Preprint Article Version 1 This version is not peer-reviewed

A Huntington’s Disease (HD) Phenocopy Leads to the Identification of the HD Toxin as Polyalanine. The Relationship Between Repeat Length and Age of Onset Can Be Reframed as a Rate Equation and the Toxic Polyalanine Length Is Found to Be about 30.6.

Version 1 : Received: 30 May 2019 / Approved: 31 May 2019 / Online: 31 May 2019 (10:21:28 CEST)
Version 2 : Received: 7 August 2019 / Approved: 8 August 2019 / Online: 8 August 2019 (13:11:08 CEST)

How to cite: Tarnow, E. A Huntington’s Disease (HD) Phenocopy Leads to the Identification of the HD Toxin as Polyalanine. The Relationship Between Repeat Length and Age of Onset Can Be Reframed as a Rate Equation and the Toxic Polyalanine Length Is Found to Be about 30.6.. Preprints 2019, 2019050383 (doi: 10.20944/preprints201905.0383.v1). Tarnow, E. A Huntington’s Disease (HD) Phenocopy Leads to the Identification of the HD Toxin as Polyalanine. The Relationship Between Repeat Length and Age of Onset Can Be Reframed as a Rate Equation and the Toxic Polyalanine Length Is Found to Be about 30.6.. Preprints 2019, 2019050383 (doi: 10.20944/preprints201905.0383.v1).

Abstract

Huntington’s disease (HD) is one of the most well defined “repeat diseases”, associated with a short repeated genetic sequence, CAG.First, taking into account that a phenocopy of HD has a different repeat that is associated with a different gene, I suggest that the gene is not important for HD, only the repeat sequence is important, in agreement with Lee et al (2019) who reached the same conclusion using a GWAS technique.Second, taking into account that a phenocopy of HD has a CTG repeat rather than a CAG repeat, and that the toxin should be the same for both disease types and that the third base in a codon is the least important, I suggest that the reading frame is shifted for the repeat expansions and that the A/T substitution takes place on the third base. The most likely sense and antisense reading frames are then (GCA)n and (GCT)n and (GCT)n and (GCA)n and the corresponding amino acid is polyalanine.Third, the more repeats, the earlier the HD onset (Brinkman et al, 1997; Wexler, 2004). I suggest that this relationship can be thought of as a rate equation. If the concentration is proportional to the probability of creating a polyalanine of length m in a repeat expansion of length n, the corresponding equation is borne out by the data on age of onset and repeat length and m is found to be about 30.6. This explains for the first time, at least approximately, why HD is not active unless there are at least 36 CAG repeats.If true, HD may be the first disease where frameshifting is the cause of the disease.

Subject Areas

Huntington’s disease, CAG, kinetics, repeat expansions

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our diversity statement.

Leave a public comment
Send a private comment to the author(s)
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.