Prions linked to mental illness
N171S reported earlier in normal patient
N171S -- commentary
Fourth Annual Blood Safety & Screening Meeting
Sicilian goats with scrapie
Nature (1997;390:241) Wednesday November 19, 1997 press releas By Theresa Tamkins (Reuters) 20 Nov Nature 390: 241 1997 (Scientific Correspondence) H B Samaia, J de J Mari, H P Vallada, R P Moura, A J G Simpson & R R BrentaniNEW YORK -- Some families with a history of psychiatric disease may actually have a genetic mutation in the prion protein, the infectious agent linked to fatal neurological disorders such as "mad cow disease" in cattle and Creutzfeldt-Jakob disease (CJD) in humans.
Earlier this year, researchers reported that schizophrenia-like hallucinations and paranoid delusions were often the earliest symptoms of the new type of CJD found in the U.K. and France. At least 20 young adults in Europe have developed the fatal disorder, presumably as a result of eating beef infected with "mad cow disease," or bovine spongiform encephalopathy.
Those diseases are thought to be caused by prions, proteins found in every cell of the body. In some cases prions are thought to take on an abnormal shape and convert normal prions to the mutant form, building up in the brain and damaging tissue.
In the new report, a patient with a family history of psychiatric problems was found to have a previously undiscovered genetic variation in the prion protein gene (PRNP), called N171S, according to a letter in Nature.
"The patient suffered persecutory delusions, auditory hallucinations, severe depression, and had a history of suicide attempts and violent behavior over a 10-year period,"reported Dr. Ricardo Brentani of the Ludwig Institute for Cancer Research in Sao Paulo, Brazil. However, there was no sign of the staggering gait and dementia that developed in the CJD patients.
When the researchers tested family members, 5 of 11 relatives of the patient also carried the prion mutation. One was the patient's mother who suffered from similar psychiatric problems, as well as an uncle who had social withdrawal, mutism, occasional violence, and dementia later in life. Two siblings suffered alternating periods of severe depression and aggressiveness, while one sibling had no symptoms at all.
"None of these patients can be easily classified within well-defined clinical categories and all responded poorly to conventional therapies," the researchers reported.Nine other patients with family histories of schizophrenia were not found to have the N171S version of the PRNP gene. The study could not determine if the genetic variation was related in any way to the psychiatric disturbances. And more research is needed to determine how common the N171S variation is in the population.
"An analysis of a large number of affected families and individuals known to be free of any mental disorders will establish the frequency of the new PRNP genotype and the strength of its association with mental disease," concluded the researchers.Other inherited disorders are known to be caused by prions, for example Gerstmann-Strassler syndrome, characterized by mental deterioration, and fatal familial insomnia (FFI). FFI is a rare disease, occurring in an estimated 10 families in the world. The disease usually strikes after age 30 with the loss of the ability to sleep, brain degeneration, and death within 6 to 18 months.
Hum Mutat 1994;4(1):42-50 Fink JK, Peacock ML, Warren JT Jr, Roses AD, Prusiner SB[This paper is said to have detected N171S in a normal control. No indication that this person was further tracked or examined for schizophrenia. Offline. -- webmaster] Mutations of the prion protein (PrP) gene are present in patients with Gerstmann-Straussler-Scheinker syndrome (GSS), familial Creutzfeldt-Jakob disease (CJD), and fatal familial insomnia (FFI). We developed a denaturing gradient gel electrophoresis (DGGE) strategy that readily identifies point mutations in the PrP coding sequence. By comparison with appropriate controls, haplotypes often may be deduced. This method permits samples from many patients with GSS, CJD, as well as patients with unusual degenerative neurologic disorders, to be screened rapidly, sensitively, and inexpensively for the presence of known and novel PrP mutations. We illustrate the sensitivity of this approach by reporting 2 novel polymorphisms in the PrP coding sequence.
Webmaster commentary of 23 November 1997:The proposed new psychiatric allele of the prion protein in this week's Nature raises some interesting issues.
-1. There is the question of whether N171S is a mutation or neutral polymorphism. Serine at codon 171 is already found in the great apes, most notably in chimpanzee and pygmy chimpanzee, there was once a gorilla with this allele (E71FBD 6ACRC32) and serine seems to be ancestral in this lineage, as well as ancestral to placental mammals (marsupial and birds have serine).
-2. Asparagine to serine is a very conservative change, both are polar and similar in size. There are several codons in prion protein where these seem plesiomorphic, most notably codon 170. The side chain of codon 171 is fully exposed to solvent in both nmr structures, as is appropriate for N or S, and does not interact with any other amino acid nor contribute to monomer structure. It is on an exterior loop connecting beta 2 to helix C. See the relevent interactive neighborhood or a flat image for overall 3D context relative to other prion mutations and secondary structure.
-3. There is just one family so far. As the authors note, a larger set of schizophrenics needs to be sequenced; if 10% of the families continue to have this change, that would be remarkable since schizophrenics have often been in CJD control groups. No one keeps track of how many control genes have been reliably sequenced in humans in the 171 region so it is not so easy to put an upper bound on allele frequencies, other than this has not been reported before. It is not clear whether any autopsies have been done, whether this is a very slow form of CJD (35+ years from onset) or does not involve rogue conformer but rather loss of normal function.
+1. N171S occurs in an undescribed exposed "amide patch" of 5/7, sometimes 6/7, residues that are hydrogen bond donors and acceptors. Humans, unlike the other great apes, have previously experienced Q168E glutamic acid formation nearby [Q171R codon of sheep] , so perhaps N171S too pushes the prion "over the edge" in this context but not in chimps or gibbons. While not of significance for prion monomer, this patch could be involved in interactions with other subunits or other proteins, etc.
Prusiner's group has known about N171S for quite some time. It is shown, seemingly erroneously, in their October Science 278: 245 1997 article as a neutral mutation and in their October PNAS 94: 10069 1997 article, submitted on July 21, they again show this unpublished allele in Table 2. Nature gives no submission date for the Brazilian N171S correspondence. (I asked the listserve about N171S on October 10 but no one volunteered any information.)
+2. The good news is they have already engineered N171S and studied its effect as part of the "protein x" gobbledygook. It had none, rather like the neutral allele E219K. More good news: they looked at Q168E, the idiosyncratic human change, it had a "type 1" effect. The definitions of "types 1-3" are intricately entwined with speculative models by no means reliably implied by the data; notation is explained in various papers dating back to 1992.
The operational definition of "type 1" is loss of interference between co-expressed mouse-human hybrids (C-terminally human, wild type compared to allele). Type 1 hybrids are not efficiently converted into bad conformer and don't hinder conversion of normal mouse conformer into bad conformer, unlike controls.
They concluded, "The side chains of these residues protrude from the same surface of the C-terminal -helix and form a discontinuous epitope with residues 168 and 172 in an adjacent loop. Substitution of a basic residue at positions 168, 172, or 219 also prevented PrPSc formation: at a mechanistic level, these mutant PrPs appear to act as "dominant negatives..."
The bad news is that they didn't test the Q168E-N171S double construct which is unfortunately the whole issue for N171S.
+3. The Oesch 15B3 antibody that distinguishes normal and rogue conformer has its epitope 2 binding 162-170; this is not affected by in their dimer model, unlike 15B3-1 and 15B3-3. They used numbering for their bovine sequence, so YYRPVDQYS, or just one residue short. This does not say that 171 is inaccessible or involved in a subunit interface, only that it was not particularly involved in making up the antigen that gave rise to 15B3.
In summary, N171S had incomplete penetrance and variable expression in the family pedigree and is on the fringe of an area important for the conversion to bad conformer. Nevertheless, it appears fairly harmless from the monomer structural and phylogenetic perspectives, though perhaps not in conjunction with Q168E. The difference in sheet forming propensities would be slight though subtle effects are possible. There is nothing evident here that would interfere with post-translational modification, export, maturation, or stability. The affected individuals were heterozygous for codon 129 and at 171, with the valine and serine mutations on the same allele, usually a weak condition for CJD onset, though early onset and long duration are observed.
No neuropathology data was released supporting the "psychiatric-only" model, only living relatives are discussed; original patient 10 years since onset, mother 35 years, uncle 7 years, siblings unmentioned point of onset. There is no smoking gun here for either slow-CJD or loss of normal function without rogue conformer formation; it could impact some feature of the prion protein that we simply are not aware of.
James W. Larkin February 23-25, 1998 Ritz-Carlton, McLean, VirginiaSCIENTIFIC ADVISORS
Dr. Prabir Bhattacharya, Alpha Therapeutics Dr.William N. Drohan, American Red Cross Dr. Bernard Horowitz, VITEX Dr.Thomas J. Lynch, Food and Drug Administration Dr. Stephen R. Petteway, Jr., Bayer Corporation
Prions? An Alternative Viewpoint Dr. Laura Manuelidis,Yale School of Medicine (invited)
Minimizing the Risk of Transmission to TSEs by Biologicals
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Donor Pool Size and Risk of Infection Dr. Paul Brown,National Institutes of Health
Titer, Distribution, and Transfusability of Blood-Borne TSE Infectivity in Animal Models Dr. Robert G. Rohwer,Veterans Affairs Medical Center
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Scrapie Removal Study Using PLANOVA Filtration System Dr. Sakae Satoh, Asahi Chemical Industry .....
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Maria Teresa Capucchio 20 Nov 97We confirmed many cases of scrapie in three herds of goats in Sicilia.
Questions: Were these goat herds in contact at any time with flocks of sheep? How the cases were confirmed?