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	Protein Summary
	AS Summary
	Protein Functional Features
	Gene Isoform Structures and Expression Levels
	Protein Structures
	pLDDT Score Distribution
	Ramachandran Plot of Protein Structures
	Potential Active Site Information
	Protein Structure and Feature Comparision
	Protein-Protein Interaction
	Related Drugs
	Related Diseases
	Clinically Important Variants

Protein:POLR2A

Protein Summary

Gene summary

Gene name: POLR2A
ASpdb.0 ID: 5430
	Gene
Gene symbol	POLR2A
Gene ID	5430
Gene name	RNA polymerase II subunit A
Synonyms	NEDHIB\|POLR2\|POLRA\|RPB1\|RPBh1\|RPO2\|RPOL2\|RpIILS\|hRPB220\|hsRPB1
Cytomap	17p13.1
Type of gene	protein-coding
Description	DNA-directed RNA polymerase II subunit RPB13'-5' exoribonucleaseDNA-directed RNA polymerase II largest subunit, RNA polymerase II 220 kd subunitDNA-directed RNA polymerase II subunit ADNA-directed RNA polymerase III largest subunitRNA polymerase II s
Modification date	20240414
UniProtAcc	P24928

Gene ontology of this gene with evidence of Inferred from Direct Assay (IDA) from Entrez

Partner	Gene	GO ID	GO term	PubMed ID
Gene	POLR2A	GO:0000287	magnesium ion binding	27193682
Gene	POLR2A	GO:0000974	Prp19 complex	21536736
Gene	POLR2A	GO:0003899	DNA-directed 5'-3' RNA polymerase activity	9852112\|23748380
Gene	POLR2A	GO:0003968	RNA-dependent RNA polymerase activity	23395899
Gene	POLR2A	GO:0005634	nucleus	9852112\|14580349\|16109376
Gene	POLR2A	GO:0005665	RNA polymerase II, core complex	9852112
Gene	POLR2A	GO:0005730	nucleolus	16109376
Gene	POLR2A	GO:0006366	transcription by RNA polymerase II	9852112
Gene	POLR2A	GO:0008270	zinc ion binding	27193682
Gene	POLR2A	GO:0033120	positive regulation of RNA splicing	21536736
Gene	POLR2A	GO:0050436	microfibril binding	28945358
Gene	POLR2A	GO:1990841	promoter-specific chromatin binding	24441171

AS Summary

Information of the canonical protein with experimentally identified structure from PDB (2023).

UniProt Acc	File name	PDB ID	Method	Resolution	Chain	Start	End
P24928-1	P24928-1_5iyb_A.pdb	5IYB	EM	3.9	A	10	1485

ASpdb's canonical and alternatively spliced isoform information.

accession_id

gene_name

canonical_id

alternative_id

canonical_length

alternative_length

canonical_start

canonical_end

type

originalSEQ

variationSEQ

alternative_start

alternative_end

P24928

POLR2A

P24928-1

P24928-2

1970

566

558

566

Substitution

GEVMNLLMF

VCGPNGNLA

558

566

P24928

POLR2A

P24928-1

P24928-2

1970

566

567

1970

Deletion

none

566

Multiple sequence alignment of our canonical and alternatively spliced POLR2A

Matched gene isoform IDs with Ensembl and RefSeq of our canonical and alternative spliced genes of POLR2A

UniProt-id

ENSG

ENST

ENSP

UniProt-id

NM ID

NP ID

Amino acid sequences of our canonical and alternatively spliced POLR2A

accession_id	Protein sequence
P24928-1	MHGGGPPSGDSACPLRTIKRVQFGVLSPDELKRMSVTEGGIKYPETTEGGRPKLGGLMDPRQGVIERTGRCQTCAGNMTECPGHFGHIEL AKPVFHVGFLVKTMKVLRCVCFFCSKLLVDSNNPKIKDILAKSKGQPKKRLTHVYDLCKGKNICEGGEEMDNKFGVEQPEGDEDLTKEKG HGGCGRYQPRIRRSGLELYAEWKHVNEDSQEKKILLSPERVHEIFKRISDEECFVLGMEPRYARPEWMIVTVLPVPPLSVRPAVVMQGSA RNQDDLTHKLADIVKINNQLRRNEQNGAAAHVIAEDVKLLQFHVATMVDNELPGLPRAMQKSGRPLKSLKQRLKGKEGRVRGNLMGKRVD FSARTVITPDPNLSIDQVGVPRSIAANMTFAEIVTPFNIDRLQELVRRGNSQYPGAKYIIRDNGDRIDLRFHPKPSDLHLQTGYKVERHM CDGDIVIFNRQPTLHKMSMMGHRVRILPWSTFRLNLSVTTPYNADFDGDEMNLHLPQSLETRAEIQELAMVPRMIVTPQSNRPVMGIVQD TLTAVRKFTKRDVFLERGEVMNLLMFLSTWDGKVPQPAILKPRPLWTGKQIFSLIIPGHINCIRTHSTHPDDEDSGPYKHISPGDTKVVV ENGELIMGILCKKSLGTSAGSLVHISYLEMGHDITRLFYSNIQTVINNWLLIEGHTIGIGDSIADSKTYQDIQNTIKKAKQDVIEVIEKA HNNELEPTPGNTLRQTFENQVNRILNDARDKTGSSAQKSLSEYNNFKSMVVSGAKGSKINISQVIAVVGQQNVEGKRIPFGFKHRTLPHF IKDDYGPESRGFVENSYLAGLTPTEFFFHAMGGREGLIDTAVKTAETGYIQRRLIKSMESVMVKYDATVRNSINQVVQLRYGEDGLAGES VEFQNLATLKPSNKAFEKKFRFDYTNERALRRTLQEDLVKDVLSNAHIQNELEREFERMREDREVLRVIFPTGDSKVVLPCNLLRMIWNA QKIFHINPRLPSDLHPIKVVEGVKELSKKLVIVNGDDPLSRQAQENATLLFNIHLRSTLCSRRMAEEFRLSGEAFDWLLGEIESKFNQAI AHPGEMVGALAAQSLGEPATQMTLNTFHYAGVSAKNVTLGVPRLKELINISKKPKTPSLTVFLLGQSARDAERAKDILCRLEHTTLRKVT ANTAIYYDPNPQSTVVAEDQEWVNVYYEMPDFDVARISPWLLRVELDRKHMTDRKLTMEQIAEKINAGFGDDLNCIFNDDNAEKLVLRIR IMNSDENKMQEEEEVVDKMDDDVFLRCIESNMLTDMTLQGIEQISKVYMHLPQTDNKKKIIITEDGEFKALQEWILETDGVSLMRVLSEK DVDPVRTTSNDIVEIFTVLGIEAVRKALERELYHVISFDGSYVNYRHLALLCDTMTCRGHLMAITRHGVNRQDTGPLMKCSFEETVDVLM EAAAHGESDPMKGVSENIMLGQLAPAGTGCFDLLLDAEKCKYGMEIPTNIPGLGAAGPTGMFFGSAPSPMGGISPAMTPWNQGATPAYGA WSPSVGSGMTPGAAGFSPSAASDASGFSPGYSPAWSPTPGSPGSPGPSSPYIPSPGGAMSPSYSPTSPAYEPRSPGGYTPQSPSYSPTSP SYSPTSPSYSPTSPNYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTS PSYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTSPNYSPTSPNYTPTSPSYSPTSPSYSPTSPNYTPTSPNYSPTSPSYSPTSPSYSPT SPSYSPSSPRYTPQSPTYTPSSPSYSPSSPSYSPASPKYTPTSPSYSPSSPEYTPTSPKYSPTSPKYSPTSPKYSPTSPTYSPTTPKYSP
P24928-2	MHGGGPPSGDSACPLRTIKRVQFGVLSPDELKRMSVTEGGIKYPETTEGGRPKLGGLMDPRQGVIERTGRCQTCAGNMTECPGHFGHIEL AKPVFHVGFLVKTMKVLRCVCFFCSKLLVDSNNPKIKDILAKSKGQPKKRLTHVYDLCKGKNICEGGEEMDNKFGVEQPEGDEDLTKEKG HGGCGRYQPRIRRSGLELYAEWKHVNEDSQEKKILLSPERVHEIFKRISDEECFVLGMEPRYARPEWMIVTVLPVPPLSVRPAVVMQGSA RNQDDLTHKLADIVKINNQLRRNEQNGAAAHVIAEDVKLLQFHVATMVDNELPGLPRAMQKSGRPLKSLKQRLKGKEGRVRGNLMGKRVD FSARTVITPDPNLSIDQVGVPRSIAANMTFAEIVTPFNIDRLQELVRRGNSQYPGAKYIIRDNGDRIDLRFHPKPSDLHLQTGYKVERHM CDGDIVIFNRQPTLHKMSMMGHRVRILPWSTFRLNLSVTTPYNADFDGDEMNLHLPQSLETRAEIQELAMVPRMIVTPQSNRPVMGIVQD

Protein Functional Features

Main function of this protein. (from UniProt)

POLR2A (go to UniProt):P24928

Retention analysis result of protein across 39 protein features of UniProt such as six molecule processing features, 13 region features, four site features, six amino acid modification features, two natural variation features, five experimental info features, and 3 secondary structure features. Here, because of limited space for viewing, we only show the protein feature retention information belong to the 13 regional features. All retention annotation result can be downloaded at
download page
* Minus value of BPloci means that the break pointn is located before the CDS.

- Retained protein feature among the 13 regional features.

Accession_id	Subsection	Start	End	Funcitonal feature	Splicing information
P24928	Repeat	1593	1599	Note=1;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1600	1606	Note=2%3B approximate;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1608	1614	Note=3;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1615	1621	Note=4;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1622	1628	Note=5;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1629	1635	Note=6;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1636	1642	Note=7;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1643	1649	Note=8;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1650	1656	Note=9;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1657	1663	Note=10;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1664	1670	Note=11;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1671	1677	Note=12;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1678	1684	Note=13;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1685	1691	Note=14;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1692	1698	Note=15;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1699	1705	Note=16;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1706	1712	Note=17;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1713	1719	Note=18;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1720	1726	Note=19;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1727	1733	Note=20;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1734	1740	Note=21;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1741	1747	Note=22;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1748	1754	Note=23;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1755	1761	Note=24;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1762	1768	Note=25;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1769	1775	Note=26;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1776	1782	Note=27;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1783	1789	Note=28;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1790	1796	Note=29;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1797	1803	Note=30;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1804	1810	Note=31;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1811	1817	Note=32;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1818	1824	Note=33;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1825	1831	Note=34;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1832	1838	Note=35;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1839	1845	Note=36;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1846	1852	Note=37;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1853	1859	Note=38;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1860	1866	Note=39;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1867	1873	Note=40;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1874	1880	Note=41;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1881	1887	Note=42;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1888	1894	Note=43;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1895	1901	Note=44;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1902	1908	Note=45;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1909	1915	Note=46;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1916	1922	Note=47;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1923	1929	Note=48;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1930	1936	Note=49;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1940	1946	Note=50;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1947	1953	Note=51%3B approximate;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Repeat	1954	1960	Note=52%3B approximate;Ontology_term=ECO:0000255;evidence=ECO:0000255	Type=Deletion;Start=567;End=1970
P24928	Region	832	873	Note=Bridging helix;Ontology_term=ECO:0000250;evidence=ECO:0000250\|UniProtKB:G3MZY8	Type=Deletion;Start=567;End=1970
P24928	Region	1083	1124	Note=Trigger loop;Ontology_term=ECO:0000250;evidence=ECO:0000250\|UniProtKB:G3MZY8	Type=Deletion;Start=567;End=1970
P24928	Region	1546	1970	Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Deletion;Start=567;End=1970
P24928	Region	1593	1960	Note=C-terminal domain (CTD)%3B 52 X 7 AA approximate tandem repeats of Y-[ST]-P-[STQ]-[ST]-P-[SRTEVKGN]	Type=Deletion;Start=567;End=1970
P24928	Compositional bias	1565	1584	Note=Pro residues;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Deletion;Start=567;End=1970
P24928	Compositional bias	1607	1963	Note=Polar residues;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Deletion;Start=567;End=1970

Gene Isoform Structures and Expression Levels for POLR2A

Gene structures of our canonical and alternative spliced genes of POLR2A
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.

Expression levels of gene isoforms across GTEx.

Expression levels of gene isoforms across TCGA.

Protein Structures

PDB and CIF files of the predicted protein structures
* Here we show the 3D structure of the proteins using Mol*. AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. Model confidence is shown from the pLDDT values per residue. pLDDT corresponds to the model’s prediction of its score on the local Distance Difference Test. It is a measure of local accuracy (from AlphfaFold website). To color code individual residues, we transformed individual PDB files into CIF format.

3D view using mol* of P24928-1

3D view using mol* of P24928-2

pLDDT Score Distribution

pLDDT score distribution of the predicted protein structures from AlphaFold2
* AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100.

pLDDT distribution across the protein length of P24928-1

pLDDT distribution across the protein length of P24928-2

Ramachandran Plot of Protein Structures

Ramachandran plot of the torsional angles - phi (φ)and psi (ψ) - of the residues (amino acids) contained in this protein peptide.

Ramachandran plot of P24928-1

Potential Active Site Information

The potential binding sites of these proteins were identified using SiteMap, a module of the Schrodinger suite.

UniProt-id	Site score	Size	D score	Volume	Exposure	Enclosure	Contact	Phobic	Philic	Balance	Don/Acc	Residues
P24928-1	1.095	285	1.145	1163.113	0.55	0.764	0.935	1.093	0.779	1.403	1.184	21,22,23,24,25,26,27,28,30,31,34,82,83,84,85,96,99 ,241,242,247,248,249,250,251,252,253,254,256,257,2 59,260,262,276,280,317,318,337,339,340,342,343,347 ,348,349,350,353,354,1427,1436,1439,1440,1443,1459 ,1460,1709,1710,1711,1712,1713,1714,1715,1716,1717 ,1719,1720
P24928-2	1.042	84	1.131	165.326	0.578	0.67	0.83	2.007	0.405	4.952	1.182	95,194,195,196,197,198,215,216,217,218,219,303,304 ,307,308,309,311,312,325

Protein Structure and Feature Comparision

Protein Structure Comparision Using Template Modeling Scores (TM-score).

Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Canonical validated structure (PDB)(green)

3D view using mol* of P24928-1_P24928-1_5iyb_A.pdb

Protein Structure Comparision Visualization with mol*. between Canonical validated structure (PDB)(orange) vs Alternative predicted structure (AF2)(green)

3D view using mol* of P24928-1_5iyb_A_P24928-2.pdb

Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Alternative predicted structure (AF2)(green)

3D view using mol* of P24928-1_P24928-2.pdb

Protein Feature Comparison of the protein sequendary structures among the protiens.

./stats/secondary_structure/figure/P24928-1_vs_P24928-2.png

Protein Feature Comparison of the relative accessible surface area (ASA) among the protiens.

./stats/relative_asa/P24928-1_vs_P24928-2.png

Protein-Protein Interaction

Interactors from UniProt.

Accession_id

Subsection

Start

End

Funcitonal feature

Splicing information

Interactors from STRING.

Gene name

Interactors

Related Drugs to POLR2A

Drugs targeting this gene/protein.
(DrugBank)

UniProt accession

Gene name

DrugBank ID

Drug name

Drug group

Actions

Related Diseases to POLR2A

Previous studies relating to the alternative splicing of POLR2A and disease information from the MeSH term (PubMed)

Gene	PMID	Title	Abstract	MeSH ID	MeSH term
POLR2A	24711643	Identifying biological pathways that underlie primordial short stature using network analysis.	Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure.	D004392	Dwarfism
POLR2A	24711643	Identifying biological pathways that underlie primordial short stature using network analysis.	Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure.	D006130	Growth Disorders
POLR2A	24711643	Identifying biological pathways that underlie primordial short stature using network analysis.	Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure.	D009123	Muscle Hypotonia

Clinically important variants in POLR2A

(ClinVar, 04/20/2024)

accession_id

uniprot_id

gene_name

Type

Variant

Clinical_significance