ClinVar Genomic variation as it relates to human health

In a Finnish family with Creutzfeldt-Jakob disease (CJD; 123400), Goldfarb et al. (1991) identified a G-to-A transition in the PRNP gene, resulting in an asp178-to-asn (D178N) substitution. Nieto et al. (1991) found that the D178N mutation was the cause of transmissible CJD in an American family of Dutch descent, an American family of Hungarian descent, and a French family from Brittany. The Finnish family was the only familial CJD identified in that country (Haltia et al., 1991). The pedigree included 15 affected members in 4 generations in a pattern consistent with autosomal dominant inheritance. The mean age at onset was 47, periodic EEG activity was not observed, and the mean duration of illness of 27.5 months was longer than usual in either familial or sporadic CJD. Neuropathologic examination of brain biopsy and autopsy specimens showed spongiform change without amyloid plaques, and brain tissue from 1 patient transmitted disease to a capuchin monkey. Goldfarb et al. (1992) identified the D178N mutation in 7 unrelated families of western European origin, among which a total of 65 members were known to have died from CJD. The mutation was detected in each of 17 tested patients, including at least 1 affected member of each family, and in 16 of 36 of their first-degree relatives, but not in affected families with other mutations, patients with the nonfamilial form of the disease, or 83 healthy control persons. Linkage analysis in informative families yielded a lod score of 5.30, which, because no recombinants were found, strongly suggested that the codon 178 mutation was the cause of the disease. Brown et al. (1992) compared a group of 43 patients from 7 families affected by CJD caused by the D178N mutation to a group of 211 patients with the sporadic form of the disease. In general, the patients with the codon 178 mutation had an earlier age of onset of illness, almost always presenting as an insidious loss of memory, a longer duration of illness, and an absence of periodic EEG activity. Transmission of the disease to primates was accomplished using brain tissue homogenates from 6 of 10 patients, resulting in significantly shorter incubation periods than those due to sporadic CJD inocula. These findings were interpreted as indicating an accelerated induction of polymerized amyloid protein by its mutationally altered template precursor. Brown et al. (1992) suggested that the earlier age of onset in patients with the codon 178 mutation than in the sporadic patient group may reflect differing rates at which normal host precursor protein is converted into amyloid polymer. If one accepts that an altered protein molecule may serve as a nucleating template to initiate and sustain the conversion process, a 1-per-million probability of its random occurrence would equal the worldwide incidence of sporadic CJD. Precursor protein that has a primary structure already altered by the codon 178 mutation can be presumed to have a correspondingly altered 3-dimensional structure, and this structure may facilitate by a million-fold its conversion to the beta-pleated sheet configuration of amyloid fibrils. An exception to the phenotypic rule of early onset found by Brown et al. (1992) was described by Laplanche et al. (1992) in a man with the D178N mutation who was well and professionally active until the age of 57 years when he had onset of loss of memory, vertigo, and disorientation, leading to professional disability 9 months later. The presence of periodic EEG activity also distinguished him from others carrying this mutation. Multiple genetic or environmental factors may modulate the clinical presentation of CJD associated with the codon 178 mutation. 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. Familial CJD was first described in the Backer family living in northern Germany (Meggendorfer, 1930). Further clinical and neuropathologic details were reported by others. Autopsies were performed on 3 members of this family in the 1920s and 1940s. Kretzschmar et al. (1995) presented DNA sequencing data from brain tissue that had been embedded in celloidin 72 years previously. PCR amplification of DNA showed the D178N mutation. Goldfarb et al. (1992) demonstrated that the D178N mutation in conjunction with the met129 polymorphism on the same allele (176640.0005) was responsible for fatal familial insomnia (FFI; 600072). They found that CJD was associated with val129 in all 15 affected members of 6 kindreds, whereas met129 was associated with FFI in all 15 affected members of 5 kindreds. Analysis of the PRNP region by Dagvadorj et al. (2002) in 13 families and 2 sporadic patients with either CJD caused by D178N and 129V or FFI caused by D178N and 129M (176640.0010) showed that the D178N chromosomes had independent origins in each affected pedigree or patient. In addition, a de novo spontaneous PRNP mutation was observed in 1 family. Noting that the mutation involving codon 178 occurred at a CpG dinucleotide motif that is considered to be a hotspot for spontaneous human mutations, Dagvadorj et al. (2002) concluded that cases associated with the D178N mutation result from multiple recurrent mutational events. Zarranz et al. (2005) reported 23 patients from 13 Spanish families with prion disease. Nine families were of Basque origin, 6 of which were genetically related by haplotype analysis. They identified 2 patients who were D178N and val/met129 heterozygous with fatal familial insomnia (FFI; 600072). One patient was sporadic, and 1 patient had a relative with the same genotype who presented with CJD. PrPSc isotype analysis was not informative. The largest family had 5 affected individuals. The genotype in all 5 family members was D178N and met129 homozygous (176640.0010) but only 2 presented with FFI. The 3 other family members presented with CJD, 2 with ataxia and 1 with acalculia, aphasia and dementia. In another family with D178N and met129 homozygous, 1 patient had classic FFI presenting with insomnia, 1 had FFI presenting with depression, apathy, and autonomic dysfunction, and 2 other family members presented with CJD. Overall, 7 patients with D178N and met129 homozygous had a clinical and neuropathologic profile compatible with CJD. Zarranz et al. (2005) concluded that there must be other environmental or genetic factors that influence the phenotypic expression of the D178N mutation, and that FFI and CJD due to this genotype are extremes of a phenotypic spectrum rather than 2 discrete entities. Dossena et al. (2008) generated a transgenic mouse model expressing the mouse homolog of the D178N/M129V mutation. These mice developed clinical and pathologic features reminiscent of CJD, including motor dysfunction, memory impairment, cerebral prion protein deposition, and gliosis. Other features included EEG abnormalities and severe alterations of sleep-wake patterns similar to those observed in human patients. Neurons from the mutant mice showed swelling of the endoplasmic reticulum (ER) with intracellular retention of mutant prion protein, suggesting that ER dysfunction could contribute to the pathology of CJD. The mutant protein was protease-resistant and formed aggregations. (less)

In a Finnish family with Creutzfeldt-Jakob disease (CJD; 123400), Goldfarb et al. (1991) identified a G-to-A transition in the PRNP gene, resulting in an asp178-to-asn (D178N) substitution. Nieto et al. (1991) found that the D178N mutation was the cause of transmissible CJD in an American family of Dutch descent, an American family of Hungarian descent, and a French family from Brittany. The Finnish family was the only familial CJD identified in that country (Haltia et al., 1991). The pedigree included 15 affected members in 4 generations in a pattern consistent with autosomal dominant inheritance. The mean age at onset was 47, periodic EEG activity was not observed, and the mean duration of illness of 27.5 months was longer than usual in either familial or sporadic CJD. Neuropathologic examination of brain biopsy and autopsy specimens showed spongiform change without amyloid plaques, and brain tissue from 1 patient transmitted disease to a capuchin monkey. Goldfarb et al. (1992) identified the D178N mutation in 7 unrelated families of western European origin, among which a total of 65 members were known to have died from CJD. The mutation was detected in each of 17 tested patients, including at least 1 affected member of each family, and in 16 of 36 of their first-degree relatives, but not in affected families with other mutations, patients with the nonfamilial form of the disease, or 83 healthy control persons. Linkage analysis in informative families yielded a lod score of 5.30, which, because no recombinants were found, strongly suggested that the codon 178 mutation was the cause of the disease. Brown et al. (1992) compared a group of 43 patients from 7 families affected by CJD caused by the D178N mutation to a group of 211 patients with the sporadic form of the disease. In general, the patients with the codon 178 mutation had an earlier age of onset of illness, almost always presenting as an insidious loss of memory, a longer duration of illness, and an absence of periodic EEG activity. Transmission of the disease to primates was accomplished using brain tissue homogenates from 6 of 10 patients, resulting in significantly shorter incubation periods than those due to sporadic CJD inocula. These findings were interpreted as indicating an accelerated induction of polymerized amyloid protein by its mutationally altered template precursor. Brown et al. (1992) suggested that the earlier age of onset in patients with the codon 178 mutation than in the sporadic patient group may reflect differing rates at which normal host precursor protein is converted into amyloid polymer. If one accepts that an altered protein molecule may serve as a nucleating template to initiate and sustain the conversion process, a 1-per-million probability of its random occurrence would equal the worldwide incidence of sporadic CJD. Precursor protein that has a primary structure already altered by the codon 178 mutation can be presumed to have a correspondingly altered 3-dimensional structure, and this structure may facilitate by a million-fold its conversion to the beta-pleated sheet configuration of amyloid fibrils. An exception to the phenotypic rule of early onset found by Brown et al. (1992) was described by Laplanche et al. (1992) in a man with the D178N mutation who was well and professionally active until the age of 57 years when he had onset of loss of memory, vertigo, and disorientation, leading to professional disability 9 months later. The presence of periodic EEG activity also distinguished him from others carrying this mutation. Multiple genetic or environmental factors may modulate the clinical presentation of CJD associated with the codon 178 mutation. 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. Familial CJD was first described in the Backer family living in northern Germany (Meggendorfer, 1930). Further clinical and neuropathologic details were reported by others. Autopsies were performed on 3 members of this family in the 1920s and 1940s. Kretzschmar et al. (1995) presented DNA sequencing data from brain tissue that had been embedded in celloidin 72 years previously. PCR amplification of DNA showed the D178N mutation. Goldfarb et al. (1992) demonstrated that the D178N mutation in conjunction with the met129 polymorphism on the same allele (176640.0005) was responsible for fatal familial insomnia (FFI; 600072). They found that CJD was associated with val129 in all 15 affected members of 6 kindreds, whereas met129 was associated with FFI in all 15 affected members of 5 kindreds. Analysis of the PRNP region by Dagvadorj et al. (2002) in 13 families and 2 sporadic patients with either CJD caused by D178N and 129V or FFI caused by D178N and 129M (176640.0010) showed that the D178N chromosomes had independent origins in each affected pedigree or patient. In addition, a de novo spontaneous PRNP mutation was observed in 1 family. Noting that the mutation involving codon 178 occurred at a CpG dinucleotide motif that is considered to be a hotspot for spontaneous human mutations, Dagvadorj et al. (2002) concluded that cases associated with the D178N mutation result from multiple recurrent mutational events. Zarranz et al. (2005) reported 23 patients from 13 Spanish families with prion disease. Nine families were of Basque origin, 6 of which were genetically related by haplotype analysis. They identified 2 patients who were D178N and val/met129 heterozygous with fatal familial insomnia (FFI; 600072). One patient was sporadic, and 1 patient had a relative with the same genotype who presented with CJD. PrPSc isotype analysis was not informative. The largest family had 5 affected individuals. The genotype in all 5 family members was D178N and met129 homozygous (176640.0010) but only 2 presented with FFI. The 3 other family members presented with CJD, 2 with ataxia and 1 with acalculia, aphasia and dementia. In another family with D178N and met129 homozygous, 1 patient had classic FFI presenting with insomnia, 1 had FFI presenting with depression, apathy, and autonomic dysfunction, and 2 other family members presented with CJD. Overall, 7 patients with D178N and met129 homozygous had a clinical and neuropathologic profile compatible with CJD. Zarranz et al. (2005) concluded that there must be other environmental or genetic factors that influence the phenotypic expression of the D178N mutation, and that FFI and CJD due to this genotype are extremes of a phenotypic spectrum rather than 2 discrete entities. Dossena et al. (2008) generated a transgenic mouse model expressing the mouse homolog of the D178N/M129V mutation. These mice developed clinical and pathologic features reminiscent of CJD, including motor dysfunction, memory impairment, cerebral prion protein deposition, and gliosis. Other features included EEG abnormalities and severe alterations of sleep-wake patterns similar to those observed in human patients. Neurons from the mutant mice showed swelling of the endoplasmic reticulum (ER) with intracellular retention of mutant prion protein, suggesting that ER dysfunction could contribute to the pathology of CJD. The mutant protein was protease-resistant and formed aggregations. (less)