IDO gene - metabolic trap question

[ebethc]

what are the four mutations on the IDO2 gene that Dr Phair is referring to?

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https://www.mdpi.com/2075-4418/9/3/82
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating noncommunicable disease brandishing an enormous worldwide disease burden with some evidence of inherited genetic risk. Absence of measurable changes in patients’ standard blood work has necessitated ad hoc symptom-driven therapies and a dearth of mechanistic hypotheses regarding its etiology and possible cure. A new hypothesis, the indolamine-2,3-dioxygenase (IDO) metabolic trap, was developed and formulated as a mathematical model. The historical occurrence of ME/CFS outbreaks is a singular feature of the disease and implies that any predisposing genetic mutation must be common. A database search for common damaging mutations in human enzymes produces 208 hits, including IDO2 with four such mutations. Non-functional IDO2, combined with well-established substrate inhibition of IDO1 and kinetic asymmetry of the large neutral amino acid transporter, LAT1, yielded a mathematical model of tryptophan metabolism that displays both physiological and pathological steady-states. Escape from the pathological one requires an exogenous perturbation. This model also identifies a critical point in cytosolic tryptophan abundance beyond which descent into the pathological steady-state is inevitable. If, however, means can be discovered to return cytosolic tryptophan below the critical point, return to the normal physiological steady-state is assured. Testing this hypothesis for any cell type requires only labelled tryptophan, a means to measure cytosolic tryptophan and kynurenine, and the standard tools of tracer kinetics. View Full-Text

 

[JES]

Probably these (source):

 

[ebethc]

thanks @JES

is the Ref or the Alt the bad allele? I think the Alt, but need confirmation... thx

 

[ebethc]

@JES
thanks for linking to Paolo's work... I understood a lot of it, but didn't get this key part (see below)... Do you understand what it means? Specifically, what is "penetrance"? does it mean that you have high tryptophan BUT it is not getting into your cells (ie, penetrating) and that's when you get CFS?

"..but how can a genetic predisposition so prevalent lead to the disease in only a small subgroup of those who carry it? The answer to that question is in figures 4 and 5: you need a very high level of tryptophan to fall into the trap, and it has to last for two months. This probably happens in rare circumstances and thus this very prevalent genetic predisposition has low penetrance: the chance that it will lead to full-blown ME/CFS is low."

 

[Snow Leopard]

Specifically, what is "penetrance"? does it mean that you have high tryptophan BUT it is not getting into your cells (ie, penetrating) and that's when you get CFS?

No.

He's just saying the SNP(s) alone are poor predictors of whether someone will later develop the illness.

 

[JES]

Yeah penetrance is just a term used to indicate that if you for example have a mutation that can lead to a genetic disorder, but most of the time it does not cause a disorder even in people who have the mutation, then its penetrance is said to be low.

I think Alt. is the bad allele, but I would be cautious about the probabilities given in that table. It has turned out that 90% of the entire population has at least one damaging SNP in IDO2, whereas 100% of ME/CFS has one. So you are likely to have one regardless.