MTRNR2L10 curation notes

Journal for the review of MTRNR2L10 (nuclear humanin-like locus). Written 2026-10-04.

MTRNR2L10 (P0CJ77, humanin-like 10, HN10) - locus-specific notes

• Chromosome X (DR Proteomes; UP000005640; Chromosome X.); PE2 (evidence at transcript level);
  24 aa MTTRGFSCLLLLIREIDLSAKRRI.
• Against humanin (MAPRGFSCLLLLTSEIDLPVKRRA) HN10 carries seven substitutions: Ala2->Thr,
  Pro3->Thr, Thr13->Ile, Ser14->Arg, Pro19->Ser, Val20->Ala and Ala24->Ile:

humanin MAPRGFSCLLLL TS EIDL PV KRRA HN10 MTTRGFSCLLLL IR EIDL SA KRRI ^^ ^^ ^^ ^

• This is the worst-case residue profile in the family, and it is the profile that drives the
  review. Read against humanin's mutagenesis map (UniProt Q8IVG9):
• Ser14->Arg is literally one of the humanin substitutions annotated as destructive:
  MUTAGEN 14 /note="S->A,R,W,E,P: Abolishes neuroprotective activity."
• Thr13->Ile is the one change in this family with a direct measurement: the polymorphic HN5
  variant carrying exactly Thr13->Ile has reduced cytoprotection
  PMID:19477263. Position 13 is also the residue Bodzioch et al. flagged for cell-surface
  receptor binding.
• Pro19->Ser and Val20->Ala together alter both residues of the second secretion determinant.
  Humanin needs Leu9-Leu11 and Pro19-Val20 for secretion
  PMID:35372353,
  and P->R and V->R each abolish secretion in humanin. Bodzioch et al. reached position 19 from
  the alignment as well PMID:19477263. HN10 is the only member of MTRNR2L1-10 that loses both Pro19 and Val20.
• Pro3->Thr is a third abolishing position (P->A: Abolishes neuroprotective activity).
• Retained: Ser7, Cys8, Leu9-Leu12 (it is one of the few that keep Leu12), Glu15-Leu18.
• So: the secretion claim is positively doubtful (both determinants of the Pro19-Val20 segment
  changed) and the activity claims rest on a sequence that carries one annotated-abolishing
  substitution (Ser14->Arg), one measured activity-reducing substitution (Thr13->Ile) and a third
  abolishing position (Pro3). This is the same situation as MTRNR2L7, which was handled as 2 REMOVE
  (extracellular) + 2 REMOVE (functional IBA) + 2 MARK_AS_OVER_ANNOTATED (cytoplasm), and I follow it.
• Literature naming this locus - two papers, both problematic:
• PMID:38630326 (Acta Neurol Belg 2024): microarray of peripheral blood in restless legs
  syndrome, with serum ELISA follow-up for "humanin-like 10" and "humanin-like 3". Two problems.
  First, circularity: the genes were picked out of the differential-expression list by the GO
  term that is itself the propagated IBA under review here
  PMID:38630326. Using a GO-term enrichment that exists only
  because of PANTHER propagation from humanin as evidence for that same propagation would be a
  closed loop, and the paper's framing of these loci as "neuroprotective genes" inherits the
  annotation rather than testing it. Second, assay specificity: HN10 matches humanin at 17 of 24
  positions and matches its sibling nuclear peptides more closely still; no humanin-like ELISA has
  been shown to discriminate among them, so a reduced "humanin-like 10" serum level
  PMID:38630326 cannot be attributed to this locus. Supports no GO annotation.
• PMID:42289503 (J Mol Neurosci 2026): rat status-epilepticus study of an
  "MTRNR2L1/MTRNR2L10 axis" with overexpression and knockdown
  PMID:42289503, prioritised from a GEO dataset
  because the genes were annotated to "regulation of signal transduction"
  PMID:42289503. The human MTRNR2L loci
  are nuclear copies of a mitochondrial rRNA segment; the abstract does not state how the
  corresponding rat sequences were identified, nor how construct specificity among near-identical
  MT-RNR2-derived sequences was established, and the human/rat locus correspondence for these
  pericentromeric insertions is not an obvious one-to-one mapping. Logged with
  correctness: LOW_QUALITY, relevance: LOW, and used for no annotation. (The same paper is
  logged the same way in the MTRNR2L1 review.)
• No peptide has been detected from this locus by mass spectrometry; no activity, binding partner or
  receptor interaction has been measured for HN10.
• Actions: 6 rows. 4 REMOVE (both GO:0005576 extracellular rows; both IBA functional rows),
  2 MARK_AS_OVER_ANNOTATED (both GO:0005737 cytoplasm rows). core_functions: []. No NEW terms: the
  participation test in CLAUDE.md cannot be met by a gene product that has not been shown to exist.

The family, and why these reviews look alike

Humanin is a 24-residue peptide encoded by a small open reading frame inside the mitochondrial 16S
rRNA gene MT-RNR2, and it is the member of this family with all the experimental evidence:
cytoprotection, BAX/BID/BIM binding, FPRL1/FPR2 engagement, the CNTFR-alpha/WSX-1/gp130 receptor
complex. Bodzioch et al. 2009 (PMID:19477263, verified - Genomics 94:247-256) found thirteen
MT-RNR2-like sequences in the nuclear genome whose reading frames would encode humanin-like peptides
HN1-HN13
PMID:19477263, and showed that at least ten are transcribed and respond to staurosporine and
beta-carotene PMID:19477263.

That paper is the single primary source behind every UniProt MTRNR2L entry, and its own title calls
the functionality potential. UniProt agrees, and says so in a CAUTION line on each entry: the
active peptide is the product of the mitochondrial gene, and whether any of the nuclear loci makes a
physiologically active peptide is open. HGNC classes these loci as pseudogenes ("MT-RNR2 like 10
(pseudogene)"). A 2022 review restates the position PMID:35372353.

What the GOA rows actually assert

MTRNR2L10 carries the same six rows as its siblings:

Tracing them:

• Both ISS rows name UniProtKB:Q8IVG9 = humanin as donor. Humanin's own extracellular and
  cytoplasm annotations are IDA/EXP, so the donor side is sound.
• Both IEA rows map UniProt's own SUBCELLULAR LOCATION lines for P0CJ77, and those lines are
  themselves ECO:0000250|UniProtKB:Q8IVG9 - by similarity to humanin. So the IEA and the ISS are
  the same humanin claim, counted twice.
• Both IBA rows descend from PANTHER:PTN002141596, the humanin-family node. The MF row's
  grounding is humanin's IDA for receptor antagonist activity (PMID:15153530, FPRL1 competition with
  amyloid-beta); the BP row's co-listed donor is UniProtKB:P0CJ72 = MTRNR2L5, whose own evidence
  is the one functional assay ever run on a nuclear humanin-like sequence.
• Note the loop closed by PMID:38630326: that paper selected MTRNR2L10 for study because of the
  GO:1900118 annotation, which exists only by propagation from humanin. The literature on this locus
  is therefore partly downstream of the annotation, which is a reason to be more careful with the
  row, not less.

Residues: where similarity stops being an argument

Humanin has an unusually complete mutagenesis map (UniProt Q8IVG9). Positions where a single
substitution abolishes neuroprotective activity: Pro3, Ser7, Cys8, Leu9, Leu12, Thr13, Ser14,
Pro19. Secretion needs Leu9-Leu11 and Pro19-Val20.

HN10 loses Pro3, Thr13, Ser14, Pro19 and Val20 - five mapped positions, including a substitution
(Ser14->Arg) that UniProt records as abolishing, and a substitution (Thr13->Ile) measured to reduce
cytoprotection in the one nuclear peptide that was ever assayed. The usual counterweight for this
family - synthetic HN5, carrying Leu12->Ser, remains cytoprotective - does not help HN10, because
HN10 keeps Leu12 and diverges instead exactly where HN5 remained humanin-like. That is why this
review removes four rows where most of the siblings only flag them: the inheritance assumption fails
on the target side, not merely for want of confirmation.

Negative and orthogonal evidence

A lookup across all thirteen loci in CARDIoGRAMplusC4D found no significant association with
coronary artery disease and no significant expression QTL
PMID:31753007.

Methodological caution that applies to every clinical report on this family

Serum "humanin-like 10" is measured by ELISA and reported as reduced in restless legs syndrome
PMID:38630326. HN10 matches humanin at 17 of 24 positions and its siblings more closely; locus-specific
immunodetection has not been demonstrated anywhere in this family, so no such measurement is used
here as evidence that this particular locus makes a peptide.