Mutations in Progranulin Gene: Clinical, Pathological, and Ribonucleic Acid Expression Findings Adolfo López de Munain, Ainhoa Alzualde, Ana Gorostidi, David Otaegui, Javier Ruiz-Martínez, Begoña Indakoetxea, Isidro Ferrer, Jordi Pérez-Tur, Amets Sáenz, Alberto Bergareche, Miriam Barandiarán, Juan José Poza, Ramón Zabalza, Irune Ruiz, Miguel Urtasun, Iñaki Fernández-Manchola, Bixen Olasagasti, Juan Bautista Espinal, Javier Olaskoaga, Marta Ruibal, Fermin Moreno, Nieves Carrera, and José Félix Martí Massó Background: There is an increasing interest in the clinico-pathological correlation of mutations in progranulin (PGRN) and frontotemporal lobar degeneration (FTLD) complex diseases. We aim to study the PGRN expression variability in patients with different clinical features for a better understanding of its roles in FTLD disease. Methods: We sequenced the PGRN gene in 72 patients suffering from FTLD (25 familial and 47 sporadic cases) and in 24 asymptomatic at-risk relatives. We also analyzed PGRN expression in blood by quantitative real-time polymerase chain reaction from 37 patients, 8 asymptomatic mutation carriers, and 10 control subjects as well as in brain tissue from 16 patients and 9 control subjects. Results: Four novel mutations were associated with familial and sporadic FTLD and familial dementia associated with amyotrophic lateral sclerosis. We identified a close association between the IVS6-1GA mutation in PGRN and corticobasal syndrome. Brain tissue was available for carriers of two of the four mutations (IVS6-1 GA and P357HfsX3). Immunohistochemical analysis revealed ubiquitin- and TDP- 43positive and /-synuclein negative immunoreactive neuronal intranuclear inclusions. The relative expression of PGRN in the clinical sample was significantly lower in carriers of the IVS6-1 GA than in control subjects. Conclusions: Progranulopathies are a major cause of the main phenotypes included in the FTLD complex. According to our results, the level of expression of PGRN in blood could be a useful marker both for diagnostics of part of the spectrum of FTLD conditions and for monitoring future treatments that might boost the level of PGRN in this disorder. Key Words: Expression, FTLD, progranulin F rontotemporal lobar degeneration (FTLD) is actually a complex group of non-Alzheimer dementias, whose no- sology remains controversial. Up to 20 different nosologi- cal features have been used to describe these conditions, includ- ing clinical, pathological, and genetic phenomena (1). The main clinical subtypes of FTLD are frontotemporal dementia (FTD), in which behavioral and personality changes predominate, seman- tic dementia, and progressive primary non-fluent aphasia (PPA), with prominent early language disturbances. In addition, two pathological entities with prominent motor and gait disturbances, corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), are also classified as FTLD. Corticodentatonigral degeneration described by Rebeiz et al. (2) and subsequently renamed corticobasal degeneration (CBD) (3) was firstly recognized to have a pathological picture close to Pick disease with distinctive -positive pathology. Nevertheless, cases of corticobasal syndrome (CBDS) were reported in association with other pathological hallmarks as -negative inclusions of the motor neuron disease or lacking distinctive pathology (4,5). Each of these clinical forms of FTLD probably reflects different topographical distributions of underlying patholo- gies (6). Nevertheless, clinical and pathological overlap is very common and, accordingly, clinical misdiagnosis is fre- quent (7,8). The pathology of the FTLD is diverse and includes cases characterized by the abnormal deposition of hyperphosphory- lated intracytoplasmatic  protein (MAPT) in neurons and glial cells as well as cases without  inclusions. The latter are a heterogeneous group of disorders with ubiquitin-positive but - and -synuclein-negative neuronal inclusions (FTLD-U), motor neuron disease, and other rare disorders with no distinctive histopathology or neuronal inclusions composed of neuronal intermediate filaments (9 –15). In tauopathies, genetic studies identified mutations in MAPT in a small proportion of cases (15). In FTLD-U, other genes such as CHMP2B (16), valosin-contain- ing protein (VCP)(17), and, more recently, progranulin (PGRN) (18 –25) have been considered as causative factors. The variety of clinical diagnoses and anatomopathological pictures, together with the relative complexity of the genetic etiology of the FTLD complex, points toward the existence of common mechanisms playing a role in the development of the disease in all these clinical conditions that differ, inter alia, in either the localization of the insult or in its nature. In any case, the lack of a reliable biological marker that could help in the diagnosis of these disorders adds an additional layer of complex- ity to their study. If such a marker became available, all areas of study, including diagnosis, research, and therapeutic interven- tion, would be greatly enhanced by it. From the Servicio de Neurología (ALdM, JR-M, BI, MB, JJP, RZ, MU, IF-M, BO, JBE, JO, NC, JFMM); Unidad Experimental (ALdM, AA, AG, DO, AS); Servi- cio de Anatomía Patológica (IR), Hospital Donostia, San Sebastián; Servi- cio de Neurología (JR-M), Hospital de Mendaro, Mendaro; Servicio de Neurología (AB), Hospital Bidasoa, Hondarribia; Servicio de Neurología (MR, FM), Hospital Ntra. Sra. de la Antigua, Zumarraga, Gipuzkoa; Institut de Neuropatología (IF), Hospital Universitario de Bellvitge, Hospitalet de Llobregat, Barcelona; and the Unitat de Genètica Molecular (JP-T), Insti- tut de Biomedicina de València-CSIC, València, Spain. Address reprint requests to A. López de Munain, M.D., Ph.D., Neurology Department, Hospital Donostia, Paseo del Dr. Beguiristain 105-116, San Sebastián 20014 Spain; E-mail: munain@chdo.osakidetza.net. Received April 6, 2007; revised July 26, 2007; accepted August 29, 2007. BIOL PSYCHIATRY 2008;63:946 –952 0006-3223/08/$34.00 doi:10.1016/j.biopsych.2007.08.015 © 2008 Society of Biological Psychiatry