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Prion Protein Mutation Database


Allele count in gnomAD control population: Pro105Leu 0; Pro105Ser 1; Pro105Thr 0

Cases in literature: Pro105Leu 25; Pro105Ser 2; Pro105Thr 7

Penetrance: High

Clinical presentation:

Mutants Pro105Leu/Ser/Thr cause Gerstmann-Straussler-Sheinker disease.

Twenty-five cases of mutation Pro105Leu are reported in the literature. Twenty-three of these are from nine Japanese families, of which two are pre-symptomatic and twenty-one have the manifest GSS-105 phenotype. One case is a British patient and one a de novo American case (see Table of Cases below). All Pro105Leu cases had the mutation in cis with valine at codon 129. The Val polymorphism is relatively uncommon in the normal Japanese population; 91.6% methionine homozygosity, 8.4% heterozygotes and 0% valine homozygosity, with allele frequencies of Met:Val 0.958:0.042 1. In contrast, the normal UK population has a genotype frequency of 36.7% Met/Met129, 51% heterozygotes and 12.3% Val/Val129 and allele frequencies of Met:Val: 0.625:0.375 2,3.

There are two American cases of Pro105Ser, on a Val129 background, one of which was pre-symptomatic at the time of reporting. Seven cases of Pro105Thr are reported to date, of which three occur against a Met129 background, two against a Val129 background, and in two cases the genotype at codon 129 is Met/Val129 heterozygous but it is not known which is the in cis allele (see Table of Cases).

The predominant clinical features associated with the Pro105Leu mutant are protracted clinical duration and spastic paraparesis, in the absence of prominent ataxia, in addition to progressive dementia4. However, the clinical spectrum is widened by reports of ataxia without spasticity, extrapyramidal signs and involuntary movements4–7, and there is clinical variation even within the same family, as is true for other GSS-causing mutations8. Neuropathologically, mutant Pro105Leu results in the diffuse deposition of GSS-type plaques in the cerebrum with sparing of the cerebellum and there is absence of spongiform degeneration7,9.

The Pro105Ser phenotype (one symptomatic case to date) was suggestive of frontotemporal dementia with parkinsonism, and a histologic profile that includes an unusual distribution of GSS-type plaques with an intense focus of spongiform degeneration in the putamen10. This clinical picture differs from that seen in the Pro105Thr mutants, which is characterised by cerebellar ataxia and dementia that is rapidly progressive when on a Met129 11 allele and of slower progression when on a Val129 allele12. Unlike in mutant Pro105Leu, spongiform degeneration is evident in the brains of patients harbouring the Pro105Ser10 and Pro105Thr mutants12.

Comparison of mutants Pro105Leu, Pro105Ser and Pro105Thr

Substitution at position 105Codon sequenceIn cis residue 129Number of casesClinical phenotypePathologic phenotypePrPSc Western blot
ProlineCCAMethionine or ValineNormalNone
LeucineCTAValine25Spastic paraparesis and dementiaMixture of multicentric and punctate PrP plaques spread diffusely throughout the cerebrum, with sparing of the cerebellum. No spongiform degeneration.6-7 kDa unglycosylated
SerineTCAValine2FTD-like with parkinsonismMulticentric PrP plaques in hippocampus, punctate plaques in cerebellum and intense spongiform degeneration in basal ganglia.21 kDa unglycosylted and 26 kDa monoglycosylated. No low molecular weight bands.
ThreonineACAMethionine or Valine7On a Met129 background – rapidly progressive syndrome with ataxia, dementia and some psychiatric features. On a Val129 background, a slower progressing syndrome of cerebellar ataxia and dementia.No neuropathology for Met in cis case. Where the mutant is on the valine 129 allele there was spongiform encephalopathy with dense synaptic PrP deposition in the cerebral cortex and unicentric PrP plaques in deeper cortical layers6 kDa unglycosylated PK-resistant fragment and partially glycosylated bands at 15 kDa and 25 kDa (Valine 129 background)

We have reviewed all symptomatic and pre-symptomatic Pro105Leu/Ser/Thr cases reported in the literature from the first report in 1993 to date (shaded reports are excluded from analyses for lack of individual level data). We find a total of 34 cases with a substitution of proline at position 105; 25 of which are Pro105Leu (24 Met/Val129 with Val129 in cis and one Val/Val129), 2 Pro105Ser-Val129 (both Met/Val129) and 7 Pro105Thr mutants (five Met/Val129 of which 3 are confirmed as Met in cis and two are Val/Val129 homozygous). The average age of onset for Pro105Leu-Val129 cases (n = 22) is 43.4 years (range 9 to 53 years, SD 9.1) and mean clinical duration-to-death (n = 9) is 111 months (range 27 to 228 months, SD 59.7). The single symptomatic Pro105Ser patient had an age of onset of 30 years with clinical duration-to-death of 120 months. Of the six symptomatic Pro105Thr cases, the mean age of onset is 33 years (range 13 to 45 years, SD 11.0) with mean duration-to-death (n = 3) of 48 months (range 36 to 72 months, SD 20.8).

The table below shows a summary of age of onset and clinical duration-to-death data, with survival analysis (Kaplan-Meier curves). Download Kaplan-Meier tables here.

Mutation Without censored data Survival curve including censored data
Mean+/-SD (years) n Median IQR Range n
Pro105Leu 43.4 +/- 9.1 22 45 41-48 9-53 22
Pro105Thr 33 +/- 11.0 6 35.5 30-39 13-45 6
Mutation Without censored data Survival curve including censored data
Mean+/-SD (years) n Median IQR Range n
Pro105Leu 111 +/- 59.7 9 144 96-144 27-228 22
Pro105Thr 48 +/- 20.8 3 71.5 36-72 36-72 5

Figure: Kaplan-Meier curves for Pro105Leu and Pro105Thr age of onset and clinical duration-to-death. The Kaplan-Meier curve is shown as a solid line and the 95% confidence limits are shown as dotted lines. In clinical duration graphs b) and d) censored data is shown as open circles.

a) Pro105Leu-Val129 Age of Onset
(all codon 129 haplotypes)

b) Pro105Leu-Val129 Clinical Duration to Death
(all codon 129 haplotypes)

c) Pro105Thr Age of Onset
(all codon 129 haplotypes)

d) Pro105Thr Clinical Duration to Death
(all codon 129 haplotypes)

Table of cases: In the column of DNA-confirmed cases, the number in brackets represents the total number of cases contained within the report. They may not have all be counted due to cases being reported in a previous publication, the details of which will be given in the table. F, female; M, male. Shaded reports are excluded from total counts for each mutant and further analyses due to lack of individual level data.

Mutation Case report Country of origin Number of DNA-confirmed Pro105 mutant patients Details of kindred and family members studied Gender Age at onset Duration of illness (months) Genotype at polymorphic sites Presentation and other clinical details
Pro105Leu Kitamoto T 1993 [9, 13] Japan 5 Five patients from three families studied – counted here.

Patient 1 and 2 are sisters and clinicopathological findings are reported by Nakazato Y 1991 (Patient 1) and Isshiki T 1994 (Patient 2).

Patient 3 previously reported by Terao Y 1992.

Patients 4 and 5 are sister and brother clinicopathological findings reported by Amano A 1992 (patient 4) and Kubo M 1995 (patient 5)

3 F
2 M
38-48 84-144
(One patients alive at > 60 months)
5 Met/Val (with valine in cis) All presented with spastic gait disturbance. Most prominent clinical findings were bilateral pyramidal tract signs and hyperreflexia. None showed cerebellar signs.
Neuropathological findings in patients 1, 2 and 4 showed many PrP-positive amyloid plaques in cerebrum with a few in cerebellum. Patient 2 had a few NFTs.
Pro105Leu Yamada M 1993 [14] Japan 3 No other family member has similar disease. His mother died aged 78 with gastric cancer and had dementia, but no motor symptoms. Father died of heart disease aged 60. Sisters displayed no neurological symptoms. The Pro105Leu mutation was detected in his two sons, both in their 20s and asymptomatic at time of report. His unaffected younger sister was negative for mutation. M 42 132 3 Met/Val (with valine in cis)
3 Glu/Glu219
One the unaffected sons also has a 24 base-pair deletion between aa 56 and 76 on non-mutant allele. This was also found in his mother.
Progressive spastic paraparesis, ataxia and dementia.
Pro105Leu Itoh Y 1994 [15] Japan (1) This report details the neuropathological findings of the patient described in Yamada M 1993, and is counted there. M 42 132 Numerous PrP-positive amyloid plaques throughout the cerebral cortex, but rare in the cerebellum.
Pro105Leu Yamada M 1999 [7] Japan 1 Further study of Japanese family initially described by Yamada M 1993. Patient 1 (II-2) corresponds to the index case in Yamada M 1993 and is counted there. Patient 2 (II-1) is a sister of patient 1 who is positive for the Pro105Leu mutation and is detailed here. Another younger sister, II-3, was deemed negative, and the two unaffected sons of II-2 (III-3 and III-4) were found to be positive by Yamada M 1993 and are counted there. F 50 96 Met/Val (with valine in cis)
Clinical course characterised by action myoclonus and dementia. Neuropathology reveals many PrP-positive plaques throughout cerebrum and rarely in cerebellum. In addition, there were many neurofibrillary tangles.
Pro105Leu Yamazaki M 1999 [16] Japan 2 Mother of index case had gait disturbance and died of a slowly progressing neurodegenerative disease aged 52. Her maternal uncle and aunt also died of similar a similar neurological disease. Her sister had gait disturbance and died aged 50, and her brother had gait disturbance and severe dementia. The brother was also found to harbour the Pro105Leu mutant on the Val129 allele however, age of onset not given. 1 F
1 M

(brother onset not given)


(brother alive aged 55 years at time of report)

2 Met/Val (with valine in cis)

2 Glu/Glu219

Index patient presented with gait apraxia, atypical parkinsonism and developed dementia, without spastic paraparesis. Brother presented with spastic weakness of lower limbs and developed severe dementia.

Co-localisation of PrP and A in same amyloid plaques noted on post-mortem in index case. (See also Furukawa F 2018 and Ishikawa K 2018)

Pro105Leu Shiraishi A 2002 [17] Japan 1 Another member of the family reported by Yamazaki M 1999. In this case, a second affected sister is described. F 50 228 Met/Val (valine in cis)


Presented with pains in various areas of the body – sensory and psychiatric symptoms persisted for three years before neurological manifestation of GSS. Then gait disturbance and cognitive deficits emerged. Extremely slow clinical progression – died aged 69 years.
Pro105Leu Iwasaki Y 2009 [6] Japan 1 Family from Aichi Prefecture. Father, three sisters and a brother showed similar neurological symptoms to index case. M 40 Alive (>132 months) Met/Val (with valine in cis) Presented with progressive gait disturbance, and later dysarthria and cognitive impairment ensued. Spastic paraparesis has not developed > 11 years from onset.
Pro105Leu Beck JA 2010 [18] UK 1 Index case was found to have to be compound heterozygous at PRNP: Pro105Leu and Val209Met in trans. Genotyping of her elderly parents revealed a maternal Val209Met (Met/Val129) variant only. First case of Pro105Leu reported outside of East Asia. F 33 Alive at time of report aged 43 years, 120 months from onset. Val/Val129 Clinical course was of rapid cognitive decline with psychiatric disturbance, incontinence, leg spasms and cerebellar dysfunction. Aged 43 she was severely unwell being bed bound with a gastrotomy and requiring 24-hour care.
Pro105Leu Nozaki I 2020 [19] Japan 5 Prospective 10-year surveillance of prion disease in Japan. Pro105Leu comprises 2.3% (5/216) of familial prion disease in Japan and is the 5th most common mutation 1 F
5 M
Mean 41.6 Mean 99.7 4 Met/Val (in cis allele not reported)

4 Glu/Glu219

Pro105Leu Higuma M 2013 [20] Japan 8 Japanese patients known to the national system for surveillance of prion diseases from April 1999 to August 2011. 2 F
6 M
Mean 44.3 Mean 111.2 7 Met/Val129 (with valine in cis)

7 Glu/Glu219

Pro105Leu Mano KK 2016 [4] Japan 9 Japanese families with Pro105Leu mutation, Nine members from three families were studied. Mean age of onset in affected members was 47.2 years. The three families shared a long common haplotype suggesting that they were descendants from a common ancestor 7 F
2 M


48 (case III-3 of family 2)

Remainder alive at time of report. On average they became wheelchair bound in 5 years and bed bound in 10 years

9 Met/Val129 (with valine in cis) Clinically presented with atypical Parkinsonism with progressive dementia. The tremor was a postural tremor rather than resting tremor.
Pro105Leu Takada LT 2017 [21] US 1 De novo Pro105Leu mutation in 9-year-old child, that was not found in his parents. No family history for prion disease or neurodegenerative disorders. M 9 Alive at time of report aged 12 years, 36 months from onset Not reported. Distinct clinical features of very early age of onset and early cognitive impairment. Aged 9, school performance began to decline. His handwriting changed aged 10. By age 11 he had seizures and gait ataxia, and by 12 years he was wheel-chair bound.
Pro105Leu Furukawa F 2018 [23] Japan (1) Further clinicopathological data on patient reported by Shiraishi A 2002. F 50 228 Met/Val129 (with valine in cis)


(apolipoprotein E e3/e3)

Neuropathological examination reveals PrP plaques co-localised with A42. (See also Yamazaki M 1999 and Ishikawa K 2018)
Pro105Leu Ishizawa K 2018 [8] Japan 1 (3) Report details new member of family originally confirmed in Kitamoto T 1993. Case 1 and 2 in this paper correspond to Patients 1 and 2 (sisters) in Kitamoto T 1993 and are counted there. This paper adds confirmation of the son of Case 2 (patient 2). The son is designated Case 3. M 47 27 Met/Val129 (with valine in cis) Presented with stereotyped behaviour and speech, then developed gait disturbance, myoclonus, restlessness and agitation. There were no signs of clinical paraparesis during clinical course.
Neuropathological examination undertaken in all three cases. PrP was seen to colocalise with A in the brain of case 2 (See Furukawa F 2018, Yamazaki M 1999)
Pro105Ser Tunnell E 2008 [10] US 2 Only case in the literature describing Pro105Ser mutant.

One parent (the authors have masked which this is) carried the Pro105Ser-Val129 allele and the other parent carried the 24-base pair deletion, which is a polymorphism not know to affect prion disease risk. It is of note, that neither parent was reported to have any symptoms, although no formal neurological or psychological testing was undertaken.


Unaffected parent gender masked


Unaffected parent aged 60

120 Met/Val129 (with valine in cis)
The non-mutant allele on the Met129 allele was found to have a 24-base pair deletion in the octapeptide repeat region.
Clinical presentation suggested FTD with Parkinsonism.
Neuropathological analysis reveals multicentric PrP plaques in hippocampus, punctate plaques in cerebellum and intense spongiform degeneration in the putamen.
Pro105Thr Rogaeva E 2006 [11] India 3 Family residing in Canada of East-Indian origin displayed autosomal dominant inheritance of a rapidly progressive neurodegenerative disorder. Three affected members were confirmed. Proband (case 6548), his mother (6549) and his maternal uncle (case 1940) 1 F
2 M
13 (6548)
39 (6549)
35 (1940)
6548 alive 48 months but doing very poorly

6549 alive but requiring full-time care 12 months from onset

1940 died 36 months from onset

6548 Met/Val (with Met in cis)

6549 Met/Met129

1940 Met/Met129

Phenotype in this family characterised by dementia and motor decline, including ataxia, that is rapidly progressive.
Proband (6548) phenotype was unique in its marked psychiatric disturbance at onset and preserved cognition.
Pro105Thr Communication between researchers [23] US 2 Family records unfortunately were lost and they were not fully characterised. Father of son and daughter is apparent founder. He died aged 42 with CJD, but genetic analysis not undertaken. Son developed sporadic CJD-like symptoms aged 30 and tested positive for P105T and was Met/Val129 although the in cis allele not known. An asymptomatic daughter also tested positive for P105T-M/V129 1 F
1 M
30 Not known 2 Met/Val (in cis allele not known) Sporadic CJD-like phenotype.
Pro105Thr Polymenidou M 2011 [12] Switzerland 2 Family from Switzerland. Index case presented aged 36 (III:4). His father (II:1) died aged 48 years after a five year history of progressive dementia with gait disorder. A brother (III:2) developed progressive memory problems aged 45. The proband and his brother were confirmed to carry the Pro105Thr-Val/Val129 mutation. Two sisters (III:1 and III:3) were asymptomatic and did not harbour the P105T mutant – they were Met/Val129 and Met/Met129, respectively 2 M 36 and 45 72 and 36 2 Val/Val129 Progressive cognitive deficit and cerebellar ataxia, leading to mutism.
Neuropathological examination undertaken in proband (III:4).

Neurological examination:

See Table of Cases above and individual reports.

Clinical investigations:

See Table of Cases above and individual reports.

Genetic analysis:


c.314C>T leading to CCA-to-CTA change at codon 105, resulting in Pro105Leu missense mutation. In 24 of 25 cases, where the codon 129 genotype was known, the Pro105Leu mutant occurred in cis with valine 129; of which 23 were Met/Val heterozygotes, one was Val/Val129 homozygote.


c.313C>T leading to CCA-to-TCA change at codon 105, resulting in Pro105Ser mutation. In the two reported cases, the patients have Met/Val129 heterozygote with Pro105Leu in cis with valine 129.


c.313C>A leading to CCA-to-ACA change at codon 105, resulting in Pro105Thr mutation. There are seven cases reported in the literature to date. Of these, the codon 129 residues are known in 5 patients: three were in cis with Met 129 (one Met/Val129 and two Met/Met129) and two patients were in cis with Val 129 on a Val/Val129 background.

Neuropathological studies:


There is no spongiform change seen in any region of the brain. Multicentric or unicentric PrP amyloid plaques are found throughout the cerebral cortex, with relative sparing of the cerebellum. Some patients were noted to have a considerable number of neurofibrillary tangles9. In addition, in some brains, amyloid- was seen to colocalise with PrPSc in the same plaque8,16,22. Such co-localisation of PrPSc and amyloid- has previously been described for other GSS-causing mutants, namely, Pro102Leu24 and Ala117Val25, as well as in familial CJD with Glu200Lys mutations26. Such co-localisation may suggest that the two proteins have biological or physiochemical interactions, indeed, there are compelling experimental models showing that PrP can bind amyloid- with high affinity27-28. Western blot analyses of Pro105Leu brain homogenate does not show major bands of high-molecular weight proteinase K-resistant PrP fragments but rather only a minor band at 6-7 kDa representing un-glycosylated PrPSc, which may be consistent with a lack of spongiform change in this mutant7,22.


In addition to spongiform encephalopathy, large multicentric amyloid plaques were present in the neocortex, hippocampus and cerebellum. Tau pathology was not observed. The PrPSc pattern from brain homogenate consisted of two fragments of 21 and 26 kDa, representing unglycosylated and monoglycosylated PrPSc isoforms, respectively10. This pattern of incomplete glycosylation (lacking the diglycosylated band) has not previously been reported for GSS-linked mutants10, but has been seen in CJD-associated Gly114Val (Cali I 2018) Thr183Ala29 and Val180Ile30 mutant-brain homogenate.


Neuropathological examination in patients with Pro105Thr on a Met129 background has not yet been undertaken. On a Val129 allele, the mutant brain showed spongiform encephalopathy with dense synaptic PrP deposition in the cerebral cortex and unicentric plaques in the deeper cortical layers. Western blot analysis of brain homogenates revealed a 6 kDa unglycosylated proteinase-K resistant fragment and two further partially glycosylated bands of 15 and 25 kDa12.

Structure-based protein function annotation:

Proline 105 lies in the second charge cluster, CC2 (aa 101-110), containing four positively charged lysine residues, and is evolutionary a perfectly conserved residue amongst mammalian species31-32.

There are five residues linked to GSS-causing mutations in the flexible N-terminus of human PrP: Pro84Ser, Pro102Leu, Pro105Leu/Ser/Thr, Gly114Val and Ala117Val. It is very likely that the proline mutants induce their pathogenic effects through a similar mechanism – namely, that which weakens the neuroprotective N-C PrPC domain arrangement (see detailed analysis in Pro84Ser and Pro102Leu mutation subpages)

In silico Pathogenicity predictions:

Pon-P2 (independent)33:

  Pro105Leu Pro105Ser Pro105Thr
Probability of pathogenicity 0.795 0.514 0.692
Standard error 0.104 0.079 0.075
Prediction Unknown Unknown Unknown

Revel (ensemble)34:

  Pro105Leu Pro105Ser Pro105Thr
Score 0.863 0.709 0.781
Prediction Pathogenic Non-pathogenic Pathogenic

A stringent REVEL score threshold of 0.75 is applied, above which the variant is classified as pathogenic.


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