title: LRRK2 mutations in Parkinson's disease: confirmation of a gender effect in the Italian population.
abstract: BACKGROUND
  The relative risk of developing idiopathic PD is 1.5 times greater in men than in women, but an increased female prevalence in LRRK2-carriers has been described in the Ashkenazi Jewish population. We report an update about the frequency of major LRRK2 mutations in a large series of consecutive patients with Parkinson's disease (PD), including extensive characterization of clinical features. In particular, we investigated gender-related differences in motor and non-motor symptoms in the LRRK2 population.
  
  
  METHODS
  2976 unrelated consecutive Italian patients with degenerative Parkinsonism were screened for mutations on exon 41 (G2019S, I2020T) and a subgroup of 1190 patients for mutations on exon 31 (R1441C/G/H). Demographic and clinical features were compared between LRRK2-carriers and non-carriers, and between male and female LRRK2 mutation carriers.
  
  
  RESULTS
  LRRK2 mutations were identified in 40 of 2523 PD patients (1.6%) and not in other primary parkinsonian syndromes. No major clinical differences were found between LRRK2-carriers and non-carriers. We found a novel I2020L missense variant, predicted to be pathogenic. Female gender was more common amongst carriers than non-carriers (57% vs. 40%; p = 0.01), without any gender-related difference in clinical features. Family history of PD was more common in women in the whole PD group, regardless of their LRRK2 status.
  
  
  CONCLUSIONS
  PD patients with LRRK2 mutations are more likely to be women, suggesting a stronger genetic load compared to idiopathic PD. Further studies are needed to elucidate whether there is a different effect of gender on the balance between genetic and environmental factors in the pathogenesis of PD.
authors.affiliation: Parkinson Institute, Istituti Clinici di Perfezionamento, via Bignami 1, 20126 Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cilia
authors.affiliation: Parkinson Institute, Istituti Clinici di Perfezionamento, via Bignami 1, 20126 Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Siri
authors.affiliation: Medical Genetics Laboratory, Foundation IRCCS "Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena", Milan, Italy.
authors.forename: Damiana
authors.initials: D
authors.lastname: Rusconi
authors.affiliation: Parkinson Institute, Istituti Clinici di Perfezionamento, via Bignami 1, 20126 Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Allegra
authors.affiliation: MOX, Dipartimento di Matematica, Politecnico di Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ghiglietti
authors.affiliation: Parkinson Institute, Istituti Clinici di Perfezionamento, via Bignami 1, 20126 Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sacilotto
authors.affiliation: Parkinson Institute, Istituti Clinici di Perfezionamento, via Bignami 1, 20126 Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Zini
authors.affiliation: Parkinson Institute, Istituti Clinici di Perfezionamento, via Bignami 1, 20126 Milan, Italy.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Zecchinelli
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Duga
authors.affiliation: MOX, Dipartimento di Matematica, Politecnico di Milano, Italy.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Paganoni
authors.affiliation: Parkinson Institute, Istituti Clinici di Perfezionamento, via Bignami 1, 20126 Milan, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Pezzoli
authors.affiliation: Medical Genetics Laboratory, Foundation IRCCS "Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena", Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Seia
authors.affiliation: Parkinson Institute, Istituti Clinici di Perfezionamento, via Bignami 1, 20126 Milan, Italy. Electronic address: goldwurm@parkinson.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Goldwurm
mesh_terms: D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007558:Italy; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012727:Sex Characteristics
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
keywords: Gender; Genetics; LRRK2; Parkinson disease