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Giuliano Binettic, Stefano Cappab,e, Nereo Bresolina, Elio Scarpinia and Daniela ... dProteomics Unit, IRCCS Centro S. Giovanni di Dio-FBF, Brescia, Italy.


Journal of Alzheimer’s Disease 26 (2011) 19–26 DOI 10.3233/JAD-2011-102124 IOS Press

A Novel MAPT Mutation Associated with the Clinical Phenotype of Progressive Nonfluent Aphasia Chiara Villaa , Laura Ghezzia , Anna M. Pietrobonia , Chiara Fenoglioa , Francesca Cortinia , Maria Serpentea , Claudia Cantonia , Elisa Ridolfia , Alessandra Marconeb , Luisa Benussic , Roberta Ghidonic,d , Francesca Jacinia , Andrea Arighia , Giorgio G. Fumagallia , Alessandra Mandellia , Giuliano Binettic , Stefano Cappab,e , Nereo Bresolina , Elio Scarpinia and Daniela Galimbertia, * a Department

of Neurological Sciences, University of Milan, IRCCS Fondazione C`a Granda, Ospedale Maggiore Policlinico, Milan, Italy b Division of Neurology, San Raffaele Turro Hospital, San Raffaele Scientific Institute, Milan, Italy c NeuroBioGen-Lab-Memory Clinic, IRCCS Centro S. Giovanni di Dio-FBF, Brescia, Italy d Proteomics Unit, IRCCS Centro S. Giovanni di Dio-FBF, Brescia, Italy e Vita-Salute San Raffaele University, Milan, Italy

Accepted 14 March 2011

Abstract. A number of mutations in microtubule associated protein tau gene (MAPT), causing frontotemporal lobar degeneration (FTLD) with tau pathology, are located in the four-repeated microtubule (MT) binding domains and affect the ability of tau to bind MTs. Here, we describe a novel variant lying in the second MT domain, found in a female patient diagnosed clinically with progressive nonfluent aphasia (PNFA), with a positive family history for dementia. At 65 years, she started developing progressive language deficits, characterized by expression difficulties and word coordination impairment. She came to our attention at 67 years. Her MMSE score was 22/30. A Brain CT scan showed mild diffuse cortical atrophy, ventricles’ asymmetry (left > right), and very mild signs of chronic vasculopathy. Cerebrospinal fluid analysis showed normal amyloid-␤42 , tau, and P-tau levels. She was diagnosed with PNFA according to current diagnostic criteria. A novel exon 10 MAPT variant was identified (g.123798G > A), which leads to an amino acidic change (p.Gly304Ser) in the second MT microtubule binding domain. In silico analysis predicted that this variant is damaging on protein structure and function. Additional 168 FTLD patients and 503 controls screened (1342 chromosomes) did not carry the variant, suggesting that it is a mutation rather than a polymorphism. The amino acid change likely compromises the ability of tau to properly regulate the dynamic behavior of microtubules. Keywords: frontotemporal lobar degeneration (FTLD), MAPT, mutation, phenotype, progressive nonfluent aphasia (PNFA)

INTRODUCTION Frontotemporal lobar degeneration (FTLD) refers to a group of dementias associated with circumscribed degeneration of the frontal and temporal lobes [1]. The current consensus criteria [2] identifies three clinical syndromes: behavioral variant of Frontotemporal dementia (bvFTD) [3], progressive nonfluent apha∗ Correspondence to: Daniela Galimberti, Tel.: +39 2 55033847; Fax: +39 2 50320430; E-mail: [email protected]

sia (PNFA) [4], and semantic dementia (SD), which reflects the clinical heterogeneity of FTLD. The majority of pathologies associated with FTLD clinical syndromes include either tau-positive (FTLDtau) or tau-negative, ubiquitin-positive immunostaining (FTLD-U). The majority of familial FTLD cases are caused by mutations in the genes encoding for microtubule associated protein tau (MAPT), leading to FTLD-tau, or progranulin (GRN), leading to FTLD-U (see [5] for review).

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C. Villa et al. / A Novel MAPT Mutation Associated with the Clinical Phenotype of Progressive Nonfluent Aphasia

The first mutation in MAPT was identified in 1998 [6]. To date, 44 different pathogenic MAPT mutations have been described in a total of 133 families (http://www.molgen.ua.ac.be/). They fall into two classes: the first consists of single amino acid substitutions or deletions that generally decrease the ability of tau to bind microtubules (MT) and to promote microtubule assembly in vitro. The second class affects the regulation of MAPT mRNA splicing, altering the ratio of 4-repeat to 3-repeat tau expression. The mutations are clustered in exons 9–13, encoding MT binding domains and flanking regions, except for two mutations in exon 1 [7, 8]. Here, we report on a new mutation in exon 10, located in the second microtubule binding domain, found in a patient diagnosed clinically with PNFA.

SUBJECTS AND METHODS Subjects The proband was admitted to the Alzheimer Centre of the University of Milan, Policlinico Hospital, Italy and underwent a standard diagnostic workup, including detailed past medical history, general and neurological examination, routine blood tests, formal neurocognitive assessment (including Mini Mental State Examination (MMSE), Frontal Assessment Battery, Trail Making Test, fluency verbal test, Clock Drawing Test, digit span test, verbal learning tests, Corsi’s spatial test, Boston Naming Test), brain imaging, and lumbar puncture (LP). The patient underwent venipuncture for blood collection. Diagnosis of PNFA was made according to current clinical criteria [2, 9]. Four additional asymptomatic family members gave their informed formal consent for the genetic analysis (Fig. 1). As they live far from the proband and did not have the possibility to come personally to our center, we sent a detailed questionnaire to each subject together with a kit for DNA isolation from saliva. Additional 168 Italian patients referred to the Ospedale Policlinico and diagnosed clinically with FTLD (75 males and 93 females, mean age at onset ± SEM: 73.3 ± 0.60 years) were studied. They were diagnosed with bvFTD (n = 138, 62 males and 76 females, mean age at onset ± SEM: 73.0 ± 0.65 years), PNFA (n = 18, 6 males and 12 females, mean age at onset ± SEM: 75.7 ± 2.04 years), and SD (n = 12, 7 males and 5 females, mean age at onset ± SEM: 70.7 ± 1.52 years). Four patients with bvFTD had concomitant motor neuron disease.

The control group consisted of 503 non-demented volunteers matched for ethnic background and age (190 males and 313 females, mean age ± SEM: 67.5 ± 0.51 years) without memory and psychobehavioral dysfunctions (MMSE ≥ 28), recruited at Policlinico Hospital (Milan), San Raffaele Turro Hospital (Milan), and Centro S. Giovanni di Dio-FBF (Brescia). The age of controls did not significantly differ from that of patients (p > 0.05). The study has been approved by the Institutional Review board of the Dept. of Neurological Sciences, University of Milan, Fondazione C`a Granda, IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena. Informed consent to participate in this study was given by all subjects or their caregivers. Amyloid-β (Aβ42 ), tau, and phospho-tau (P-tau) determination Cerebrospinal fluid (CSF) was obtained in polypropylene tubes by LP at the L4/L5 or L3/L4 interspace, centrifuged at 4◦ C and stored at ≤−30◦ C until analysis. A␤1-42 , tau, and P-tau CSF levels were determined with human specific ELISA kits (Innogenetics). A␤1-42 and tau reference levels were considered according to Sjogren et al. [10]. Regarding P-tau, we considered as reference value the concentration suggested by the manufacturer’s protocol (A), leading to an amino acidic change (p.Gly304Ser) in the second MT binding domain, in a female patient diagnosed clinically with PNFA. This mutation could impact the functioning of the second MT binding domain of tau and could play a key role in the pathologic process of tau aggregation.









ACKNOWLEDGMENTS This work was supported by grants from Monzino Foundation, Cariplo Foundation (2009–2633); Progetto Regione Lombardia (Delibera N◦ VIII/008724); FIRB 2006 “Gen-Etica”, Fondazione C´a Granda, IRCSS Ospedale Maggiore Policlinico Milano, Programma Strategico RF 2007, conv. PS39, Italian Ministry of Health, and Ing. Cesare Cusan. Author’s disclosures available online (http://www.jalz.com/disclosures/view.php?id=822).




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