ClinVar Genomic variation as it relates to human health

In Caucasian control individuals, Doh-ura et al. (1989) identified an A-to-G transition at the first nucleotide of codon 129 of the PRNP gene, resulting in a met129-to-val (M129V) substitution. The authors concluded that the M129V substitution represents a polymorphic change. Owen et al. (1990) confirmed that M129V is a polymorphism and suggested that it might be useful for genetic linkage studies of transmissible dementias in which mutation in the PRNP gene had not yet been identified. On the basis of studies in 36 Caucasians, Owen et al. (1990) estimated that the met129 allele had a frequency of 0.68 and the val129 allele 0.32. They referred to these alleles as A1 and A2, respectively. In a study of all patients in the United Kingdom who developed acquired Creutzfeldt-Jakob disease (CJD; 123400) following treatment with human cadaveric pituitary hormone, Collinge et al. (1991) found a significant excess of val129 homozygotes. In the UK general population, Palmer et al. (1991) found the frequency of met129 homozygotes to be 37% and val/met129 heterozygotes to be 51%. In contrast, the frequency of met129 homozygotes and val/met129 heterozygotes among patients with sporadic CJD was 83% and 9%, respectively. The authors concluded that homozygosity for met129 confers susceptibility for the development of sporadic CJD. They suggested that dimerization of the prion protein is an important element in the pathogenesis of CJD, and that this is more likely to occur in homozygotes than in heterozygotes. Doh-ura et al. (1991) suggested that either homozygosity or heterozygosity for the val129 mutation could result in prion disease in Japanese patients, and that it usually took the form of Gerstmann-Straussler disease. De Silva et al. (1994) found amyloid plaques in only 7 of 29 cases of sporadic CJD. In the patients with amyloid plaques, 43% were val129 homozygous, 29% were val/met heterozygous, and 29% were met129 homozygous. These figures contrasted with the frequencies found in all sporadic CJD cases that they reviewed: 9% val129 homozygous, 9% val/met heterozygous, and 83% met129 homozygous. The findings suggested that the 129 polymorphism can influence the neuropathologic phenotype of human spongiform encephalopathies. Goldfarb et al. (1992) reported the interesting observation that when the val129 allele was present on the same chromosome as the asp178-to-asn mutation (D178N), the phenotype was that of CJD (see 176640.0007), whereas the met129/asn178 allele (176640.0010) segregated with fatal familial insomnia (600072). In inherited prion diseases, mutant isoforms spontaneously assume conformations depending on the mutation. An interaction between methionine or valine at position 129 and asparagine at position 178 might result in 2 abnormal isoforms that differ in conformation and pathogenic consequences. Monari et al. (1994) provided an explanation for the difference in phenotype of the D178N mutation depending on whether methionine or valine was present as residue 129. They found that the abnormal isoforms of the prion protein in the 2 diseases differed both in the relative abundance of glycosylated forms and in the size of the protease-resistant fragments. The size difference was consistent with a different protease cleavage site, suggesting a different conformation of the protease-resistant prion protein present in the 2 diseases. These differences were thought to be responsible for the type and location of the lesions that characterized the 2 disorders. Therefore, the combination of the mutation at codon 178 and the polymorphism at codon 129 determines the disease phenotype by producing 2 altered conformations of the prion protein. See review of Gambetti et al. (1993). Aguzzi (1997) pointed out that all cases of bovine spongiform encephalopathy, or 'mad cow disease' in humans, have been of the homozygous met129 genotype. He cited unpublished observations of a cluster of cases due to contaminated electrodes used in brain studies in which all but 1 of the cases were determined to be met129 homozygotes; the exception was a single val/met129 heterozygote who had a more protracted course than did the others. By PRNP genotyping of frozen blood samples from 92 patients with kuru (245300), Cervenakova et al. (1998) found that homozygosity at codon 129, particularly for methionine, was associated with significantly earlier age at onset and a shorter duration of illness compared to heterozygosity at codon 129. However, other clinical characteristics were similar for all genotypes at codon 129. Cervenakova et al. (1998) noted that all cases of variant CJD, which is caused by oral ingestion of infected tissue, have been shown to be homozygous for met129. As kuru is the most appropriate transmissible prion disease for comparison to vCJD by virtue of its oral and/or mucocutaneous route of infection, the authors hypothesized that evolution of vCJD may be associated with genetic heterogeneity at PRNP codon 129. Deslys et al. (1998) reported the course of a French cohort of patients treated with growth hormone (GH) purified from human pituitary glands and contaminated with the CJD agent between January 1984 and June 1985. During this time, 968 patients were treated with GH. The authors found that 51 of the 54 confirmed probable cases of CJD in this cohort showed the following pattern of distribution of the genotype at codon 129: 6 met/val (12%); 13 val/val (25%); 32 met/met (63%). Because heterozygous patients represent about half of the contaminated population, Deslys et al. (1998) assumed that 45 heterozygous patients received the same infectious doses as the 45 homozygous patients. However, the number of CJD cases in the heterozygote group was 7.5 times lower than expected. Furthermore, the CJD cases that did develop in met/val heterozygotes showed a delay in onset; there was a 5-year delay in the appearance of the first case in a heterozygote after the first case among homozygotes. On the basis of scrutiny of the NMR structure of the complete 208-residue polypeptide chain of mouse Prnp, Riek et al. (1998) pointed to the hydrogen bond between residues 128 and 178 as providing a structural basis for the observed highly specific influence of the polymorphism at position 129 in human PRNP on the disease phenotype that segregates with the D178N mutation. Head et al. (2001) reported a case of sporadic CJD in a Dutch woman who was homozygous for valine at codon 129. Plaitakis et al. (2001) identified 9 cases of sporadic CJD on the island of Crete between 1997 and 2001 and estimated that the cases represented an annual incidence 5-fold higher than that expected based on the island's population. Molecular analysis revealed no mutations in the PRNP gene in any of 7 patients studied. Five patients were homozygous for methionine at codon 129, and 2 patients were homozygous for valine at codon 129. Genotyping of controls revealed that codon-129 allele frequencies were 0.76:0.24 met:val, which is significantly different from that of other Caucasian populations. Erginel-Unaltuna et al. (2001) determined the genotype frequencies of the M129V polymorphism in 100 unrelated healthy Turkish subjects. They were 57% met/met, 34% met/val, and 9% val/val, with an allele frequency ratio of 0.74:0.26 met:val. The frequencies of the met/met genotype and of the met allele were significantly higher in the Turkish population than those in a pooled Caucasian population, but nearly identical to those in the population of the island of Crete reported by Plaitakis et al. (2001). The higher frequency of 129met homozygotes in Turkey than in western Europe suggested that the Turkish population is at greater risk of developing CJD. Using short synthetic peptides of the human prion protein corresponding to the region of the 129 polymorphism and containing either methionine or valine, Petchanikow et al. (2001) showed that the methionine-containing peptide had a greater propensity to adopt a beta-sheet conformation and to aggregate into amyloid-like fibrils, findings that are characteristic of the pathogenic prion isoform. Petchanikow et al. (2001) concluded that the presence of met at position 129 confers a higher susceptibility for the protein to be converted into the pathogenic isoform, but noted that the findings have to be evaluated in the context of the entire prion protein. Since homozygosity MM at codon 129 is a recognized risk factor in all forms of Creutzfeldt-Jacob disease, Brandel et al. (2003) studied the distribution of the codon 129 polymorphism in patients in France and in the U.K. with CJD transmitted iatrogenically by human growth hormone. The overall frequencies of codon 129 genotypes in these patients differed from those in the population unaffected by CJD. An excess of VV homozygotes was noted among those with iatrogenic CJD compared with sporadic CJD cases. The proportion of MM genotype in U.K. patients was surprisingly low (4%) compared with that in French patients (62%). There was no evident explanation for this different distribution, which might be due to infection with different strains of prion in human growth hormone. In 52 Dutch patients with sporadic CJD and 250 controls, Croes et al. (2004) found a significant association between the M129V polymorphism and CJD, with a greater than 3-fold increased risk for V homozygotes (OR, 3.22; 95% CI, 1.00-10.45; p = 0.05). They also assessed haplotype interaction using the M129V polymorphism and the T174M polymorphism on the PRND (604263) gene and found that among sporadic CJD patients there was a significant increase in carriers of MM-MM (OR, 4.35; 95% CI, 1.05-8.09; p = 0.04). Wadsworth et al. (2004) found that generation of variant CJD in transgenic mice required expression of human prion protein with methionine at position 129. Expression of human PRP with valine-129 resulted in a distinct phenotype and persistence of a barrier to transmission of BSE-derived prions on subpassage. Polymorphic residue 129 of human PRP dictated propagation of distinct prion strains after BSE prion infection. Wadsworth et al. (2004) concluded that primary and secondary human infection with BSE-derived prions may result in sporadic CJD-like or novel phenotypes in addition to variant CJD, depending on the genotype of the prion source and the recipient. Jeong et al. (2005) found that all of 150 Korean patients with sporadic CJD were homozygous for 129MM and for 219QQ (176640.0019). The authors concluded that heterozygosity at either allele confers protection against the disease. Papassotiropoulos et al. (2005) examined the impact of SNPs of the PRNP gene on long-term memory in healthy young humans. PRNP genomic region SNPs were associated with better long-term memory performance in 2 independent populations with different educational background. Among the examined PRNP SNPs, the common M129V polymorphism yielded the highest effect size. Twenty-four hours after a word list-learning task, carriers of either the 129MM or the 129MV genotype recalled 17% more information than 129VV carriers, but short-term memory was unaffected. Papassotiropoulos et al. (2005) suggested a role for the prion protein in the formation of long-term memory in humans. Zan et al. (2006) found that the frequency of the 129V allele was 0.3% in a population of 436 Han Chinese individuals, validating previous observations of low 129V frequency in East Asians. Mead et al. (2009) confirmed the results of Mead et al. (2003) that heterozygosity for the M129V polymorphism confers resistance to the development of the prion disease kuru (245300). In Mead et al. (2003), 30 elderly women who did not develop kuru despite multiple exposures were predominantly PRNP 129 heterozygotes, compared to those who did develop the disease. Mead et al. (2009) expanded these findings by studying over 3,000 people from the Eastern Highland area, including 709 who participated in mortuary feasts. In this same population, Mead et al. (2009) also observed a protective effect for heterozygosity at a different but neighboring SNP in the PRNP gene (G127V; 176640.0028). Alzheimer Disease and Dementia Reported associations between the codon 129 genotype and cognitive decline or Alzheimer disease (AD; 104300) have been conflicting. Berr et al. (1998) found an association between cognitive impairment and homozygosity for 129VV among 1,163 French individuals aged 59 to 71 years. Croes et al. (2003) presented epidemiologic evidence suggesting that individuals aged 55 to 64 years with the 129VV genotype had significantly higher decline in cognitive performance compared to those with the MV or MM genotypes. The findings did not extend to those of later ages. Dermaut et al. (2003) found a significant association between homozygosity for 129VV and early-onset Alzheimer disease among 123 Dutch patients. The findings were stronger for those with a family history. In a study of 482 AD patients, including 138 with onset before age 60 years, Riemenschneider et al. (2004) found that the 129MM genotype conferred an increased risk of developing AD in the early-onset group (odds ratio of 1.92, p = 0.013). The risk increased with decreasing age and was more significant in those patients without the APOE E4 allele (107741). No association was observed in patients with late-onset AD. Riemenschneider et al. (2004) noted that the pathogenic mechanism of PrP involvement in AD may be different from that in prion diseases. In contrast, Combarros et al. (2000) found no association between homozygosity for either 129MM or 129VV among 278 Spanish patients with sporadic AD stratified for both early- and late-onset. Similarly, Casadei et al. (2001) and Ohkubo et al. (2003) found no association between AD and the codon 129 genotype among Italian and Japanese patients, respectively. Primary Progressive Aphasia Among 415 Caucasian controls, Li et al. (2005) found that the codon 129 genotype distribution was 49.9% MM, 42.4% MV, and 7.7% VV. The 129 genotype among 39 patients with primary progressive aphasia (PPA; see frontotemporal dementia, FTD, 600274) was significantly different, at 12.8% MM, 84.6% MV, and 2.6% VV, yielding an age-adjusted odds ratio for the MV genotype of 8.47 for disease development compared to controls. Significant codon 129 genotype differences were not observed among 256 patients with amyotrophic lateral sclerosis (ALS; 105400) or 281 patients with AD. Li et al. (2005) suggested that PrP may indirectly modify the phenotype of PPA. Rohrer et al. (2006) found no significant association between PRNP allele frequencies at codon 129 and FTD spectrum disorders among 66 patients with various forms of FTD. (less)

In Caucasian control individuals, Doh-ura et al. (1989) identified an A-to-G transition at the first nucleotide of codon 129 of the PRNP gene, resulting in a met129-to-val (M129V) substitution. The authors concluded that the M129V substitution represents a polymorphic change. Owen et al. (1990) confirmed that M129V is a polymorphism and suggested that it might be useful for genetic linkage studies of transmissible dementias in which mutation in the PRNP gene had not yet been identified. On the basis of studies in 36 Caucasians, Owen et al. (1990) estimated that the met129 allele had a frequency of 0.68 and the val129 allele 0.32. They referred to these alleles as A1 and A2, respectively. In a study of all patients in the United Kingdom who developed acquired Creutzfeldt-Jakob disease (CJD; 123400) following treatment with human cadaveric pituitary hormone, Collinge et al. (1991) found a significant excess of val129 homozygotes. In the UK general population, Palmer et al. (1991) found the frequency of met129 homozygotes to be 37% and val/met129 heterozygotes to be 51%. In contrast, the frequency of met129 homozygotes and val/met129 heterozygotes among patients with sporadic CJD was 83% and 9%, respectively. The authors concluded that homozygosity for met129 confers susceptibility for the development of sporadic CJD. They suggested that dimerization of the prion protein is an important element in the pathogenesis of CJD, and that this is more likely to occur in homozygotes than in heterozygotes. Doh-ura et al. (1991) suggested that either homozygosity or heterozygosity for the val129 mutation could result in prion disease in Japanese patients, and that it usually took the form of Gerstmann-Straussler disease. De Silva et al. (1994) found amyloid plaques in only 7 of 29 cases of sporadic CJD. In the patients with amyloid plaques, 43% were val129 homozygous, 29% were val/met heterozygous, and 29% were met129 homozygous. These figures contrasted with the frequencies found in all sporadic CJD cases that they reviewed: 9% val129 homozygous, 9% val/met heterozygous, and 83% met129 homozygous. The findings suggested that the 129 polymorphism can influence the neuropathologic phenotype of human spongiform encephalopathies. Goldfarb et al. (1992) reported the interesting observation that when the val129 allele was present on the same chromosome as the asp178-to-asn mutation (D178N), the phenotype was that of CJD (see 176640.0007), whereas the met129/asn178 allele (176640.0010) segregated with fatal familial insomnia (600072). In inherited prion diseases, mutant isoforms spontaneously assume conformations depending on the mutation. An interaction between methionine or valine at position 129 and asparagine at position 178 might result in 2 abnormal isoforms that differ in conformation and pathogenic consequences. Monari et al. (1994) provided an explanation for the difference in phenotype of the D178N mutation depending on whether methionine or valine was present as residue 129. They found that the abnormal isoforms of the prion protein in the 2 diseases differed both in the relative abundance of glycosylated forms and in the size of the protease-resistant fragments. The size difference was consistent with a different protease cleavage site, suggesting a different conformation of the protease-resistant prion protein present in the 2 diseases. These differences were thought to be responsible for the type and location of the lesions that characterized the 2 disorders. Therefore, the combination of the mutation at codon 178 and the polymorphism at codon 129 determines the disease phenotype by producing 2 altered conformations of the prion protein. See review of Gambetti et al. (1993). Aguzzi (1997) pointed out that all cases of bovine spongiform encephalopathy, or 'mad cow disease' in humans, have been of the homozygous met129 genotype. He cited unpublished observations of a cluster of cases due to contaminated electrodes used in brain studies in which all but 1 of the cases were determined to be met129 homozygotes; the exception was a single val/met129 heterozygote who had a more protracted course than did the others. By PRNP genotyping of frozen blood samples from 92 patients with kuru (245300), Cervenakova et al. (1998) found that homozygosity at codon 129, particularly for methionine, was associated with significantly earlier age at onset and a shorter duration of illness compared to heterozygosity at codon 129. However, other clinical characteristics were similar for all genotypes at codon 129. Cervenakova et al. (1998) noted that all cases of variant CJD, which is caused by oral ingestion of infected tissue, have been shown to be homozygous for met129. As kuru is the most appropriate transmissible prion disease for comparison to vCJD by virtue of its oral and/or mucocutaneous route of infection, the authors hypothesized that evolution of vCJD may be associated with genetic heterogeneity at PRNP codon 129. Deslys et al. (1998) reported the course of a French cohort of patients treated with growth hormone (GH) purified from human pituitary glands and contaminated with the CJD agent between January 1984 and June 1985. During this time, 968 patients were treated with GH. The authors found that 51 of the 54 confirmed probable cases of CJD in this cohort showed the following pattern of distribution of the genotype at codon 129: 6 met/val (12%); 13 val/val (25%); 32 met/met (63%). Because heterozygous patients represent about half of the contaminated population, Deslys et al. (1998) assumed that 45 heterozygous patients received the same infectious doses as the 45 homozygous patients. However, the number of CJD cases in the heterozygote group was 7.5 times lower than expected. Furthermore, the CJD cases that did develop in met/val heterozygotes showed a delay in onset; there was a 5-year delay in the appearance of the first case in a heterozygote after the first case among homozygotes. On the basis of scrutiny of the NMR structure of the complete 208-residue polypeptide chain of mouse Prnp, Riek et al. (1998) pointed to the hydrogen bond between residues 128 and 178 as providing a structural basis for the observed highly specific influence of the polymorphism at position 129 in human PRNP on the disease phenotype that segregates with the D178N mutation. Head et al. (2001) reported a case of sporadic CJD in a Dutch woman who was homozygous for valine at codon 129. Plaitakis et al. (2001) identified 9 cases of sporadic CJD on the island of Crete between 1997 and 2001 and estimated that the cases represented an annual incidence 5-fold higher than that expected based on the island's population. Molecular analysis revealed no mutations in the PRNP gene in any of 7 patients studied. Five patients were homozygous for methionine at codon 129, and 2 patients were homozygous for valine at codon 129. Genotyping of controls revealed that codon-129 allele frequencies were 0.76:0.24 met:val, which is significantly different from that of other Caucasian populations. Erginel-Unaltuna et al. (2001) determined the genotype frequencies of the M129V polymorphism in 100 unrelated healthy Turkish subjects. They were 57% met/met, 34% met/val, and 9% val/val, with an allele frequency ratio of 0.74:0.26 met:val. The frequencies of the met/met genotype and of the met allele were significantly higher in the Turkish population than those in a pooled Caucasian population, but nearly identical to those in the population of the island of Crete reported by Plaitakis et al. (2001). The higher frequency of 129met homozygotes in Turkey than in western Europe suggested that the Turkish population is at greater risk of developing CJD. Using short synthetic peptides of the human prion protein corresponding to the region of the 129 polymorphism and containing either methionine or valine, Petchanikow et al. (2001) showed that the methionine-containing peptide had a greater propensity to adopt a beta-sheet conformation and to aggregate into amyloid-like fibrils, findings that are characteristic of the pathogenic prion isoform. Petchanikow et al. (2001) concluded that the presence of met at position 129 confers a higher susceptibility for the protein to be converted into the pathogenic isoform, but noted that the findings have to be evaluated in the context of the entire prion protein. Since homozygosity MM at codon 129 is a recognized risk factor in all forms of Creutzfeldt-Jacob disease, Brandel et al. (2003) studied the distribution of the codon 129 polymorphism in patients in France and in the U.K. with CJD transmitted iatrogenically by human growth hormone. The overall frequencies of codon 129 genotypes in these patients differed from those in the population unaffected by CJD. An excess of VV homozygotes was noted among those with iatrogenic CJD compared with sporadic CJD cases. The proportion of MM genotype in U.K. patients was surprisingly low (4%) compared with that in French patients (62%). There was no evident explanation for this different distribution, which might be due to infection with different strains of prion in human growth hormone. In 52 Dutch patients with sporadic CJD and 250 controls, Croes et al. (2004) found a significant association between the M129V polymorphism and CJD, with a greater than 3-fold increased risk for V homozygotes (OR, 3.22; 95% CI, 1.00-10.45; p = 0.05). They also assessed haplotype interaction using the M129V polymorphism and the T174M polymorphism on the PRND (604263) gene and found that among sporadic CJD patients there was a significant increase in carriers of MM-MM (OR, 4.35; 95% CI, 1.05-8.09; p = 0.04). Wadsworth et al. (2004) found that generation of variant CJD in transgenic mice required expression of human prion protein with methionine at position 129. Expression of human PRP with valine-129 resulted in a distinct phenotype and persistence of a barrier to transmission of BSE-derived prions on subpassage. Polymorphic residue 129 of human PRP dictated propagation of distinct prion strains after BSE prion infection. Wadsworth et al. (2004) concluded that primary and secondary human infection with BSE-derived prions may result in sporadic CJD-like or novel phenotypes in addition to variant CJD, depending on the genotype of the prion source and the recipient. Jeong et al. (2005) found that all of 150 Korean patients with sporadic CJD were homozygous for 129MM and for 219QQ (176640.0019). The authors concluded that heterozygosity at either allele confers protection against the disease. Papassotiropoulos et al. (2005) examined the impact of SNPs of the PRNP gene on long-term memory in healthy young humans. PRNP genomic region SNPs were associated with better long-term memory performance in 2 independent populations with different educational background. Among the examined PRNP SNPs, the common M129V polymorphism yielded the highest effect size. Twenty-four hours after a word list-learning task, carriers of either the 129MM or the 129MV genotype recalled 17% more information than 129VV carriers, but short-term memory was unaffected. Papassotiropoulos et al. (2005) suggested a role for the prion protein in the formation of long-term memory in humans. Zan et al. (2006) found that the frequency of the 129V allele was 0.3% in a population of 436 Han Chinese individuals, validating previous observations of low 129V frequency in East Asians. Mead et al. (2009) confirmed the results of Mead et al. (2003) that heterozygosity for the M129V polymorphism confers resistance to the development of the prion disease kuru (245300). In Mead et al. (2003), 30 elderly women who did not develop kuru despite multiple exposures were predominantly PRNP 129 heterozygotes, compared to those who did develop the disease. Mead et al. (2009) expanded these findings by studying over 3,000 people from the Eastern Highland area, including 709 who participated in mortuary feasts. In this same population, Mead et al. (2009) also observed a protective effect for heterozygosity at a different but neighboring SNP in the PRNP gene (G127V; 176640.0028). Alzheimer Disease and Dementia Reported associations between the codon 129 genotype and cognitive decline or Alzheimer disease (AD; 104300) have been conflicting. Berr et al. (1998) found an association between cognitive impairment and homozygosity for 129VV among 1,163 French individuals aged 59 to 71 years. Croes et al. (2003) presented epidemiologic evidence suggesting that individuals aged 55 to 64 years with the 129VV genotype had significantly higher decline in cognitive performance compared to those with the MV or MM genotypes. The findings did not extend to those of later ages. Dermaut et al. (2003) found a significant association between homozygosity for 129VV and early-onset Alzheimer disease among 123 Dutch patients. The findings were stronger for those with a family history. In a study of 482 AD patients, including 138 with onset before age 60 years, Riemenschneider et al. (2004) found that the 129MM genotype conferred an increased risk of developing AD in the early-onset group (odds ratio of 1.92, p = 0.013). The risk increased with decreasing age and was more significant in those patients without the APOE E4 allele (107741). No association was observed in patients with late-onset AD. Riemenschneider et al. (2004) noted that the pathogenic mechanism of PrP involvement in AD may be different from that in prion diseases. In contrast, Combarros et al. (2000) found no association between homozygosity for either 129MM or 129VV among 278 Spanish patients with sporadic AD stratified for both early- and late-onset. Similarly, Casadei et al. (2001) and Ohkubo et al. (2003) found no association between AD and the codon 129 genotype among Italian and Japanese patients, respectively. Primary Progressive Aphasia Among 415 Caucasian controls, Li et al. (2005) found that the codon 129 genotype distribution was 49.9% MM, 42.4% MV, and 7.7% VV. The 129 genotype among 39 patients with primary progressive aphasia (PPA; see frontotemporal dementia, FTD, 600274) was significantly different, at 12.8% MM, 84.6% MV, and 2.6% VV, yielding an age-adjusted odds ratio for the MV genotype of 8.47 for disease development compared to controls. Significant codon 129 genotype differences were not observed among 256 patients with amyotrophic lateral sclerosis (ALS; 105400) or 281 patients with AD. Li et al. (2005) suggested that PrP may indirectly modify the phenotype of PPA. Rohrer et al. (2006) found no significant association between PRNP allele frequencies at codon 129 and FTD spectrum disorders among 66 patients with various forms of FTD. (less)

In Caucasian control individuals, Doh-ura et al. (1989) identified an A-to-G transition at the first nucleotide of codon 129 of the PRNP gene, resulting in a met129-to-val (M129V) substitution. The authors concluded that the M129V substitution represents a polymorphic change. Owen et al. (1990) confirmed that M129V is a polymorphism and suggested that it might be useful for genetic linkage studies of transmissible dementias in which mutation in the PRNP gene had not yet been identified. On the basis of studies in 36 Caucasians, Owen et al. (1990) estimated that the met129 allele had a frequency of 0.68 and the val129 allele 0.32. They referred to these alleles as A1 and A2, respectively. In a study of all patients in the United Kingdom who developed acquired Creutzfeldt-Jakob disease (CJD; 123400) following treatment with human cadaveric pituitary hormone, Collinge et al. (1991) found a significant excess of val129 homozygotes. In the UK general population, Palmer et al. (1991) found the frequency of met129 homozygotes to be 37% and val/met129 heterozygotes to be 51%. In contrast, the frequency of met129 homozygotes and val/met129 heterozygotes among patients with sporadic CJD was 83% and 9%, respectively. The authors concluded that homozygosity for met129 confers susceptibility for the development of sporadic CJD. They suggested that dimerization of the prion protein is an important element in the pathogenesis of CJD, and that this is more likely to occur in homozygotes than in heterozygotes. Doh-ura et al. (1991) suggested that either homozygosity or heterozygosity for the val129 mutation could result in prion disease in Japanese patients, and that it usually took the form of Gerstmann-Straussler disease. De Silva et al. (1994) found amyloid plaques in only 7 of 29 cases of sporadic CJD. In the patients with amyloid plaques, 43% were val129 homozygous, 29% were val/met heterozygous, and 29% were met129 homozygous. These figures contrasted with the frequencies found in all sporadic CJD cases that they reviewed: 9% val129 homozygous, 9% val/met heterozygous, and 83% met129 homozygous. The findings suggested that the 129 polymorphism can influence the neuropathologic phenotype of human spongiform encephalopathies. Goldfarb et al. (1992) reported the interesting observation that when the val129 allele was present on the same chromosome as the asp178-to-asn mutation (D178N), the phenotype was that of CJD (see 176640.0007), whereas the met129/asn178 allele (176640.0010) segregated with fatal familial insomnia (600072). In inherited prion diseases, mutant isoforms spontaneously assume conformations depending on the mutation. An interaction between methionine or valine at position 129 and asparagine at position 178 might result in 2 abnormal isoforms that differ in conformation and pathogenic consequences. Monari et al. (1994) provided an explanation for the difference in phenotype of the D178N mutation depending on whether methionine or valine was present as residue 129. They found that the abnormal isoforms of the prion protein in the 2 diseases differed both in the relative abundance of glycosylated forms and in the size of the protease-resistant fragments. The size difference was consistent with a different protease cleavage site, suggesting a different conformation of the protease-resistant prion protein present in the 2 diseases. These differences were thought to be responsible for the type and location of the lesions that characterized the 2 disorders. Therefore, the combination of the mutation at codon 178 and the polymorphism at codon 129 determines the disease phenotype by producing 2 altered conformations of the prion protein. See review of Gambetti et al. (1993). Aguzzi (1997) pointed out that all cases of bovine spongiform encephalopathy, or 'mad cow disease' in humans, have been of the homozygous met129 genotype. He cited unpublished observations of a cluster of cases due to contaminated electrodes used in brain studies in which all but 1 of the cases were determined to be met129 homozygotes; the exception was a single val/met129 heterozygote who had a more protracted course than did the others. By PRNP genotyping of frozen blood samples from 92 patients with kuru (245300), Cervenakova et al. (1998) found that homozygosity at codon 129, particularly for methionine, was associated with significantly earlier age at onset and a shorter duration of illness compared to heterozygosity at codon 129. However, other clinical characteristics were similar for all genotypes at codon 129. Cervenakova et al. (1998) noted that all cases of variant CJD, which is caused by oral ingestion of infected tissue, have been shown to be homozygous for met129. As kuru is the most appropriate transmissible prion disease for comparison to vCJD by virtue of its oral and/or mucocutaneous route of infection, the authors hypothesized that evolution of vCJD may be associated with genetic heterogeneity at PRNP codon 129. Deslys et al. (1998) reported the course of a French cohort of patients treated with growth hormone (GH) purified from human pituitary glands and contaminated with the CJD agent between January 1984 and June 1985. During this time, 968 patients were treated with GH. The authors found that 51 of the 54 confirmed probable cases of CJD in this cohort showed the following pattern of distribution of the genotype at codon 129: 6 met/val (12%); 13 val/val (25%); 32 met/met (63%). Because heterozygous patients represent about half of the contaminated population, Deslys et al. (1998) assumed that 45 heterozygous patients received the same infectious doses as the 45 homozygous patients. However, the number of CJD cases in the heterozygote group was 7.5 times lower than expected. Furthermore, the CJD cases that did develop in met/val heterozygotes showed a delay in onset; there was a 5-year delay in the appearance of the first case in a heterozygote after the first case among homozygotes. On the basis of scrutiny of the NMR structure of the complete 208-residue polypeptide chain of mouse Prnp, Riek et al. (1998) pointed to the hydrogen bond between residues 128 and 178 as providing a structural basis for the observed highly specific influence of the polymorphism at position 129 in human PRNP on the disease phenotype that segregates with the D178N mutation. Head et al. (2001) reported a case of sporadic CJD in a Dutch woman who was homozygous for valine at codon 129. Plaitakis et al. (2001) identified 9 cases of sporadic CJD on the island of Crete between 1997 and 2001 and estimated that the cases represented an annual incidence 5-fold higher than that expected based on the island's population. Molecular analysis revealed no mutations in the PRNP gene in any of 7 patients studied. Five patients were homozygous for methionine at codon 129, and 2 patients were homozygous for valine at codon 129. Genotyping of controls revealed that codon-129 allele frequencies were 0.76:0.24 met:val, which is significantly different from that of other Caucasian populations. Erginel-Unaltuna et al. (2001) determined the genotype frequencies of the M129V polymorphism in 100 unrelated healthy Turkish subjects. They were 57% met/met, 34% met/val, and 9% val/val, with an allele frequency ratio of 0.74:0.26 met:val. The frequencies of the met/met genotype and of the met allele were significantly higher in the Turkish population than those in a pooled Caucasian population, but nearly identical to those in the population of the island of Crete reported by Plaitakis et al. (2001). The higher frequency of 129met homozygotes in Turkey than in western Europe suggested that the Turkish population is at greater risk of developing CJD. Using short synthetic peptides of the human prion protein corresponding to the region of the 129 polymorphism and containing either methionine or valine, Petchanikow et al. (2001) showed that the methionine-containing peptide had a greater propensity to adopt a beta-sheet conformation and to aggregate into amyloid-like fibrils, findings that are characteristic of the pathogenic prion isoform. Petchanikow et al. (2001) concluded that the presence of met at position 129 confers a higher susceptibility for the protein to be converted into the pathogenic isoform, but noted that the findings have to be evaluated in the context of the entire prion protein. Since homozygosity MM at codon 129 is a recognized risk factor in all forms of Creutzfeldt-Jacob disease, Brandel et al. (2003) studied the distribution of the codon 129 polymorphism in patients in France and in the U.K. with CJD transmitted iatrogenically by human growth hormone. The overall frequencies of codon 129 genotypes in these patients differed from those in the population unaffected by CJD. An excess of VV homozygotes was noted among those with iatrogenic CJD compared with sporadic CJD cases. The proportion of MM genotype in U.K. patients was surprisingly low (4%) compared with that in French patients (62%). There was no evident explanation for this different distribution, which might be due to infection with different strains of prion in human growth hormone. In 52 Dutch patients with sporadic CJD and 250 controls, Croes et al. (2004) found a significant association between the M129V polymorphism and CJD, with a greater than 3-fold increased risk for V homozygotes (OR, 3.22; 95% CI, 1.00-10.45; p = 0.05). They also assessed haplotype interaction using the M129V polymorphism and the T174M polymorphism on the PRND (604263) gene and found that among sporadic CJD patients there was a significant increase in carriers of MM-MM (OR, 4.35; 95% CI, 1.05-8.09; p = 0.04). Wadsworth et al. (2004) found that generation of variant CJD in transgenic mice required expression of human prion protein with methionine at position 129. Expression of human PRP with valine-129 resulted in a distinct phenotype and persistence of a barrier to transmission of BSE-derived prions on subpassage. Polymorphic residue 129 of human PRP dictated propagation of distinct prion strains after BSE prion infection. Wadsworth et al. (2004) concluded that primary and secondary human infection with BSE-derived prions may result in sporadic CJD-like or novel phenotypes in addition to variant CJD, depending on the genotype of the prion source and the recipient. Jeong et al. (2005) found that all of 150 Korean patients with sporadic CJD were homozygous for 129MM and for 219QQ (176640.0019). The authors concluded that heterozygosity at either allele confers protection against the disease. Papassotiropoulos et al. (2005) examined the impact of SNPs of the PRNP gene on long-term memory in healthy young humans. PRNP genomic region SNPs were associated with better long-term memory performance in 2 independent populations with different educational background. Among the examined PRNP SNPs, the common M129V polymorphism yielded the highest effect size. Twenty-four hours after a word list-learning task, carriers of either the 129MM or the 129MV genotype recalled 17% more information than 129VV carriers, but short-term memory was unaffected. Papassotiropoulos et al. (2005) suggested a role for the prion protein in the formation of long-term memory in humans. Zan et al. (2006) found that the frequency of the 129V allele was 0.3% in a population of 436 Han Chinese individuals, validating previous observations of low 129V frequency in East Asians. Mead et al. (2009) confirmed the results of Mead et al. (2003) that heterozygosity for the M129V polymorphism confers resistance to the development of the prion disease kuru (245300). In Mead et al. (2003), 30 elderly women who did not develop kuru despite multiple exposures were predominantly PRNP 129 heterozygotes, compared to those who did develop the disease. Mead et al. (2009) expanded these findings by studying over 3,000 people from the Eastern Highland area, including 709 who participated in mortuary feasts. In this same population, Mead et al. (2009) also observed a protective effect for heterozygosity at a different but neighboring SNP in the PRNP gene (G127V; 176640.0028). Alzheimer Disease and Dementia Reported associations between the codon 129 genotype and cognitive decline or Alzheimer disease (AD; 104300) have been conflicting. Berr et al. (1998) found an association between cognitive impairment and homozygosity for 129VV among 1,163 French individuals aged 59 to 71 years. Croes et al. (2003) presented epidemiologic evidence suggesting that individuals aged 55 to 64 years with the 129VV genotype had significantly higher decline in cognitive performance compared to those with the MV or MM genotypes. The findings did not extend to those of later ages. Dermaut et al. (2003) found a significant association between homozygosity for 129VV and early-onset Alzheimer disease among 123 Dutch patients. The findings were stronger for those with a family history. In a study of 482 AD patients, including 138 with onset before age 60 years, Riemenschneider et al. (2004) found that the 129MM genotype conferred an increased risk of developing AD in the early-onset group (odds ratio of 1.92, p = 0.013). The risk increased with decreasing age and was more significant in those patients without the APOE E4 allele (107741). No association was observed in patients with late-onset AD. Riemenschneider et al. (2004) noted that the pathogenic mechanism of PrP involvement in AD may be different from that in prion diseases. In contrast, Combarros et al. (2000) found no association between homozygosity for either 129MM or 129VV among 278 Spanish patients with sporadic AD stratified for both early- and late-onset. Similarly, Casadei et al. (2001) and Ohkubo et al. (2003) found no association between AD and the codon 129 genotype among Italian and Japanese patients, respectively. Primary Progressive Aphasia Among 415 Caucasian controls, Li et al. (2005) found that the codon 129 genotype distribution was 49.9% MM, 42.4% MV, and 7.7% VV. The 129 genotype among 39 patients with primary progressive aphasia (PPA; see frontotemporal dementia, FTD, 600274) was significantly different, at 12.8% MM, 84.6% MV, and 2.6% VV, yielding an age-adjusted odds ratio for the MV genotype of 8.47 for disease development compared to controls. Significant codon 129 genotype differences were not observed among 256 patients with amyotrophic lateral sclerosis (ALS; 105400) or 281 patients with AD. Li et al. (2005) suggested that PrP may indirectly modify the phenotype of PPA. Rohrer et al. (2006) found no significant association between PRNP allele frequencies at codon 129 and FTD spectrum disorders among 66 patients with various forms of FTD. (less)