PMCHL1 (5p14.3) is a primate-specific chimeric locus, classified by HGNC as a pseudogene, that arose 30-35 million years ago by retroposition of an antisense pro-melanin-concentrating hormone (PMCH) transcript into an intron of the brain cadherin gene CDH12, followed by de novo creation of exons and splice sites. It is a 5'-truncated copy of PMCH: it lacks the region encoding the PMCH signal peptide and N-terminal pro-region, but retains sequence corresponding to the C-terminal NGE-, NEI- and MCH-peptide segments, each carrying amino-acid substitutions. The locus is transcribed in testis and in fetal, newborn and adult brain, producing sense unspliced and spliced RNAs and noncoding antisense RNAs. The UniProt entry (86 aa) corresponds to a short ORF on sense transcripts (VMCH-p8) with a novel, lysine-rich putative nuclear localization signal at its N-terminus in place of a secretory signal peptide. VMCH-p8 was translated only in vitro and, weakly, in transfected cells; it was not detected by antibody in human or macaque tissues that express PMCHL RNA, and the transcripts are proposed to act as mRNA-like noncoding RNAs. No function of a PMCHL1 protein has been demonstrated.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005576 extracellular region | NAS PMID:8326825 Isolation and characterization of the human melanin-concentr... | REMOVE | Summary: Author-statement localization from the 1993 description of the variant MCH gene as expressing a prohormone. The putative product lacks a signal peptide and no protein has been detected in tissues, so extracellular location is unsupported. Reason: PMID:8326825 inferred a prohormone from the variant gene before its structure was known in detail. Later work showed the locus is a 5'-truncated copy of PMCH (PMID:11070051), and the ORF captured by UniProt begins with a novel lysine-rich putative nuclear localization signal rather than the PMCH signal peptide (PMID:19068116; PMCHL1-bioinformatics/RESULTS.md: PMCH 1-80, including signal peptide 1-21, has no counterpart). A protein without a signal peptide would not be secreted, and no endogenous protein was detected in testis or brain (PMID:19068116). The NAS statement is superseded; there is no basis for an extracellular location. Supporting Evidence: PMID:8326825 suggest that these neuropeptides may influence the activity of numerous mammalian neuronal systems PMID:19068116 The putative 8 kD protein corresponding to ORF1, previously named VMCH-p8, presents a putative nuclear localisation signal (NLS) at the N-terminus (KPKKK file:human/PMCHL1/PMCHL1-bioinformatics/RESULTS.md Without a signal peptide the product would not enter the secretory pathway |
| GO:0007165 signal transduction | IEA GO_REF:0000108 | REMOVE | Summary: Inter-ontology inference from the InterPro-derived melanin-concentrating hormone activity annotation, which is itself unsupported for this product. Reason: This row is derived from GO:0030354 (melanin-concentrating hormone activity), which is removed below. The product lacks the secretory signal peptide needed to make a peptide hormone, its existence as a protein is unconfirmed (PE5; HGNC pseudogene; not detected by Western blot in expressing tissues, PMID:19068116), and no signalling role has been tested. Supporting Evidence: PMID:19068116 This strongly suggests that these putative proteins are not translated in vivo in the human and macaque tissues that we tested. |
| GO:0007268 chemical synaptic transmission | IEA GO_REF:0000002 | REMOVE | Summary: InterPro2GO mapping from the prepro-MCH family signature (IPR005456), matched by the C-terminal PMCH-derived segment of this putative ORF. Reason: IPR005456 matches because the ORF contains PMCH-derived NGE/NEI/MCH-like sequence, but the family-level process presumes a secreted neuropeptide precursor. This product has no signal peptide, carries substitutions in the MCH- and NEI-like segments, and was not detected in brain or testis (PMID:19068116). Brain transcripts of the locus are largely antisense, and there is no evidence that an MCH precursor is produced from the variant loci (PMID:9729295). Supporting Evidence: PMID:9729295 Thus, there is no evidence that the MCH peptide-precursor molecule is produced in the brain by the human-variant pMCHL loci. PMID:19068116 This strongly suggests that these putative proteins are not translated in vivo in the human and macaque tissues that we tested. |
| GO:0030354 melanin-concentrating hormone activity | IEA GO_REF:0000002 | REMOVE | Summary: InterPro2GO mapping of hormone activity onto a 5'-truncated, signal-peptide-less copy of the PMCH C-terminal region whose protein has not been detected. Reason: Melanin-concentrating hormone activity requires a mature, secreted cyclic MCH peptide released from pro-MCH by processing in the secretory pathway. PMCHL1 is a 5'-truncated version of the MCH gene (PMID:11070051). The putative 86-aa product aligns only to PMCH 81-165 and lacks the signal peptide (PMCHL1-bioinformatics/RESULTS.md). Its MCH-like segment carries four substitutions relative to human MCH (M150T, R152S, R160Q, P161S in PMCH numbering), although the disulfide cysteines are retained. No endogenous protein was detected (PMID:19068116). The hormone activity is therefore unsupported. Retaining the cysteines alone does not establish activity, because a peptide that is never secreted cannot act as a hormone. Supporting Evidence: PMID:11070051 They correspond to a 5'-end truncated version of the MCH gene mapped on chromosome 12q23 and encoding a neuropeptide precursor. file:human/PMCHL1/PMCHL1-bioinformatics/RESULTS.md MCH region (PMCH 147-165): M150->T71, R152->S73, R160->Q81, P161->S82 PMID:19068116 Western blot analyses of human and macaque tissues expressing PMCHL RNA failed to reveal any protein corresponding to VMCH-p8 and protein variants encoded by spliced transcripts. |
| GO:0031777 type 1 melanin-concentrating hormone receptor binding | IBA GO_REF:0000033 | REMOVE | Summary: Phylogenetic inheritance of MCHR1 ligand binding from the euteleost pro-MCH node onto a primate-specific, truncated retrocopy that does not encode a secreted precursor and is probably not translated. Reason: The IBD at PTN002636265 (taxon Euteleostomi, seeded by rat Pmch, RGD:3358) correctly places MCHR1-ligand function at the root of the PMCH family. PMCHL1 is inside that clade only because it descends from a PMCH transcript that was retroposed about 30-35 Mya. PANTHER separates it into its own subfamily (PTHR12091:SF1, PRO-MCH-LIKE PROTEIN 1-RELATED). The retrocopy shows loss of the features the function depends on. It is 5'-truncated and lacks the signal peptide and N-terminal pro-region (PMCH 1-80 absent), so no MCH peptide can be processed or secreted. It has a novel N-terminal putative NLS (PMID:19068116). Its MCH-like segment is substituted. The locus is annotated by HGNC as a pseudogene. No protein was detected in human or macaque tissues, nor in HEK293 cells transfected with ORF1-bearing constructs (PMID:19068116). The product is unlikely to exist as a ligand, so the inherited binding function should not apply. Propagation Review Root cause: PROPAGATION BAD Failure modes: PSEUDO OR SUBACTIVITY LOSS FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN002636265 · PTN002636265 SUPPORTS SOURCE BUT NOT TARGET IBD at Euteleostomi pro-MCH node (seed RGD:3358 rat Pmch) is sound for PMCH orthologs; the primate PMCHL subfamily (PTHR12091:SF1) is a truncated, signal-peptide-less retrocopy that should be excluded from this node's propagation. Supporting Evidence: PMID:11181993 the PMCHL1 gene was created near 25 million years ago (Ma) by a complex mechanism of exon shuffling through retrotransposition of an antisense MCH messenger RNA coupled to de novo creation of splice sites PMID:19068116 Even though high levels of ORF1-bearing PMCHL1/2 transcripts were detected by RT-PCR, no signal corresponding to the VMCH-p8 protein could be detected (data not shown). file:human/PMCHL1/PMCHL1-bioinformatics/RESULTS.md PMCH residues 1-80 have no counterpart in Q16048 |
| GO:0032227 negative regulation of synaptic transmission, dopaminergic | IBA GO_REF:0000033 | REMOVE | Summary: Phylogenetically inherited neuromodulatory process from the pro-MCH node. It does not apply to a non-secreted, probably untranslated primate retrocopy. Reason: This IBA comes from the same PTN002636265 node as the MCHR1-binding row. It rests on MCH acting as a secreted neuropeptide in the brain. PMCHL1 cannot supply that peptide: its ORF lacks the signal peptide, and in the brain the variant locus yields antisense RNA with no evidence of an MCH precursor (PMID:9729295). The putative VMCH-p8 product was not detected in fetal, newborn or adult brain (PMID:19068116). No PMCHL1-specific role in dopaminergic transmission has been reported. Propagation Review Root cause: PROPAGATION BAD Failure modes: PSEUDO OR SUBACTIVITY LOSS FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN002636265 · PTN002636265 SUPPORTS SOURCE BUT NOT TARGET Same Euteleostomi pro-MCH IBD (seed RGD:3358); valid for PMCH, not for the PTHR12091:SF1 PMCHL retrocopies, which lack the secretory precursor architecture. Supporting Evidence: PMID:9729295 Thus, there is no evidence that the MCH peptide-precursor molecule is produced in the brain by the human-variant pMCHL loci. PMID:19068116 This strongly suggests that these putative proteins are not translated in vivo in the human and macaque tissues that we tested. |
| GO:0045202 synapse | IEA GO_REF:0000108 | REMOVE | Summary: Location inferred by GOC logic from the chemical synaptic transmission IEA, which is itself removed. Reason: This row derives from GO:0007268 (chemical synaptic transmission, InterPro2GO), which is removed. There is no evidence that a PMCHL1 protein exists in neurons. The putative ORF lacks a secretory signal and has an N-terminal putative nuclear localization signal (PMID:19068116), so synaptic location is unsupported. Supporting Evidence: PMID:19068116 The putative 8 kD protein corresponding to ORF1, previously named VMCH-p8, presents a putative nuclear localisation signal (NLS) at the N-terminus (KPKKK |
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Download this section (compressed HTML)Q: Should the PANTHER PTN002636265 IBD (MCHR1 binding; negative regulation of dopaminergic transmission) be blocked for subfamily PTHR12091:SF1 (PMCHL1/PMCHL2)? These are primate retrocopies lacking the PMCH signal peptide, with no detectable protein.
Q: Does UniProt Q16048 (86 aa) represent the same ORF as VMCH-p8, which Schmieder et al. 2008 describe as 72 aa? If not, which transcript supports the 86-aa model?
Q: Should a PE5 entry whose locus HGNC classifies as a pseudogene receive any InterPro2GO or IBA function annotation by default?
Experiment: Re-examine ribosome-profiling and deep proteomics data from human testis and fetal brain for translation of the PMCHL1 ORF1/VMCH-p8 reading frame, using PMCHL1-specific peptides that discriminate it from PMCH and PMCHL2.
Type: ribosome profiling / targeted mass spectrometry
Experiment: Test the proposed noncoding-RNA role of PMCHL1 transcripts by knockdown of sense and antisense PMCHL1 RNAs in a human neural progenitor model.
Type: RNA knockdown
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