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Prion Protein Mutation Database

Truncating mutations

Most pathogenic mutations in the prion protein gene (PRNP) are point mutations causing the classic prion disease presentation of rapidly progressive dementia, cerebellar ataxia and myoclonus or slower progressing Parkinsonian and ataxic syndromes1. Truncating mutations in PRNP, however, are very rare. They comprise nonsense variants, and base insertions and deletions causing reading frameshifts that generate a premature termination codon (See table). 

PRNP has only one protein-coding exon (exon 2 – see PrP Gene Structure), as such premature stop codons are expected to result in a truncated PrPC polypeptide, rather than in nonsense-mediated decay, which is intron-dependent2. Proteins encoded by single exons are hypothesised to possess the intrinsic property of transcriptional robustness, such that they contain fewer ‘fragile’ codons (whose mistranscription can generate nonsense errors in a single step)3.  There are eighteen fragile codons. Six amino acids are encoded exclusively by fragile codons (Cys, Gln, Glu, Lys, Trp and Tyr), four amino acids can be encoded by either fragile or robust codons (Arg, Gly, Leu and Ser), with the remining ten codons are encoded exclusively by robust codons3. 28% (71/253 aa) of the prion protein is formed of fragile codons, with sixty residues being contributed to by obligate codons: Cys (4 aa), Gln (15 aa), Glu (9 aa), Lys (10 aa), Trp (9 aa) and Tyr (13 aa); the remining eleven are contributed by Arg (2/11 aa), Gly (8/45 aa), Leu (0/12 aa) and Ser (1/15 aa), where it appears that there is depletion of fragile codon usage. Of the fourteen nonsense mutations reported in PrP, two (Arg37X and Gly131X) are of facultative residues and occur at sites of fragile codon usage. The remaining twelve nonsense mutations are formed of mutated Gln (5 aa), Tyr (5 aa) and Trp (2 aa) – see table. 

There is limited evidence to suggest that the pathogenicity of PrP-truncating mutants is dictated by position within the amino acid sequence4; truncation at residues  ≥ 145 (C-terminus) cause prion disease, whereas, truncation at residues ≤ 131 leave the patient neurologically intact (see table).   Premature stop mutations at residue positions ≥ 145 were first reported to cause a slowly progressive, Alzheimer’s-like dementing illness, with neurofibrillary tangles and deposition of prion (PrPSc)-amyloid in the form of cortical amyloid plaques, either with or without cerebral amyloid angiopathy – Tyr145Stop5-6, Gln160X7-8, Tyr226X9, Gln227X9. Recently however, truncating PRNP mutations that feature chronic diarrhoea, dysautonomia and peripheral neuropathy with both central nervous system and peripheral PrPSc-amyloid deposition10, as part of the newly-described PrP systemic amyloidosis phenotype1 –  Gln160X11, Tyr162X12, Tyr163X10,13-15, Tyr169X15 and 195X due to mutation causing a reading frameshift16. It is of note, that mutation Gln160X, which invariably is caused by the same nucleotide base change (c.478C>T), is found to cause two distinct clinical phenotypes (see table). Truncating mutations in residues ≤ 1314,17, are associated with limited clinico-pathological data, however, where  information is known there is no overt neurological deficit at ages 52, 73 and 79 years4 (see table), suggesting that N-terminal truncations of PrPC are tolerated. This aligns with the fact that prion diseases require the presence of PrPC, rate of prion disease progression is closely correlated with PrP expression level18,19 and neurodegeneration is not seen in mice, cows or goats that lack PrP20-23. Therefore, if an N-terminus truncation leads to a protein product that neither resembles the native PrP fold, nor retains its conversion potential to PrPSc, it is interesting that truncations beginning only 14 residues upstream of the seemingly benign Gln131X mutation, are neurologically deleterious, and should provide sufficient PrPC dosage to precipitate prion disease. More data, however, are needed to understand the apparent differential pathogenicity, based on sequence location, of the PrPC truncating mutants. 

Furthermore, truncation mutations yield an ‘anchorless’ prion protein, lacking the C-terminal glycosylphosphatidylinositol (GPI) anchor signal (aa 231 – SMVLFSSPPVILLISFLIFLIV – aa 252) that would otherwise tether PrPC to the cell membrane. Mice generated to express GPI-anchorless protein, reveal that this PrPC product is neither present in lipid rafts nor at the plasma membrane, but upon prion inoculation, retains its conversion potential to PrPSc, which subsequently manifests as abundant PrPSc-amyloid  deposits, especially around blood vessels24-26. In these mice, infectivity was preserved but clinical onset of disease was delayed, and neurodegeneration was attributed to direct damage by amyloidogenic PrPSc accumulation. Neuropathologically, prion diseases are characterised by the presence of diffuse or amyloidogenic deposition of PrPSc, neuropil vacuolation (spongiosis) that is specific and independent of PrPSc accumulation27, as well as astrogliosis and microglial activation. Interestingly, these mice displayed a notable lack of spongiosis. There is growing evidence that in prion diseases there are two mechanistically different, yet related phenomena: (1) the conversion of PrPC to PrPSc – prion propagation – and (2) neurotoxic signalling27-28. The latter of which, is likely dependent on membrane attachment of PrPSc via its GPI-anchor and on the localisation of PrPC within lipid rafts27. As such, in anchorless prion protein it is clear that conversion potential to PrPSc is both retained and enhanced, but neurotoxicity is decreased27. This is in keeping with clinical findings of patients with C-terminal truncating mutations – Tyr145X5-6, Gln160X8, Tyr163X10 and Tyr226X9 – whose post-mortem brains show a similar pattern or vascular and perivascular PrPSc deposits, consistent with cerebral amyloid angiopathy, but with no evidence of spongiform degeneration that is typical of prion diseases. These data support the notion that both the cerebrovascular (PrP-CAA) and indeed the peripheral (systemic PrP-amyloidosis) phenotype associated with protein-truncating mutations, relates specifically to loss of the GPI anchor, rather than just C-terminal truncation of PrPC 1,10 and raises concern of potential widespread dissemination of unanchored PrPSc in patients harbouring such mutations. 

PRNP termination codonAllele countCountry of
proband
Genotype
at codon
129 of index
case
Age at
clinical onset
(years)
Age at
death
(years)
Phenotype and clinical notesReferences
Gly20Glyfs84X
(c.59_60insC)
1Netherlands79-year-old female study participant. She is in good health and free of dementia, or any other overt neurological disease, at time of report. She has five siblings and two children. Family history of note, is that one of her siblings had a stroke aged less than 65 years.Minikel EV 2016 (4)
Arg37X
(c.109C>T)
2Sweden and
North-
Western
Europe (NOS)
First patient is a 73-year-old Swedish male enrolled as a control case in a schizophrenia study. He underwent heart bypass surgery in 2008, has a family history of cardiovascular disease and has four siblings. He has no overt neurological disease and reports no family history of neurodegeneration or neuropathy. The second patient in whom this truncation is found, is a female from North-Western Europe in the 40-45 age bracket, however, no further data are known for her.Minikel EV 2016 (4)
and 2020 (17)
Gln41X
(c.121c>T)
1Latino (NOS)Male aged between 60-65. No further data are known.Minikel EV 2020
(17)
Gln75X
(c.223C>T)
1Finland52-year-old male with mild type 2 diabetes. No overt neurological disease at time of report.Minikel EV 2016 (4)
Trp81X
(c.243G>A)
1Ashkenazi Jewish female. No further data are known.Minikel EV 2020
(17)
Trp99X
(c.297G>A)
1North-
Western
Europe (NOS)
Female. No further data are known.Minikel EV 2020
(17)
Gly131X
(c.391G>T)
1Southern
Europe (NOS)
77-year-old male, cognitively well with no family history of dementia. Enrolled in a study of coronary artery disease. Patient has hypertension and well-controlled dyslipidaemia. He has undergone coronary artery bypass grafting, has two adult children and no overt neurological disease at time of report.Minikel EV 2016 (4)
and 2020 (17)
Tyr145Stop
(c.435T>C)
1JapanMet3859Female patient developed memory disturbance and disorientation aged 38 years, with subsequent onset of a slowly progressive dementia, for which the diagnosis was Alzheimer’s disease. She became bed-ridden aged 50 years. A CT brain undertaken at age 58 showed severe cerebral atrophy with dilatation of the lateral ventricles. At post-mortem, the histopathologic diagnosis was that of PrP cerebral amyloid
angiopathy. Diffuse atrophy of the cerebrum and severe dilatation of the lateral ventricles was noted. Microscopically, the two most characteristic lesions were (1) amyloid deposits in parenchymal and leptomeningeal blood vessels and in the
perivascular neuropil and (2) neurofibrillary lesions in cerebral grey matter. Neuronal loss and gliosis was severe. Amyloid angiopathy involved primarily the walls of the small and medium-sized vessels of the cerebral and cerebellar grey matter and to a lesser extent the leptomeningeal vessels. τ-positive neurofibrillary lesions were also found. There was no spongiosis.
Kitamoto T 1993 (5) Ghetti B 1996 (6)
Gln160X
(c.478C>T)
7Austria and USAMet30-5947-67Two Austrian brothers both had mutation Q160X in cis with Met129. The index patient had onset of dementia aged 32 years and a severe, rapidly progressing course, while his elder brother had disease onset aged 48 years and a mild course of disease. The wild type allele of the younger brother, with rapid course, encodes M129 and that of the older brother, with milder course, encodes V129. Serial EEGs of index younger brother were abnormal with diffuse theta increment and intermittent theta groups but without seizure activity. CT and MR brain imaging at age 35 of the index brother showed severe ventricular and sulcal enlargement. MR brain of the elder brother undertaken at age 55 years, showed almost normal findings with only slight cerebellar atrophy. At the time of publication, disease durations for the brothers was at 6 and 8 years, respectively – at that time no neurological signs of CJD or ataxia had been noted. Their father had early onset dementia aged 48 years with a severe course resembling that of the index younger brother. He died of pneumonia aged 60 years with post-mortem analysis revealing a reduced brain weight of 1200 g, diffuse cortical atrophy and extensive enlargement of ventricles. Finckh U 2000 (7)
American female teaching assistant presenting aged 42 years with a three-year history of progressive short-term memory impairment and depression. She was married with two children. She developed cognitive impairment with emotional lability, depression, anergia and significant sleep disturbance. Neuropsychological testing found impaired memory performance, with relatively preserved attention and construction. She was subsequently diagnosed with Alzheimer’s disease and died aged 47 years following an eight-year course. At the time of presentation, neurological examination was unremarkable, with normal cranial nerve, motor, sensory and gait evaluation. There was no evidence of myoclonus or ataxia. Laboratory testing, EEG and MR brain were also unremarkable at that time. Over the five years that she was known, she developed significant language impairment, mild Parkinsonism and loss of ADLs. Three years prior to her death her neurological examination was notable for symmetrically brisk reflexes and an essential-like tremor. Post-mortem brain examination revealed a brain weight of 980 g, with mild to moderate frontotemporal atrophy. In addition, there was extensive limbic and neocortical neurofibrillary tangle formation and neuritic plaques consistent with a neuropathological diagnosis of Alzheimer’s disease. The neuritic plaques were positive for PrP. Her mother died aged 67 with post-mortem confirmed Alzheimer’s disease after an eight-year course of dementia (age of onset: 59 years). Of note, the mother developed a post-prandial diarrhoeal illness two years after the onset of cognitive and behavioural changes, that continued to her death. The mother’s brain showed similar neuropathological changes. The proband was found to be Met/Val at codon 129, whereas her mother was Met/Met at position 129 and also had the Q160Stop mutation. Of note, the age of disease onset of the proband, with valine at position 129 of the wild-type allele, was twenty years earlier than that of her mother, with Met129 in the wild-type allele.Jayadev S 2011 (8)
31-year-old right-handed gentleman presented with possible behavioural variant frontotemporal dementia due to a four-year history of frontal dementia syndrome, with cyclical vomiting and diarrhoea. He had no known learning disability but was historically a below-average student. He married age 22 years, worked in a welding shop while studying applied technology in college. His marriage was characterised by mismanaged finances and his wife’s substance abuse. He divorced aged 27 and returned home to his parents. His dementia syndrome affected behaviour, memory, executive function, speech/language and motor function, while relatively sparing visuospatial function. The most salient features were behavioural disinhibition, emotional lability, impaired judgement, distractibility and decreased social tact, consistent with cortico-subcortical orbitofrontal dysfunction. Examination on presentation revealed slightly mydriatic pupils with an irregular and sluggishly constricting left pupil. He had mildly increased tone, preserved and symmetric deep tendon reflexes and decreased temperature and joint position sense with intact vibration and light touch in the distal lower limbs. He had a postural hand tremor and a wide-based gait with mild retropulsion. MR brain revealed severe white matter atrophy (likely contributing to) enlarged ventricles in the bilateral temporal horns, widened Sylvian fissures and severe atrophy of the orbitofrontal cortex. There was no evidence of stroke. Repeat neurological examination and brain imaging revealed no significant changes. CSF was unremarkable, and remained so at repeat testing, with normal total tau and neuron-specific enolase, and negative 14-3-3 protein. EEG revealed diffuse background slowing and attenuated cerebral activity, without epileptiform potentials or periodic discharges. Nerve conduction studies provided evidence of a length-dependent primarily axonal sensorimotor polyneuropathy. There was a strong paternal family history of diarrhoea with dysautonomia, peripheral neuropathy and a memory-predominant cognitive syndrome. The proband patient was homozygous for Met at codon 129. His father had the same Q160X mutation with codon 129 heterozygosity (M/V), and at age 56 was asymptomatic. His 50-year old paternal cousin once-removed also has the Q160X mutation with codon 129 Met homozygosity and has similar symptoms to the proband. 
Fong JC 2017 (11)
Tyr162X
(c.486C>G)
1ItalyMet5050 year old gentleman presents with a two-month history of difficulties in micturition and erectile dysfunction against a fifteen year background of chronic diarrhoea. He was also noted to have severe postural hypotension. At the time of study, there were no features of cognitive impairment present. The patient’s mother, a maternal aunt and two cousins were also affected by chronic diarrhoea and had dies within their sixth decade of life. MR brain and whole spine imaging did not reveal any abnormalities. CSF examination showed a high total protein and S100b protein levels, whereas 14-3-3 protein level was normal. Neurophysiology revealed mild axonal sensorimotor neuropathy in the lower limbs. Sural nerve biopsy did not show any amyloid deposits, however, immunohistochemical analysis reveals perivascular PrP deposits. Genetic analysis reveals the Y162X nonsense mutation with Met homozygosity at the polymorphic 129 codon. Bommarito G 2018 (12)
Tyr163X
(c.489C>G)
6UKVal27-5342-70Study of a large British family with the Y163X PRNP mutation, transmitted in an autosomal dominant manner, whose clinical phenotype is associated with chronic diarrhoea and hereditary sensory and autonomic neuropathy onset in the 30s. The onset of cognitive problems and seizurres occurred when the patients were in their 40s or 50s. The average age at time of death was 57 years. Electrophysiological studies in five patients showed a progressive, length-dependent, predominantly sensory, axonal neuropathy. Neuropsychological assessment of three patients revealed the most prominent finding to be impairment of memory and executive function when the patients were in their 50s. MR brain imaging showed generalised volume loss in the supratentorial compartment in one patient, but was otherwise normal in the others. CSF examination showed an elevation of total tau and S100b protein, and elevated amounts of 14-3-3 protein in one patient. In this family, the Y163X mutation is found in association with Val at position 129 or the prion protein. Pathological analysis reveals cerebral amyloid angiopathy and widespread prion protein amyloid deposition in the central and peripheral nervous system, as well as in systemic organs. The diagnosis is PrP systemic amyloidosis.Mead S 2013 (10)
69-year-old male presented with 16-year history of numbness and paraesthesia of both feet, symptomatic postural hypotension and lower urinary tract symptoms. There was a long history of adult-onset diarrhoea which preceded his sensory symptoms by ten years, as well as cognitive impairment. His mother also had symptomatic postural hypotension and foot ulceration developing in her sixth decade; she died in the seventh decade. It is not known if she suffered from chronic diarrhoea or cognitive impairment. Examination reveals wasting of the intrinsic foot muscles, normal tone and absent ankle reflexes. Sensation to pinprick was reduced to the mid-calf bilaterally, vibration sense reduced to the knees, light touch reduced to the ankles and joint position sense reduced at the hallux. He was unable to perform tandem gait and Romberg’s sign was positive. Neurophysiological studies showed a length-dependent predominantly axonal motor and sensory neuropathy with subtle demyelinating features. Cognitive testing revealed major deficits in memory and executive function. MR brain imaging showed age-appropriate cerebral atrophy.Themistocleous AC 2014 (13)
Tyr163X
(c.478_479insAAGTGTACT)
3ItalyVal33-5659 and 68The proband is a gentleman presenting aged 45 years with chronic diarrhoea. Over the subsequent ten years he developed urinary retention, with post micturition- and postural-syncope. Aged 63, he developed cognitive impairment and confusion. Aged 66, examination revealed short-term memory lapses, sluggishly reacting pupils, brisk reflexes, reduced vibration sense in the lower limbs, positive Romberg’s sign, an ataxic gait and myoclonus. Neurophysiological studies revealed sensorimotor axonal polyneuropathy. Neuropsychological testing showed a selective deficit of visual attention, verbal memory and local reasoning at age 65 progressing to multi-domain cognitive impairment a year later. MR brain imaging was unremarkable. CSF analysis showed increased total protein, positive 14-3-3- level and markedly elevated total tau and Nfl-l levels. The proband died aged 68. A similar clinical picture is seen in this patient’s brother, who died aged 59, and in a member of another branch of the family. Unlike the mutations in the British patients outlined above, the resultant Y163X mutant in this patient is the results of a small nine-base-pair duplication in the PRNP open reading frame resulting in the p.Y163X truncation. This mutation was found in cis with Val at codon 129. 
Capellari S 2014 (14) and 2018 (15)
Tyr169X 
(c.507C>A associated with an in cis c.508A>G)
2ItalyMet40Female proband with onset of chronic diarrhoea, reduced appetite and early satiety at age 40 years. Over the following twenty years, she lost a significant amount of weight requiring parenteral feeding, developed urinary incontinence and significant orthostatic hypotension, without cognitive impairment. The age of onset was also 40 years in her brother, with a similar clinical picture. Examination of the proband at age 61 revealed claw-feet, reduced deep tendon reflexes in the lower limbs, bilateral ptosis and mild strabismus. An axonal neuropathy was not found but a sensorimotor axonal neuropathy was found in her brother. Cognitive testing of the proband was globally normal and MR brain imaging was unremarkable. Two mutations were found in this family. A c.507C>A variant determining a p.Y169X nonsense mutation with an in cis missense c.508A>G variant resulting in the redundant p.S170G change.Capellari S 2018 (15)
Gln186X
(c.556C>T)
1USADementia. No further clinical data are available.
Minikel 2016 (4) and 2020 (17)
Asp178Glufs25X resulting in a stop codon at position 1951JapanMet26Patient began to have urinary retention of up to 2L aged 26 years. At age 30, she developed significant orthostatic hypotension. Aged 31, she began to display memory disturbances and following this, she suffered with frequent vomiting and diarrhoea. Her mother developed dementia, urinary disturbance and orthostatic hypotension with frequent syncopal episodes at the age of 47 and died without diagnosis aged 48 years. The maternal grandfather of the index patient was said to have developed dementia with urinary incontinence and orthostatic hypotension at the age of 52 and died aged 62 years. Examination of the index patient reveals her to be of very low BMI with atrophic muscles in the distal limbs. She had severely reduced pain and temperature sensation distally and was areflexic. She had severe orthostatic hypotension. Cognitive testing showed mild decline. CSF analysis revealed elevated total protein, neuron-specific enolase, 14-3-3- and tau protein levels. Sural nerve biopsy showed moderate loss of myelinated fibres but did not reveal amyloid deposits. Genetic analysis confirms a two-base-pair (CT) deletion in codon 178 that causes a de novo 25 amino acid stretch 3’ from the mutation site consequently leading to a premature stop codon at position 195.
Matsuzono K 2013 (16)
Tyr226X
(c.678C>A)
1NetherlandsVal545755-year-old lady referred to neurology with worsening cognitive function, forgetfulness and decreased concentration over the previous year. She presented with aphasia, was disorientated and showed impaired memory and visuospatial functioning. There were no pyramidal or extra-pyramidal signs, myoclonic jerks or cerebellar symptoms. Following her admission, she did however, develop brisk reflexes and apraxia. Towards the end of the course of disease, she became akinetic and mute with myoclonic jerks. She died age 57 years, 27 months after onset of symptoms. She was investigated at presentation; MR brain imaging showed hyperintensity of the white matter, CSF analysis was positive for protein 14-3-3 and EEG showed generalised slowing with periodic synchronous wave complexes. The wild-type allele encoded Met at position 129. Post-mortem neuropathological examination reveals a grossly unremarkable brain of weight 1300 g. Microscopic analysis shows diffuse and severe PrP amyloid angiopathy, without neurofibrillary tangles.  Of note, the patient’s mother had been diagnosed with ‘probable CJD’ on the basis of comparable symptoms and signs – she died aged 75, 18 months after onset of her symptoms.Jansen C 2010 (9)
Gln227X
(c.679C>T)
Val404542-year-old lady referred to neurology for evaluation of a slowly progressive hypokinetic rigid syndrome with cognitive decline. For the previous 2.5 years she had experienced difficulties with word-finding and memory, as well as personality change. Examination revealed mask-like facies, dysarthria and variably increased tone in all limbs, with cogwheeling. Reflexes were normal and eye movements intact. There were no pyramidal or cerebellar signs. CT head showed moderate atrophy of the left frontal lobe and less severe atrophy of the left temporal lobe. SPECT scanning showed hypoperfusion in the left frontal and temporal cortex extending into the parietal cortex. She was clinically diagnosed with frontotemporal dementia. She deteriorated over the next three years, developing tremors in her right hand and foot, epileptic seizures and became completely dependent on care. In her last two years of life she became mute with increased seizure frequency. She died age 45 years, 72 months after clinical onset. Of note, a paternal aunt had died age 42 years with comparable symptoms. The patient’s wild-type allele encodes Met at position 129. Post-mortem investigation revealed a brain weighing 990 g with atrophy of the frontal lobe and caudate nucleus, with marked ventricular dilation. Microscopic examination revealed numerous multicentric amyloid plaques and high burden of neurofibrillary tangles in the cerebral grey matter, in which the cerebellum was spared. There was absence of amyloid angiopathy.  The substantia nigra was slightly pale with marked loss of pigmented neurons. Biochemical studies of brain homogenates demonstrated the presence of an PrPSc fragment of approximately 7 kDa weight, that is unglycosylated and truncated at both the N- and C- termini.  This case has been classified as an unusual GSS disease phenotype with numerous cerebral multicentric amyloid plaques and severe neurofibrillary lesions without PrP-CAA. 
Jansen C 2010 (9)
Leu234Profs7X1FinlandOver 90This mutation was found in a female patient enrolled in the Finnish twins Alzheimer disease cohort. Patient diagnosed with Alzheimer’s disease based on clinical examination only and died aged greater than 90 years old of pneumonia. Had a dizygotic twin whose genotype is not known. L234Pfs7X variant changes the C-terminal GPI signal of prion protein from SMVLFSSPPVILLISFLIFLIVGX to SMVPSPLHLX. This new sequence does not adhere to the known rules of GPI anchor attachment: GPI signals must contain a 5-10 polar residue spacer followed by 15-20 hydrophobic residues. Thus this mutant is predicted to produce an anchorless PrPC protein. 
Minikel EV 2020 (17)

References

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