title: Genetic mutations in early-onset Parkinson's disease Mexican patients: molecular testing implications.
abstract: Mutations in PARK2, PINK1, and DJ-1 have been associated with autosomal recessive early-onset Parkinson's disease. Here, we report the prevalence of sequence and structural mutations in these three main recessive genes in Mexican Mestizo patients. The complete sequences of these three genes were analyzed by homo/heteroduplex DNA formation and direct sequencing; exon dosage was determined by multiplex ligation-dependent probe amplification and real-time PCR in 127 patients belonging to 122 families and 120 healthy Mexican Mestizo controls. All individuals had been previously screened for the three most common LRRK2 mutations. The presence of two mutations in compound heterozygous or homozygous genotypes was found in 16 unrelated patients, 10 had mutations in PARK2, six in PINK1, and none in DJ-1. Two PARK2-PINK1 and one PARK2-LRRK2 digenic cases were observed. Novel mutations were identified in PARK2 and PINK1 genes, including PINK1 duplication for the first time. Exon dosage deletions were the most frequent mutations in PARK2 (mainly in exons 9 and 12), followed by those in PINK1. The high prevalence of heterozygous mutations in PARK2 (12.3%) and the novel heterozygous and homozygous point mutations in PINK1 observed in familial and sporadic cases from various states of Mexico support the concept that single heterozygous mutations in recessive Parkinson's disease genes play a pathogenic role. These data have important implications for genetic counseling of Mexican Mestizo patients with early-onset Parkinson's disease. The presence of digenic inheritance underscores the importance of studying several genes in this disease. A step-ordered strategy for molecular diagnosis is proposed.
authors.affiliation: Neurogenetics Department, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City, Mexico; PhD Candidate in Biological and Health Sciences, Universidad Autónoma Metropolitana, Mexico City, Mexico.
authors.forename: Nancy
authors.initials: N
authors.lastname: Monroy-Jaramillo
authors.forename: Jorge Luis
authors.initials: JL
authors.lastname: Guerrero-Camacho
authors.forename: Mayela
authors.initials: M
authors.lastname: Rodríguez-Violante
authors.forename: Marie-Catherine
authors.initials: MC
authors.lastname: Boll-Woehrlen
authors.forename: Petra
authors.initials: P
authors.lastname: Yescas-Gómez
authors.forename: María Elisa
authors.initials: ME
authors.lastname: Alonso-Vilatela
authors.forename: Marisol
authors.initials: M
authors.lastname: López-López
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D008297:Male; D008800:Mexico; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D057089:Pathology, Molecular / Q000379:methods; D011494:Protein Kinases / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D055815:Young Adult; D000099202:PTEN-Induced Putative Kinase
chemical_list: D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein
keywords: DJ-1; PARK2; PINK1; digenic inheritance; early-onset Parkinson's disease