title: Broadening the phenotype of TARDBP mutations: the TARDBP Ala382Thr mutation and Parkinson's disease in Sardinia.
abstract: Mutations in the TARDBP gene are a cause of autosomal dominant amyotrophic lateral sclerosis (ALS) and of frontotemporal lobar degeneration (FTLD), but they have not been found so far in patients with Parkinson's disease (PD). A founder TARDBP mutation (p.Ala382Thr) was recently identified as the cause of ~30% of ALS cases in Sardinia, a Mediterranean genetic isolate. We studied 327 consecutive Sardinian patients with clinically diagnosed PD (88 familial, 239 sporadic) and 578 Sardinian controls. One family with FTLD and parkinsonism was also included. The p.Ala382Thr heterozygous mutation was detected in eight unrelated PD patients (2.5%). The three patients from the FTLD/parkinsonism family also carried this mutation. Within the control group, there were three heterozygous mutation carriers. During follow-up, one of these individuals developed motoneuron disease and another, a rapidly progressive dementia; the third remains healthy at the age of 79 but two close relatives developed motoneuron disease and dementia. The eight PD patients carrying the p.Ala382Thr mutation had all sporadic disease presentation. Their average onset age was 70.0 years (SD 9.4, range 51-79), which is later but not significantly different from that of the patients who did not carry this mutation. In conclusion, we expand the clinical spectrum associated with TARDBP mutations to FTLD with parkinsonism without motoneuron disease and to clinically definite PD. The TDP-43 protein might be directly involved in a broader neurodegenerative spectrum, including not only motoneuron disease and FTLD but also PD.
authors.affiliation: Department of Clinical Genetics, Erasmus MC, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Quadri
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cossu
authors.forename: Valeria
authors.initials: V
authors.lastname: Saddi
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Simons
authors.forename: Daniela
authors.initials: D
authors.lastname: Murgia
authors.forename: Maurizio
authors.initials: M
authors.lastname: Melis
authors.forename: Anna
authors.initials: A
authors.lastname: Ticca
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bonifati
mesh_terms: D000368:Aged; D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution / Q000502:physiology; D016022:Case-Control Studies; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000502:physiology; D009410:Nerve Degeneration / Q000235:genetics; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*; D013912:Threonine / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D013912:Threonine; D000409:Alanine