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Abstract: Mutations in the parkin gene and the PTEN-induced putative kinase 1 gene (PINK1) have been identified as the most common causes of autosomal recessive early-onset Parkinson disease (EOPD). To investigate the presence of the parkin and PINK1 gene mutation(s) and to explore genotype–phenotype correlations in American Caucasian families with EOPD from North American, we screened these two genes in probands of six families by direct sequencing, semi-quantitative PCR and RT-PCR. No PINK1 gene mutation was found in any of the probands, but compound heterozygous mutations (EX 3 del and EX 3_4 del) in the parkin gene were identified in one family. Extended analysis of the parkin-positive family showed the phenotype of patients was that of classic autosomal recessive EOPD, characterized by early age at onset, slow progression, beneficial response to levodopa, and levodopa-related motor complications. Three heterozygous mutation carriers (EX 3 del or EX 3_4 del) were free of any neurological symptoms. None of 62 healthy controls harbored EX 3 del or EX 3_4 del mutation. Our data suggest that compound heterozygous mutations (EX 3 and EX 3_4 del) in the parkin gene were the cause of EOPD in one of six Caucasian families; heterozygous EX 3 del and heterozygous EX 3_4 del forms were insufficient to cause this disorder, consistent with a loss-of-function mechanism of the parkin mutations. The results may provide new insights into the cause and diagnosis of PD and have implications for genetic counseling. [Copyright &y& Elsevier]

Abstract: In addition to the G2019S mutation in the leucine-rich repeat kinase 2 gene (LRRK2), which is particularly frequent in patients of Ashkenazi Jewish and Northern African origin, three amino acid substitutions (R1441C, R1441G, and R1441H), all at the same residue (R1441), have been identified as important genetic causes of Parkinson disease (PD). To evaluate the frequency of R1441C/G/H and G2019S mutations in the LRRK2 gene in North American patients with PD and to explore genotype–phenotype correlations, we screened 496 PD patients from North America. One Hispanic female was heterozygous for the LRRK2 R1441G mutation, and six other cases including 2 non-Jewish/non-Hispanic whites, 3 Ashkenazi Jewish, and 1 Hispanic, were found to be heterozygous for the LRRK2 G2019S mutation. G2019S mutation in the LRRK2 gene is a common mutation associated with PD in a North American population, especially in Jewish PD patients (10.7%), while the R1441C/G/H mutation occurs at a relatively low frequency in North Americans except possibly in Hispanics for R1441G. All six G2019S carriers shared a common haplotype with that observed in Europeans and North Africans. The clinical features of all seven cases with LRRK2 mutation were quite broad and included early and late disease onset. These finding may provide new insights into the cause and diagnosis of PD and have implications for genetic counseling. [Copyright &y& Elsevier]

Abstract: The proneural protein Neurogenin 2 (NEUROG2) is a transcription factor of importance for the differentiation and survival of midbrain dopaminergic neurons. To determine whether genetic variation in the coding region of the NEUROG2 gene plays a role in the etiology of Parkinson''s disease (PD), we screened DNA samples from 202 PD patients and 201 normal controls. No mutation in the NEUROG2 gene was identified in our PD cohort, except that novel compound heterozygous variants (Gly56Arg and Asp206Glu) were found in a 91-year normal male, suggesting that mutations in the coding region of the NEUROG2 gene play little or no role in the development of PD. [Copyright &y& Elsevier]

Abstract: Parkinson disease (PD) is one of the most common neurodegenerative disorders with major clinical features of bradykinesia, rigidity, resting tremor, and postural instability. At least thirteen gene loci responsible for PD or parkinsonism have been found and nine causative genes have been identified. Recently, Asn56Ser or Asn457Thr mutations in the Grb10-Interacting GYF Protein-2 gene (GIGYF2) were found to occur in about 2.4% familial PD Italian and French patients. We conducted genetic examination of Asn56Ser or Asn457Thr mutations, but none was found in 310 PD patients from North America. We did identify a non-disease-associated polymorphism Pro460Thr. Our results suggest that the GIGYF2 Asn56Ser and Asn457Thr mutations are a rare cause of PD in North American Caucasian population. [Copyright &y& Elsevier]