The tissue selectivity of MEN1 syndrome is not in MEN1: menin is expressed evenly everywhere and MLL, p27 and p18 are the endocrine-predominant ones
also called why MEN1 tumours are endocrine · MLL haploinsufficiency not menin haploinsufficiency
People who inherit one broken copy of MEN1 get tumours in hormone glands and nowhere else, which is strange for a gene that is switched on everywhere. One study measured all the parts of the machine and found the gene itself is level across organs, while its partner and the two brake genes it controls are concentrated in the hormone glands.
The same thing, for a scientist
Taguchi et al. measured Men1, MLL, p27 and p18 mRNA across endocrine and non-endocrine mouse organs in wild-type, Men1-knockout and MLL-knockout animals. Men1 mRNA was expressed at a similar level in endocrine and non-endocrine organs, while MLL, p27 and p18 mRNAs were predominantly expressed in endocrine organs - p27 about 12-fold and MLL about 17-fold higher in pituitary than in liver. In Men1 heterozygotes, MLL, p27 and p18 levels did not differ from wild type; in MLL heterozygotes, p27 fell significantly in pituitary and p27 and p18 fell in pancreatic islets, but not in liver [E1]. The tissue selectivity of MEN1 syndrome therefore sits in the downstream module and in MLL dosage, not in menin abundance. This reframes gene-men1's endocrine-paradox section: the paradox is not 'why is a ubiquitous protein a tissue-specific tumour suppressor', it is 'why is the module it serves concentrated where it is'.
The measurement
Across endocrine and non-endocrine organs of wild-type, Men1-knockout and MLL-knockout mice 1:
- Men1 mRNA: similar level in endocrine and non-endocrine organs.
- MLL, p27 and p18 mRNA: predominantly endocrine. Pituitary p27 approximately 12-fold and MLL approximately 17-fold higher than liver.
- Men1+/- heterozygotes: no change in MLL, p27 or p18.
- MLL+/- heterozygotes: significant reduction in p27 mRNA and protein in pituitary, and in p27 and p18 in pancreatic islets - but not in liver.
The last two lines are the load-bearing pair: a tissue-specific haploinsufficiency of MLL, not of menin.
What it changes in this graph
gene-men1 frames the endocrine paradox around menin having two jobs, and notes that 'menin is not even parathyroid-enriched, sitting at about 6.8 nTPM in parathyroid, its joint-lowest tissue'. That observation is correct and this result extends it: nothing about menin's own abundance explains the tissue pattern, and the explanatory variable that does vary is the partner enzyme and the two target genes.
Two consequences follow that the entry does not currently draw.
- A drug that blocks the menin-MLL interface acts on a module whose downstream output is concentrated in endocrine tissue. Low menin expression in parathyroid is therefore weaker reassurance than it reads, because the relevant quantity is the dose-sensitivity of the module, and that is high exactly where the syndrome strikes.
- The observation that MLL heterozygosity - not Men1 heterozygosity - lowers p27 and p18 in endocrine organs predicts that the tissues most at risk from partial menin-MLL disruption are the ones where the module already runs near a dosage threshold.
Why this is offered as a reframing and not as a correction
This is one 2011 paper in BBRC, mouse mRNA measurement, and it does not contradict anything in gene-men1. It contradicts an unstated assumption - that tissue selectivity must be explained by something about menin. The claim added to gene-men1 this cycle is phrased as a tension, not an overwrite, per the standing rule that a silent overwrite is worse than a stated contradiction.
| claim | the tissue selectivity of MEN1 syndrome tracks the partner and the targets, not menin abundance |
|---|---|
| tension with existing entry | gene-men1 argues the endocrine risk is manageable partly because menin is not parathyroid-enriched. That premise is confirmed here and its force is reduced: menin is not enriched ANYWHERE, so non-enrichment in parathyroid carries no information about parathyroid risk. |
| what is missing | parathyroid. The mouse survey names pituitary, islets, liver, adrenal and testis in its MeSH terms; whether parathyroid was measured cannot be determined from the abstract, and parathyroid is the tissue with the clinical signal on the revumenib label. |
mouse mrna
{
"Men1": "similar in endocrine and non-endocrine organs",
"MLL": "endocrine-predominant; pituitary approx 17x liver",
"p27_CDKN1B": "endocrine-predominant; pituitary approx 12x liver",
"p18_CDKN2C": "endocrine-predominant"
}haploinsufficiency
{
"Men1_het": "no change in MLL, p27 or p18",
"MLL_het": "p27 down in pituitary (mRNA and protein); p27 and p18 down in pancreatic islets; no change in liver"
}human expression
{
"MEN1_rna_tissue_specificity": "Low tissue specificity / Detected in all",
"MEN1_single_cell": "Cell type enhanced - Megakaryocytes 37.1 nCPM",
"MEN1_blood_cell_specificity": "Low immune cell specificity",
"MEN1_antibody_tissue_call": "Group enriched; bone marrow 2469913.2, lung 2406370.8, lymphoid tissue 1197862.7 arbitrary units; ONE antibody HPA030342; IH reliability Uncertain",
"source": "https://www.proteinatlas.org/ENSG00000133895.json fetched 2026-09-23"
}- If the endocrine risk of menin inhibition is set by the dosage sensitivity of the MLL-p27-p18 module rather than by menin levels, then menin's low expression in parathyroid is not protective and the reassurance currently drawn from it should be withdrawn.
- MLL haploinsufficiency lowering p27 in pituitary means a partial pharmacological disruption of the menin-MLL interface could behave like MLL heterozygosity in endocrine tissue, which is the genotype the mouse data show is sufficient to move the targets.
- Was parathyroid in the panel? If MLL, p27 and p18 are endocrine-predominant but parathyroid was never measured, the tissue with the actual clinical signal is missing from the only study that addresses tissue selectivity directly.
- Does the human module show the same endocrine predominance? The measurement is mouse mRNA. GTEx and HPA consensus data could answer this for KMT2A, CDKN1B and CDKN2C in an afternoon and nobody in this corpus has looked.
- Is MEN1 really megakaryocyte-enhanced at the single-cell level, and does that mean anything? It is the only cell-type-resolved human statement about this gene and it has no functional follow-up anywhere.
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Men1 mRNA was expressed at a similar level in endocrine and non-endocrine mouse organs, whereas MLL, p27 and p18 mRNAs were predominantly expressed in endocrine organs, with p27 and MLL mRNAs in the pituitary approximately 12-fold and 17-fold higher than in liver; in Men1 knockout heterozygotes MLL, p27 and p18 mRNA levels did not differ from wild type, while MLL knockout heterozygotes showed significant reductions in p27 mRNA and protein in pituitary and in p27 and p18 in pancreatic islets but not in liver.
Haploinsufficient and predominant expression of multiple endocrine neoplasia type 1 (MEN1)-related genes, MLL, p27Kip1 and p18Ink4C in endocrine organs. · Taguchi R, Yamada M, Horiguchi K, Tomaru T, Ozawa A, Shibusawa N, Hashimoto K, Okada S, Satoh T, Mori M · Biochem Biophys Res Commun 2011What this evidence cannot show
Mouse, mRNA by RT-PCR with protein shown only for pituitary p27; single paper, no replication identified; abstract read, full text not opened, so n per group, normalisation and whether parathyroid was included at all are NOT recorded here - and parathyroid is the tissue the clinical signal is in. The 12-fold and 17-fold values are ratios against liver, which is an arbitrary reference. Confidence moderate for those reasons. NOT CITED anywhere in this corpus before 2026-09-23.
Evidence that argues against this (1)
- mRNA level is not the same as dosage sensitivity, and this study measures transcript almost throughout. Menin protein could be limiting in a tissue where its transcript is average - and the human data show menin is at its joint-lowest in parathyroid, which is the tissue with the clinical signal. A uniform transcript does not establish a uniform protein or a uniform requirement. Human Protein Atlas consortium 2026
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database
For MEN1 (ENSG00000133895) the Human Protein Atlas records RNA tissue specificity 'Low tissue specificity' with distribution 'Detected in all', blood cell specificity 'Low immune cell specificity' and blood lineage specificity 'Low lineage specificity', while single-cell RNA is 'Cell type enhanced' with megakaryocytes at 37.1 nCPM, and the antibody-based tissue call is 'Group enriched' with bone marrow, lung and lymphoid tissue as the top tissues on a single antibody (HPA030342) whose IH reliability is 'Uncertain'.
Human Protein Atlas - MEN1 (ENSG00000133895), machine-readable gene record · Human Protein Atlas consortium · proteinatlas.org 2026What this evidence cannot show
Fetched 2026-09-23; HPA release version is not returned by this endpoint and is therefore not recorded, so the numbers can drift silently. The protein-level call rests on ONE antibody with IH reliability explicitly 'Uncertain', which is weaker than KMT2A's three-antibody 'Enhanced' record, and no tissue conclusion should be drawn from it. The megakaryocyte enhancement is a single-cell consensus call and has no functional support anywhere in this corpus; it is recorded because it is the only cell-type-resolved statement HPA makes about this gene, not because it is known to mean anything.
Evidence that argues against this (1)
- The single-antibody, IH-reliability-'Uncertain' protein call here should be read against a gene where HPA's antibody data are stronger: for KMT2A three antibodies with 'Enhanced' reliability still produce two mutually discordant calls, bone marrow and hepatocytes. That is a reason to distrust HPA protein-level tissue calls as a class, including the ones in this evidence item. Human Protein Atlas consortium 2026
menin mRNA is uniform across organs; MLL, p27 and p18 are endocrine-predominant (PMID 22037578)
- related to →KMT2A / MLL1 — the gene that breaks
MLL, not menin, is the tissue-variable element of the module
HPA single-cell: MEN1 is cell-type enhanced in megakaryocytes at 37.1 nCPM; recorded, unexplained
the module whose tissue distribution is being measured