Identification of three novel mutations (E196K, V203I, E211Q) in the prion protein gene (PRNP) in inherited prion diseases with Creutzfeldt-Jakob disease phenotype

Peoc’h, Katell; Manivet, Philippe; Beaudry, P.; Attane, Françoise; Besson, Gérard; Hannequin, Didier; Delasnerie-Lauprêtre, N; Laplanche, Jean‐Louis

doi:10.1002/(sici)1098-1004(200005)15:5<482::aid-humu16>3.0.co;2-1

Cited by 91 publications

(64 citation statements)

References 21 publications

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“…All the reported cases with this mutation lacked a family history of the prion diseases. [6][7][8] The clinical manifestations of the patients with fCJD who have a V203I heterozygous mutation are consistent with those of patients with typical sCJD. This includes rapidly progressive dementia, ataxia, tremor, and myoclonus.…”

Section: Discussionsupporting

confidence: 64%

Creutzfeldt-Jakob disease associated with a V203I homozygous mutation in the prion protein gene

Komatsu¹,

Sakai

Hamaguchi³

et al. 2014

Prion

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We report a Japanese patient with Creutzfeldt-Jakob disease (CJD) with a V203I homozygous mutation of the prion protein gene (PRNP). A 73-year-old woman developed rapidly progressive gait disturbance and cognitive dysfunction. Four months after the onset, she entered a state of an akinetic mutism. Gene analysis revealed a homozygous V203I mutation in the PRNP. Familial CJD with a V203I mutation is rare, and all previously reported cases had a heterozygous mutation showing manifestations similar to those of typical sporadic CJD. Although genetic prion diseases with homozygous PRNP mutations often present with an earlier onset and more rapid clinical course than those with heterozygous mutations, no difference was found in clinical phenotype between our homozygous case and reported heterozygous cases. IntroductionCreutzfeldt-Jakob disease (CJD) is a disease of fatal neurodegenerative conditions pathologically characterized by accumulation of the abnormal prion protein (PrP Sc ) in the central nervous system. Approximately 85-90 % of CJD cases are sporadic (sCJD) lacking any mutations in the prion protein gene (PRNP), while about 10-15% of the disorders are inherited.1 Familial CJD (fCJD) is associated with at least 20 distinct genetic mutations that are all transmitted as autosomal dominant traits, including point, deletion and insertion mutations.2 Most of the mutations that cause fCJD, are heterozygous. Pathomechanisms of homozygous mutations in the PRNP remain unclear due to the extreme rarity of the disorder. We describe a Japanese fCJD patient with a V203I homozygous point mutation in the PRNP. Case PresentationA 73-year-old Japanese woman developed gait disturbance and rapidly progressive cognitive dysfunction. She had no family history of the prion diseases or other neurological disorders; however, her parents were first cousins. Three months after the onset, she became bedridden state. On admission to our hospital, neurological examinations revealed severe cognitive impairment and left-sided hemiparesis. Hyperreflexia with positive plantar reflex was evident in the left extremities.No myoclonus or extrapyramidal signs were obvious. No visual disturbance or cerebellar signs were apparent. Routine hematological examinations and blood chemistry were unremarkable. Cerebrospinal fluid (CSF) study revealed an elevation of tau protein (22,528 pg/ml; normal range, <202 pg/ ml) and 14-3-3 protein (5,428 mg/ml; normal range, <500 mg/ml); however, there was neither pleocytosis nor an elevation of protein levels. There was no evidence of infectious diseases in the culture from the CSF. Electroencephalography (EEG) revealed diffuse slowing of the waves without apparent periodic synchronous activities. Diffusion weighted brain magnetic resonance imaging (MRI) showed hyperintensity in the right basal ganglia and the right frontal, parietal, and occipital lobes (Fig. 1). Single photon emission computed tomography images using 99m Tc-Ethylcysteinate dimer showed mild hypoperfusion in the right frontal lobe and right pariet...

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Section: Discussionsupporting

confidence: 64%

Creutzfeldt-Jakob disease associated with a V203I homozygous mutation in the prion protein gene

Komatsu¹,

Sakai

Hamaguchi³

et al. 2014

Prion

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“…However, another point-mutation in this codon, E196K, has been described in Caucasian, which is causally linked to human prion disease. 11 Majority E196K gCJD cases distributes in Germany, [12][13][14] one in France, 15 one in Italy 16 and one in China. 17 E196K gCJD patients usually present nonspecific symptoms at onset and display the features typical of sCJD during disease progression.…”

Section: Discussionmentioning

confidence: 99%

Rare E196A mutation in PRNP gene of 3 Chinese patients with Creutzfeldt-Jacob disease

Shi

Zhou

Cao

et al. 2016

Prion

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ABSTRACT. Inherited prion diseases are characterized by mutations in the PRNP gene, which account for 5-15% of human prion diseases. Here we reported 3 Chinese genetic Creutzfeldt-Jacob disease cases (gCJD) with a rare mutation in PRNP leading to an exchange of amino acid from glutamic acid (E) to alanine (A) at codon 196 (E196A). All three patients were Han Chinese without any sibship among them. They showed various unspecific symptoms at onset and displayed typical clinical manifestations of sporadic CJD with progress of disease. The same time, 2 cases showed psychotic symptoms during the clinical courses. 14-3-3 proteins were positive in cerebrospinal fluid (CSF) and special abnormality were detected in MRI of all the cases. The polymorphism of codon 129 was methionin homozygote and that of codon 219 was glutamate homozygote in all 3 patients. The disease durations of the 3 cases varied from 10 to 22 months and no disease associated family history was figured out in all the cases.

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“…4b). Indeed, the mutation E196K causes a rapidly progressive dementia and ataxia (23) and could be expected to greatly reduce the protein stability because of the elimination of salt bridges between E196, R156, and K194 (23).…”

Section: Discussionmentioning

confidence: 99%

Hot spots in prion protein for pathogenic conversion

Kuwata

Nishida

Matsumoto

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

173

222

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Prion proteins are key molecules in transmissible spongiform encephalopathies (TSEs), but the precise mechanism of the conversion from the cellular form (PrP C ) to the scrapie form (PrP Sc ) is still unknown. Here we discovered a chemical chaperone to stabilize the PrP C conformation and identified the hot spots to stop the pathogenic conversion. We conducted in silico screening to find compounds that fitted into a ''pocket'' created by residues undergoing the conformational rearrangements between the native and the sparsely populated high-energy states (PrP*) and that directly bind to those residues. Forty-four selected compounds were tested in a TSE-infected cell culture model, among which one, 2-pyrrolidin-1-yl-N-[4-[4-(2-pyrrolidin-1-yl-acetylamino)-benzyl]-phenyl]-acetamide, termed GN8, efficiently reduced PrP Sc . Subsequently, administration of GN8 was found to prolong the survival of TSE-infected mice. Heteronuclear NMR and computer simulation showed that the specific binding sites are the A-S2 loop (N159) and the region from helix B (V189, T192, and K194) to B-C loop (E196), indicating that the intercalation of these distant regions (hot spots) hampers the pathogenic conversion process. Dynamics-based drug discovery strategy, demonstrated here focusing on the hot spots of PrP C , will open the way to the development of novel anti-prion drugs.anti-prion compound ͉ binding sites ͉ chemical chaperone ͉ dynamicsbased drug discovery ͉ transmissible spongiform encephalopathy

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Identification of three novel mutations (E196K, V203I, E211Q) in the prion protein gene (PRNP) in inherited prion diseases with Creutzfeldt-Jakob disease phenotype

Cited by 91 publications

References 21 publications

Creutzfeldt-Jakob disease associated with a V203I homozygous mutation in the prion protein gene

Creutzfeldt-Jakob disease associated with a V203I homozygous mutation in the prion protein gene

Rare E196A mutation in PRNP gene of 3 Chinese patients with Creutzfeldt-Jacob disease

Hot spots in prion protein for pathogenic conversion

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