PMCHL2 (5q13.2) is a hominid-specific locus, classified by HGNC as a pseudogene. It arose 5-10 million years ago by duplication of a roughly 92 kb segment of chromosome 5p14 that contains the chimeric PMCHL1 gene, itself a retrocopy of the pro-melanin-concentrating hormone gene PMCH. Like PMCHL1, 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, with amino-acid substitutions. PMCHL2 is not transcribed in the brain. Spliced transcripts, using a PMCHL2-specific splice donor, are found only in testis and are less abundant than PMCHL1 transcripts. The UniProt entry (86 aa) is a short ORF that begins with a lysine-rich putative nuclear localization signal instead of a secretory signal peptide. No protein product has been detected, and the PMCHL transcripts are proposed to act as mRNA-like noncoding RNAs. No function of a PMCHL2 protein has been demonstrated.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| 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 putative product lacks the secretory signal peptide required for a peptide hormone (PMCHL2-bioinformatics/RESULTS.md). The locus is an HGNC pseudogene with UniProt PE5. No PMCHL protein has been detected in the tissues that express the transcripts (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. file:human/PMCHL2/PMCHL2-bioinformatics/RESULTS.md Without a signal peptide the product would not enter the secretory pathway |
| GO:0007268 chemical synaptic transmission | IEA GO_REF:0000002 | REMOVE | Summary: InterPro2GO mapping from the prepro-MCH family signature (IPR005456) onto a locus that is not expressed in the brain. Reason: IPR005456 matches the PMCH-derived C-terminal segment, but the mapped process presumes a secreted neuropeptide acting in the nervous system. PMCHL2 is not transcribed in fetal, newborn or adult brain (PMID:11070051), and the brain antisense transcripts of the variant loci come from PMCHL1, not PMCHL2 (PMID:9729295). PMCHL2 transcripts are restricted to testis (PMID:19068116). The ORF also lacks a signal peptide. Synaptic transmission is therefore unsupported. Supporting Evidence: PMID:11070051 we provided strong evidence for the expression of the PMCHL1 gene but not the PMCHL2 gene in the human fetal, newborn, and adult brains PMID:9729295 to be derived from the 5p (pMCHL1), not the 5q (pMCHL2) locus PMID:19068116 Thus, PMCHL1 transcripts are found in testis and fetal brain and are more abundant than PMCHL2 transcripts that are observed only in testis. |
| 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 with no detected protein. Reason: MCH activity requires a mature cyclic MCH peptide released from pro-MCH in the secretory pathway. PMCHL2, like 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. Its MCH-like segment is substituted at three positions (M150T, R160Q, P161R in PMCH numbering), although the disulfide cysteines are retained (PMCHL2-bioinformatics/RESULTS.md). The transcripts are restricted to testis, and no protein has been detected (PMID:19068116). A peptide that cannot be secreted cannot act as a hormone, whether or not its cysteines are conserved. 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/PMCHL2/PMCHL2-bioinformatics/RESULTS.md MCH region (PMCH 147-165): M150->T71, R160->Q81, P161->R82 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 hominid duplicate of a truncated PMCH retrocopy that encodes no secreted precursor and has no detected protein. Reason: The IBD at PTN002636265 (taxon Euteleostomi, seeded by rat Pmch, RGD:3358) is sound for PMCH orthologs. PMCHL2 descends from that node only indirectly. It is a duplicate of PMCHL1 (PMID:11181993), which is a primate retrocopy of a PMCH transcript, and PANTHER places both in their own subfamily (PTHR12091:SF1). The copy has lost what the function depends on: the signal peptide and N-terminal pro-region are absent (PMCH 1-80), and the MCH-like segment is substituted. The locus is an HGNC pseudogene that is not expressed in brain (PMID:11070051). No PMCHL protein was detected in testis or in transfected HEK293 cells (PMID:19068116). The inherited ligand 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; PTHR12091:SF1 (PMCHL1/PMCHL2) is a truncated, signal-peptide-less primate retrocopy lineage that should be excluded from this node's propagation. Supporting Evidence: PMID:11181993 PMCHL2 arose 5 to 10 Ma by an event of duplication involving a large chromosomal region encompassing the PMCHL1 locus 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/PMCHL2/PMCHL2-bioinformatics/RESULTS.md PMCH residues 1-80 have no counterpart in Q9BQD1 |
| GO:0032227 negative regulation of synaptic transmission, dopaminergic | IBA GO_REF:0000033 | REMOVE | Summary: Phylogenetically inherited brain neuromodulatory process. PMCHL2 is not expressed in brain and encodes no secreted peptide. Reason: This IBA comes from the same PTN002636265 node and depends on MCH acting as a neuropeptide in the brain. PMCHL2 is not transcribed in brain (PMID:11070051), and its transcripts are restricted to testis (PMID:19068116). The ORF lacks a signal peptide, and no PMCHL2-specific role in dopaminergic transmission has been reported. Propagation Review Root cause: PROPAGATION BAD Failure modes: PSEUDO OR SUBACTIVITY LOSS CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN002636265 · PTN002636265 SUPPORTS SOURCE BUT NOT TARGET Same Euteleostomi pro-MCH IBD (seed RGD:3358); valid for PMCH, not for PMCHL2, which lacks the secretory precursor architecture and is not expressed in brain. Supporting Evidence: PMID:11070051 we provided strong evidence for the expression of the PMCHL1 gene but not the PMCHL2 gene in the human fetal, newborn, and adult brains PMID:19068116 Thus, PMCHL1 transcripts are found in testis and fetal brain and are more abundant than PMCHL2 transcripts that are observed only in testis. |
| 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 (InterPro2GO), which is removed. PMCHL2 is not expressed in brain (PMID:11070051), and no protein product has been detected (PMID:19068116). A synaptic location is therefore unsupported. Supporting Evidence: PMID:11070051 we provided strong evidence for the expression of the PMCHL1 gene but not the PMCHL2 gene in the human fetal, newborn, and adult brains |
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Download this section (compressed HTML)Q: Should the PANTHER PTN002636265 IBD be blocked for subfamily PTHR12091:SF1 (PMCHL1/PMCHL2)? These are primate retrocopies lacking the PMCH signal peptide, with no detected protein.
Q: Is there any transcript-level support for the specific 86-aa Q9BQD1 model, given that PMCHL2 RNAs are testis-restricted and use a PMCHL2-specific splice donor (exon 3b2)?
Experiment: Search testis ribosome-profiling and deep proteomics datasets for PMCHL2-specific peptides (distinguishable from PMCHL1 and PMCH at positions such as T6 (P6 in PMCHL1) and the MCH-like segment) to establish whether any PMCHL2 product is translated.
Type: ribosome profiling / targeted mass spectrometry
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