherjee, PhD,
Pau Pastor, MD, PhD,
Nigel J. Cairns, PhD,
Sumi Chakraverty, MS,
John S. K. Kauwe, MS,
Shantia Shears, BS,
Maria I. Behrens, MD, PhD,
John Budde, BS,
Anthony L. Hinrichs, PhD,
Joanne Norton, MSN, RN, CS,
Denise Levitch, BS, RN,
Lisa Taylor-Reinwald, BA,
Michael Gitcho, PhD,
P.-H. Tu, MD, PhD,
Lea Tenenholz Grinberg, MD,
Rajka M. Liscic, MD, PhD,
Javier Armendariz, MS,
John C. Morris, MD,
and Alison M. Goate, PhD
Objective: Familial autosomal dominant frontotemporal dementia with ubiquitin-positive, tau-negative inclusions in the brain
linked to 17q21-22 recently has been reported to carry null mutations in the progranulin gene (PGRN). Hereditary dysphasic
disinhibition dementia (HDDD) is a frontotemporal dementia with prominent changes in behavior and language deficits. A
previous study found significant linkage to chromosome 17 in a HDDD family (HDDD2), but no mutation in the MAPT gene.
Longitudinal follow-up has enabled us to identify new cases and to further characterize the dementia in this family. The goals
of this study were to develop research criteria to classify the different clinical expressions of dementia observed in this large
kindred, to identify the causal mutation in affected individuals and correlate this with phenotypic characteristics in this pedigree,
and to assess the neuropathological characteristics using immunohistochemical techniques.
Methods: In this study we describe a detailed clinical, pathological and mutation analysis of the HDDD2 kindred.
Results: Neuropathologically, HDDD2 represents a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-
negative inclusions (FTLD-U). We developed research classification criteria and identified three distinct diagnostic thresholds,
which helped localize the disease locus. The chromosomal region with the strongest evidence of linkage lies within the minimum
critical region for FTLD-U. Sequencing of each exon of the PGRN gene led to the identification of a novel missense mutation,
Ala-9 Asp, within the signal peptide.
Interpretation: HDDD2 is an FTLD-U caused by a missense mutation in the PGRN gene that cosegregates with the disease
and with the disease haplotype in at-risk individuals. This mutation is the first reported pathogenic missense mutation in the
signal peptide of the PGRN gene causing FTLD-U. In light of the previous reports of null mutations and its position in the
gene, two possible pathological mechanisms are proposed: (1) the protein may accumulate within the endoplasmic reticulum due
to inefficient secretion; and (2) mutant RNA may have a lower expression because of degradation via nonsense-mediated decay.
Ann Neurol 2006;60:314–322
Frontotemporal dementia (FTD) is characterized by
early behavioral and personality changes, language de-
terioration, and later in the course of the disease, de-
mentia and parkinsonism.
FTD shows familial aggre
gation with a family history of dementia present in
41% of FTD cases.
Late pyramidal and extrapyrami
Washington University Alzheimer’s Disease Research Cen
Department of Psychiatry, Washington University School of
Medicine, St. Louis, MO;
School of Medicine University of Navarre,
Pamplona and Division of Neurosciences, Center for Applied Medical
Research (CIMA), Clı´nica Universitaria;
Departments of Pathology
and Immunology and
Neurology, Washington University School of
Medicine, St. Louis, MO;
Departamento de Neurologı´a, Facultad de
Medicina, Universidad de Chile, and Clı´nica Alemana, Santiago,
Department of Pathology, University of Sao Paulo Medical
School, Sao Paulo, Brazil;
Institute for Medical Research and Occu
pational Health, Zagreb, Croatia; and
Department of Genetics,
Washington University School of Medicine, St. Louis, MO.
Received Jul 13, 2006, and in revised form Aug 1. Accepted for
publication Aug 1, 2006.
Published online Sep 25, 2006, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20963
Address correspondence to Dr Goate, Department of Psychiatry,
Washington University School of Medicine, Campus Box 8134,
660 South Euclid Avenue, St. Louis, MO 63110.
314 © 2006 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services