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Human prion disease with a G114V mutation and epidemiological studies in a Chinese family: a case series
- Jing Ye†1,
- Jun Han†2,
- Qi Shi†2,
- Bao-Yun Zhang2,
- Gui-Rong Wang2,
- Chan Tian2,
- Chen Gao2,
- Jian-Min Chen2,
- Cun-Jiang Li1,
- Zheng Liu1,
- Xian-Zhang Li3,
- Lai-Zhong Zhang3 and
- Xiao-Ping Dong2Email author
© Ye et al; licensee BioMed Central Ltd. 2008
Received: 18 April 2008
Accepted: 17 October 2008
Published: 17 October 2008
Transmissible spongiform encephalopathies are a group of neurodegenerative diseases of humans and animals. Genetic Creutzfeldt-Jakob diseases, in which mutations in the PRNP gene predispose to disease by causing the expression of abnormal PrP protein, include familial Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia.
A 47-year-old Han-Chinese woman was hospitalized with a 2-year history of progressive dementia, tiredness, lethargy and mild difficulty in falling asleep. On neurological examination, there was severe apathy, spontaneous myoclonus of the lower limbs, generalized hyperreflexia and bilateral Babinski signs. A missense mutation (T to G) was identified at the position of nt 341 in one PRNP allele, leading to a change from glycine (Gly) to valine (Val) at codon 114. PK-resistant PrPSc was detected in brain tissues by Western blotting and immunohistochemical assays. Information on pedigree was collected notably by interviews with family members. A further four suspected patients in five consecutive generations of the family have been identified. One of them was hospitalized for progressive memory impairment at the age of 32. On examination, he had impairment of memory, calculation and comprehension, mild ataxia of the limbs, tremor and a left Babinski sign. He is still alive.
This family with G114V inherited prion disease is the first to be described in China and represents the second family worldwide in which this mutation has been identified. Three other suspected cases have been retrospectively identified in this family, and a further case with suggestive clinical manifestations has been shown by gene sequencing to have the causal mutation.
Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases of the central nervous system (CNS). The best known of human forms of TSE, Creutzfeldt-Jakob diseases (CJD), are classified into three subtypes, sporadic CJD (sCJD), iatrogenic CJD (iCJD), and genetic or familial CJD (gCJD or fCJD) . Hereditary forms of human TSE in which mutations in the prion protein gene (PRNP) predispose to disease include fCJD, Gerstmann-Sträussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI) .
To date, about 55 mutations associated with or directly linked to human TSEs have been identified . Here we report a Chinese family with a mutation at codon 114 (G114V) of the PRNP gene. The index case had clinical features, electroencephalogram (EEG) and magnetic resonance imaging (MRI) findings similar to sporadic CJD. We also present data on four suspected cases of fCJD in five consecutive generations of the family.
Brain autopsy of the proband was performed shortly after death with informed consent. Genomic DNA was extracted from the brain using Qiagen's DNA purification kit according to the manufacturer's instructions. The PRNP open reading frame was amplified by polymerase chain reaction (PCR) using a protocol and primers described elsewhere . The genotype at codon 129 of PRNP was determined by digestion with the restriction endonuclease Nsp I. Analysis of PRNP sequences was performed by direct sequencing in a MacBAC sequencer (Pharmacia, USA). A missense mutation (T to G) was identified at the position of nt 341 in one PRNP allele, leading to change from glycine (Gly) to valine (Val) at codon 114 (Figure 2B). No other nucleotide exchange was found in the rest of the PRNP sequence. Nsp I digestion and direct sequencing of the amplified product revealed a methionine homozygous genotype at codon 129 of PRNP. To identify the distribution of this point-mutation in the family, blood samples of five other family members, including the son of her first cousin (IV 2), were collected and the PRNP genes were sequenced. As suspected, the same G114V mutation was observed in the PRNP gene of IV 2. In addition, two other health family members, the proband's daughter (IV 10, age of 22) and the mother of the second case (III 1, age of 61), were found to have the same missense mutation. The son of the proband case (IV 9, age of 24) and the son of IV 2 (V 3, age of 9) were confirmed to have a wild-type PRNP sequence without such mutation. All tested family members were homozygous for methionine (M/M) at codon 129 of PRNP as in the profile of Han Chinese .
Proteinase K (PK)-resistant PrP assays
Histological and immunohistochemical (IHC) assays
Paraffin sections of occipital lobe (5 μm in thickness) were subjected to conventional staining with hematoxylin and eosin (HE) and severe and extensive vacuolation was identified in the tested tissues (Figure 3B). To identify PrPSc in brain tissues, slices of occipital lobe were immunostained using a protocol described elsewhere . Briefly, the slices were treated with 4 M guanidine hydrochloride (GdnHCl) at 4°C for 90 minutes, followed by microwave irradiation in distilled water for 25 minutes. The slices were exposed to the PrP-specific monoclonal antibody 3F4 at a dilution of 1:500 overnight at 4°C. For visualization of immunostaining, the slices were developed with a commercial ready-to-use system (Beijing Zhongshan Golden Bridge Biotechnology, China). The slices were counterstained with hematoxylin, dehydrated, and mounted in glycerolvinyl alcohol. Positive PrPSc immunoblots were found in many of the tested tissues, especially in the region of the gray matter. The deposits of PrPSc were restricted mostly to the neuronal cytoplasm. No obvious PrPSc deposits were observed in extracellular areas (Figure 3B).
This family with G114V inherited prion disease is the first to be described in China and represents the second family worldwide in which this mutation has been identified. The patient presented with clinical features similar to sporadic CJD, including a progressive neuropsychiatric disturbance, dementia, myoclonus and pyramidal signs. Cerebellar signs were observed relatively later, but became marked. MRI revealed findings consistent with those often seen in sporadic CJD, but the EEG did not show the typical periodic complexes of sporadic CJD. The CSF 14-3-3 was negative 1 year after onset. Typical spongiform degeneration and PrPSc deposits were observed in the brain and Type-I PrPSc was detected in various brain regions. Three other suspected cases have been retrospectively identified in this family, and a further case with suggestive clinical manifestations has been shown to have the causal mutation by gene sequencing. The age at clinical onset in this pedigree ranges from 32 to 45 years, which is somewhat later than cases in a Uruguayan family , which was the first to be described with a G114V mutation. However, the duration of illness and other clinical manifestations are quite similar in the two families. Interestingly, in our pedigree, the mother (III 1) of the second case carries the G114V mutation in her PRNP gene and remains healthy at the age of 61 years. This suggests that some other unknown factors may influence the phenotype of genetic human TSE.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
This work was supported by the National Science and Technology Task Force Project (2006BAD06A13-2), the National Basic Research Program of China (973 Program) (2007CB310505) and Chinese National Natural Science Foundation Grants 30571672, 30500018 and 30771914.
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