ClinVar Genomic variation as it relates to human health

In affected members of 4 of 61 (6.6%) unrelated families with autosomal dominant Parkinson disease (PARK8; 607060), Di Fonzo et al. (2005) identified a heterozygous 6055G-A transition in exon 41 of the LRRK2 gene, resulting in a gly2019-to-ser (G2019S) substitution. Two families were from Italy, and 1 each were from Portugal and Brazil. The gly2019 residue is highly conserved and is part of a 3-amino acid motif required by all human kinase proteins. Gilks et al. (2005) identified the G2019S mutation in 8 of 482 (1.6%) unrelated patients with Parkinson disease. Five of the patients had no family history of the disorder, suggesting either a de novo occurrence or reduced penetrance. Nichols et al. (2005) identified the G2019S mutation in 20 of 358 (6%) families with PD. In 1 family, 1 sib was heterozygous for the mutation and another was homozygous; the homozygous individual did not differ in clinical presentation from the sib and did not have early disease onset or more rapid progression. By sequencing the LRRK2 gene in multiplex families showing linkage to the PARK8 region, Kachergus et al. (2005) identified the G2019S mutation. The families in which the mutation was found originated from the United States, Norway, Ireland, and Poland. In patients with idiopathic Parkinson disease from the same population, further screening identified 6 more patients with the LRRK2 G2019S mutation; no mutations were found in matched control individuals. Subsequently, 42 family members of the 13 probands were examined; 22 had an LRRK2 G2019S substitution, 7 with a diagnosis of PD. All patients shared an ancestral haplotype indicative of a common founder, and, within families, LRRK2 G2019S segregated with disease (multipoint lod score 2.41). Penetrance was age dependent, increasing from 17% at age 50 to 85% at age 70 years. Hernandez et al. (2005) identified the G2019S mutation in affected members of 2 unrelated families with PARK8. One family was North American with English ancestry, and the other family was of Ashkenazi Jewish origin and had migrated from Russia. Lesage et al. (2005) identified a common haplotype containing the G2019S mutation in PD patients from several European countries (France, Belgium, Portugal, and the Netherlands) and from 3 countries in North Africa (Algeria, Morocco, and Tunisia). The minimal common region spans approximately 60 kb within the LRRK2 gene, although many patients shared larger regions. Lesage et al. (2005) estimated that the G2019S mutation occurred approximately 725 years ago, in the 13th century. Aasly et al. (2005) identified the G2019S mutation in 9 Norwegian patients from 7 families with PARK8. Eleven unaffected first-degree relatives also carried the mutation, suggesting age-related penetrance. The clinical features of affected members were typical for idiopathic Parkinson disease, including resting tremor, bradykinesia, and rigidity. Deng et al. (2005) identified the G2019S mutation in 4 (1.2%) of 326 Parkinson disease patients from North America. One of the patients had no family history of the disorder. Albrecht (2005) stated that the gly2019 residue is part of a highly conserved DFG-like motif (DYG in LRRK2) at the N terminus of the kinase activation segment of the protein. As residues in and around the DFG-like motif are important for proper positioning of magnesium and phosphates, mutations in this area may impair kinase activity. West et al. (2005) determined that the G2019S mutation, which lies within the mixed-lineage kinase-like domain, did not alter the steady-state level, turnover, or intracellular localization of the LRRK2 protein, but that G2019S appeared to enhance protein kinase activity. Brice (2005) estimated that the G2019S mutation in exon 41 of the LRRK2 gene accounts for 2 to 6% of familial and 1 to 2% of sporadic cases of Parkinson disease. The mutation is less common in Asian populations but prevalent in patients from North Africa, as observed by Lesage et al. (2006). In a newly ascertained series of North African Arabs, 23 of 59 patients with Parkinson disease were carriers of the G2019S mutation (39%), as compared with only 2 of 69 controls (3%; P less than 0.001). Ozelius et al. (2006) observed that the G2019S mutation appeared to be an important cause of both familial and sporadic Parkinson disease in a group of 120 unrelated Ashkenazi Jewish patients with Parkinson disease. The prevalence of the G2019S mutation among this group reached 29.7% in familial cases and 13.3% in sporadic cases. Lesage et al. (2005) identified the G2019S mutation in 7 (41%) of 17 North African PD families and 5 (2.9%) of 174 European PD families. One patient from Algeria was homozygous for the mutation, likely due to consanguinity. His age at onset was 56 years, similar to that of heterozygotes, suggesting that gene dosage had no effect. The G2019S mutation was also identified in 1 of 256 control individuals, a 60-year-old male of European descent with no family history of the PD. Age-dependent penetrance, estimated within 2 large affected families, increased from 33% at age 55 to 100% at older than age 76. Zabetian et al. (2006) did not identify the G2019S mutation in any of 754 patients with Alzheimer disease (AD; 104300), suggesting that it is not a cause of AD. Zabetian et al. (2006) stated that the G2019S mutation accounts for 1 to 7% of Parkinson disease in patients of European origin and 20 to 40% in Ashkenazi Jews and North African Arabs with PD. Previous studies had concluded that patients from these populations share a common Middle Eastern founder who lived in the 13th century. Zabetian et al. (2006) tested this hypothesis by genotyping 25 microsatellite and single-nucleotide polymorphism (SNP) markers in 22 families with G2019S and observed 2 distinct haplotypes. Haplotype 1 was present in 19 families of Ashkenazi Jewish and European ancestry, whereas haplotype 2 occurred in 3 European American families. Using a maximum likelihood method, the authors estimated that the families with haplotype 1 shared a common ancestor 2,250 (95% confidence interval 1,650-3,120) years ago, whereas those with haplotype 2 appeared to share a more recent founder. Their data suggested 2 separate founding events for G2019S in these populations, beginning at a time that coincided with the Jewish Diasporas. Zabetian et al. (2006) identified the G2019S mutation in Japanese patients with Parkinson disease on a haplotype background clearly distinct from the 2 others, which indicated that at least 3 founding events had occurred. Ishihara et al. (2006) found no observable phenotypic differences between 26 patients with Parkinson disease who were homozygous for the G2019S mutation, including 20 patients of Tunisian origin, and reports of patients who were heterozygous for the mutation. In addition, 3 clinically unaffected Tunisian individuals were homozygous for the mutation at ages 42, 45, and 70 years. The findings did not support a gene dosage effect. Among 302 PD patients from the Catalonia region of northeast Spain, Gaig et al. (2006) identified the G2019S mutation in 6.4% of familial and 3.4% of sporadic cases. Spanaki et al. (2006) identified the G2019S mutation in 1 (1.1%) of 92 familial PD probands on the island of Crete, thus showing a decreased frequency of the mutation compared to other Mediterranean regions. Clark et al. (2006) identified the G2019S mutation in 4.9% of 245 PD patients with onset before age 50 years and 6.2% of 259 PD patients with onset after age 50 years, a nonsignificant difference. All patients with the G2019S mutation had the same 45-kb disease-associated haplotype. The frequency of the mutation was higher in the subset of 181 cases reporting 4 Jewish grandparents (9.9%) compared to other cases (3.1%). Age-specific penetrance to age 80 was 24%, suggesting that other factors must be involved. The G2019S mutation was identified in 2 (0.6%) controls of Jewish origin who showed mild signs suggestive of the disorder on further examination. Lesage et al. (2007) identified the G2019S mutation in 6 (1.9%) of 320 European patients with sporadic PD. Five patients were of French origin. In a study of 19 Italian PD families with the G2019S mutation, Goldwurm et al. (2007) estimated the cumulative incidence of the disease to be 15% at 60 years, 21% at 70 years, and 32% at 80 years, confirming reduced penetrance. Among 33 mutation carriers, 5 over age 75 years had no sign of disease. Orr-Urtreger et al. (2007) identified a heterozygous G2019S mutation in 12.3% of 472 Jewish PD patients, and in 14.8% of the 344 patients in this group who were specifically of Ashkenazi Jewish origin. The mutation was also detected in 2.4% of Ashkenazi Jewish controls. A common shared haplotype identified by Lesage et al. (2005) was found in 97% of mutation carriers. None of 42 Jewish patients from Iraq or Morocco carried the G2019S mutation. Choi et al. (2008) did not identify the G2019S mutation among 72 unrelated Korean patients with early-onset PD before age 50, suggesting that it is not a common cause of PD in the Korean population. Lesage et al. (2008) identified the G2019S mutation in 7 (41%) of 17 North African patients with familial PD and 40 (34%) of 119 North African patients with sporadic PD. All were heterozygous for the mutation except 3 patients, who were homozygous. One (1.5%) of 66 Algerian controls was homozygous for the mutation, but showed no evidence of disease at age 41 years, which is younger than the average age of disease onset. Gorostidi et al. (2009) identified a heterozygous G2019S mutation in 3.82% of 418 PD patients from the Basque country in Spain. The frequency increased to 6% when only those who were not of Basque origin were considered. The R1441G mutation (609007.0001) was more common among those of Basque descent. The findings reinforced the importance of ethnicity when establishing mutation prevalence. Bar-Shira et al. (2009) analyzed LRRK2 haplotypes in 77 G2019S carriers, mostly Ashkenazi Jews, and in 50 noncarrier Ashkenazi PD patients. A single 243-kb haplotype was detected in all mutation carriers, indicating a common founder. The authors estimated that Ashkenazi Jews with G2019S share a common ancestor who lived approximately 1,830 years ago, around the 2nd century, after the second Jewish Diaspora. Alcalay et al. (2009) found that 34 (3.7%) of 925 patients with early-onset PD, defined as age at onset before age 51 years, carried the G2019S mutation. Compared to noncarriers, carriers of the G2019S mutation were more likely to be of Ashkenazi Jewish descent (55.9% vs 11.9%), to have a lower tremor score (p = 0.03), and to have a higher score of postural instability and gait difficulty (PIGD; 92.3% vs 58.9%, p = 0.003). The PIGD phenotype in general is associated with a more severe phenotype and a faster rate of cognitive decline compared to the tremor dominant phenotype, so the findings of this study suggested implications for disease course in G2019S mutation carriers. Mortiboys et al. (2010) found that skin fibroblasts from 5 PD patients with the G2019S mutation showed evidence of mitochondrial dysfunction, both decreased membrane potential and decreased total intracellular ATP levels. There also appeared to be increased mitochondrial elongation and interconnectivity. Liu et al. (2012) reported on the generation of induced pluripotent stem cells (iPSCs) derived from Parkinson disease patients and the implications of the LRRK2 G2019S mutation in human neural stem cell populations. Mutant neural stem cells showed increased susceptibility to proteasomal stress as well as passage-dependent deficiencies in nuclear envelope organization, clonal expansion, and neuronal differentiation. Disease phenotypes were rescued by targeted correction of the LRRK2 G2019S mutation with its wildtype counterpart in Parkinson disease iPSCs and were recapitulated after targeted knockin of the LRRK2 G2019S mutation in human embryonic stem cells. Analysis of human brain tissue showed nuclear envelope impairment in clinically diagnosed Parkinson disease patients. Liu et al. (2012) concluded that their results identified the nucleus as a previously unknown cellular organelle in Parkinson disease pathology. (less)