Leucine-rich repeat-containing protein 74A (LRRC74A), is a protein encoded by the LRRC74A gene. The protein LRRC74A (aliases C14orf166B, 14q24.3) is localized in the cytoplasm. It has a calculated molecular weight of approximately 55 kDa.[5] The LRRC74A protein is nominally expressed in the testis, salivary gland, and pancreas.[6]

LRRC74A
Identifiers
AliasesLRRC74A, C14orf166B, LRRC74, leucine rich repeat containing 74A
External IDsMGI: 3646959; HomoloGene: 19331; GeneCards: LRRC74A; OMA:LRRC74A - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_194287
NM_001385106
NM_001385107
NM_001385108

NM_001195767

RefSeq (protein)

NP_919263

NP_001182696

Location (UCSC)Chr 14: 76.83 – 76.87 MbChr 12: 86.78 – 86.81 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Gene

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The LRRC74A gene, also known as C14orf166B, is located on the positive-sense strand of locus 14q24.3. The full unspliced gene contains 17 exons.[7] LRRC74A spans from 76,826,408 to 76,870,304 for a total length of 43.9 kpb.[8]


Transcripts

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LRRC74A has four transcript variants. The most abundant variant is LRRC74A transcript variant 1, which is 1710 nucleotides in length.[7]

LRRC74A transcript variants
Accession number Transcript length Number of exons Protein length Isoform
NM_194287.3 1710 14 488 1
NM_001322426.2 1861 5 471 2
NM_001105519.3 718 4 201 3
NM_001105519.3 718 4 201 4

Protein

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The LRRC74A protein is 488 amino acids in length with a predicted molecular weight of 55 kDA and an isoelectric point of 5.22.[9] It has higher than normal levels of methionine and asparagine.[10]

Domains and structure

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The LRRC74A protein contains eight leucine-rich repeat domains in its sequence.[11] LRRC74A isoform 1 secondary structure is made up of alternating alpha helices and beta sheets.[12] Tertiary structure predictions show a horseshoe-shaped protein with high similarity to ribonuclease inhibitor[13]

 
LRRC74A Tertiary Structure prediction by I-TASSER

[14]

Isoforms

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LRRC74A has four splice isoforms. The most abundant isoform is LRRC74A protein isoform 1 which is 488 amino acids in length.[7]

LRRC74A protein isoforms
Name Transcript variant Peptide length Domains present
Isoform 1 1 488 aa 8 LRR domains
Isoform 2 2 471 aa 6 LRR domains
Isoform 3 3 464 aa 6 LRR domains
Isoform 4 4 427 aa 7 LRR domains

Regulation

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Expression pattern

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LRRC74A has overall low levels of expression compared to other proteins but within the tissues it is expressed in, it appears most prominently in the testes, salivary gland, and pancreas.[7] Within the cell, LRRC74A is localized to the cytosol.[15]

Transcript level regulation

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Predicted 5' UTR folding structure of LRRC74A

The 5' UTR of LRRC74A transcript variant 1 is 91 bp in length.[16] Analysis of potential folding structures identifies two possible stemloop structures.[17]

 
Predicted folding structure of the 3' UTR of LRRC74A

The 3' UTR is 158 bp in length and contains one polyadenylation signal.[16] It contains four predicted stemloop structures, with three loops closer to the 5' end of the UTR and one loop closer to the 3' end of the UTR.

Homology and evolution

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Paralogs

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The human LRRC74A gene has one paralog called LRRC74B. It is located at 22q11.21[18]

Orthologs

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LRRC74A has orthologs in species as distant as tunicates. Mammalian orthologs are moderately similar to human LRRC74A, with percent similarity greater than 80%. Orthologs in reptiles, birds and amphibians range from 65% to 40%. In fish and invertebrates, identity ranges from 40% to 20%. No orthologs were found in fungi, bacteria or plants.

 
Unrooted phylogenetic tree depicting the evolution of LRRC74A
Genus species Common name Taxonomic order Estimated date of divergence (MYA) Accession number Sequence length (aa) Sequence identity (%) Sequence similarity (%)
Mammalia Homo sapiens Human Primates 0 NP_919263.2 488 100 100
Mus musculus Mouse Rodentia 87 NP_001182696.1 487 65.7 77.4
Gulo gulo Wolverine Carnivora 94 KAI5767761.1 488 74.6 86.3
Ursus maritimus Polar bear Carnivora 94 XP_040497188.1 548 60.6 70.6
Balaenoptera musculus Blue whale Artiodactyla 94 XP_036697954.1 482 68.9 80.1
Gracilinanus agilia Agile gracile opossum Marsupialia 106 XP_044518037.1 468 52.5 71.5
Aves Gallus gallus Chicken Galliformes 319 XP_040528719.1 476 42.8 60.9
Melopsittacus undulatus Budgerigar Psittaciformes 319 XP_005149032.1 494 46.4 64.6
Aquila chrysaetos Golden eagle Accipitriformes 319 XP_029863093.1 492 46 62.1
Phaethon lepturus White-tailed tropicbird Phaethontiformes 319 XP_010285698.1 478 44.3 61.5
Reptilia Pelodiscus sinensis Chinese softshell turtle Testudines 319 XP_025037771.1 486 49.5 68
Pogona vitticeps Central bearded dragon Squamata 319 XP_020649579.1 483 48 64.5
Notechis scutatus Tiger snake Squamata 319 XP_026520078.1 491 45.2 61.9
Amphibia Geotrypetes seraphini Gaboon caecilian Gymnophiona 353 XP_033809167.1 540 35.6 50.3
Bufo bufo Common toad Anura 353 XP_040268304.1 536 34.5 51.4
Fish Latimeria chalumnae West Indian Ocean coelacanth Latimeriidae 414 XP_014341482.1 456 47.5 66.2
Lepisosteus oculatus Spotted gar Lepisosteiformes 431 XP_015205589.1 450 42 62.5
Salmo salar Atlantic salmon Salmoniformes 431 XP_045549789.1 648 32.3 45.1
Carcharodon carcharias Great white shark Chondrichthyes 464 XP_041070161.1 727 24 37.4
Petromyzon marinus Sea lamprey Agnatha 510 XP_032820627.1 510 32.1 49.6
Invertebrata Ciona intestinalis Vase tunicate Enterogona 603 XP_002120047.1 661 24.5 40.6

Evolution

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The LRRC74A gene appears most distantly in tunicates which diverged from humans approximately 603 million years ago.[19] Orthologs of LRRC74A and LRRC74B also occur in tunicates. LRRC74A evolves at a moderately fast rate; a 1% change in amino acid sequence required around 10 million years. Based on sequence similarity of orthologs, LRRC74A evolves at a rate in the middle of cytochrome c and fibrinogen alpha.


Clinical significance

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Disease association

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COVID-19

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A GWAS evaluating genetic mutations and clinical outcomes of patients who contracted COVID-19 found that a mutation in the LRRC74A gene was associated with higher mortality rates in infected patients, with the mutation being 7.4% more prevalent in deceased patients than living patients.[20]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000100565Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000059114Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Protein LRRC74A isoform 1 Homo sapiens". National Center for Biotechnology Information. U.S. National Library of Medicine. Retrieved 7 December 2022.
  6. ^ "LRRC74A". The Human Protein Atlas. Knut and Alice Wallenberg Foundation. Retrieved 7 December 2022.
  7. ^ a b c d "LRRC74A Leucine-rich Repeat-containing Protein 74A [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov.
  8. ^ "Genome Data Viewer - NCBI". www.ncbi.nlm.nih.gov. Retrieved 7 December 2022.
  9. ^ ""ExPASy - Compute pI/Mw tool"". Expasy.
  10. ^ "SAPS < Sequence Statistics < EMBL-EBI". www.ebi.ac.uk.
  11. ^ "protein LRRC74A isoform 1 [Homo sapiens] - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-12-13.
  12. ^ "A Protein Secondary Structure Prediction Server". JPred4.
  13. ^ "AlphaFold Protein Structure Database". alphafold.ebi.ac.uk. Retrieved 2022-12-13.
  14. ^ "I-TASSER". ZhangGroup.
  15. ^ "PSORT II Prediction". psort.hgc.jp. Retrieved 16 December 2022.
  16. ^ a b "Homo sapiens leucine rich repeat containing 74A (LRRC74A), transcript variant 1, mRNA". Retrieved 2022-12-13.
  17. ^ "RNA Folding Form". UNAFold.
  18. ^ "LRRC74B leucine rich repeat containing 74B [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 13 December 2022.
  19. ^ Kumar S, Stecher G, Suleski M. "TimeTree: The Timescale of Life". www.timetree.org. Retrieved 15 December 2022.
  20. ^ Pandit R, Singh I, Ansari A, Raval J, Patel Z, Dixit R, et al. (June 2022). "First report on genome wide association study in western Indian population reveals host genetic factors for COVID-19 severity and outcome". Genomics. 114 (4). doi:10.1016/j.ygeno.2022.110399. PMC 9169419. PMID 35680011.