LRRC74A

LRRC74A
Identifiers
Aliases	LRRC74A , C14orf166B, LRRC74, leucine rich repeat containing 74A
External IDs	MGI: 3646959; HomoloGene: 19331; GeneCards: LRRC74A; OMA:LRRC74A - orthologs
Gene location (Human) Chr. Chromosome 14 (human) [1] Band 14q24.3 Start 76,826,372 bp [1] End 76,870,304 bp [1]
Gene location (Mouse) Chr. Chromosome 12 (mouse) [2] Band 12|12 D2 Start 86,781,143 bp [2] End 86,810,571 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in left testis right testis sperm gonad muscle tissue face body of pancreas sensory nervous system sensory organ mouth Top expressed in spermatid seminiferous tubule spermatocyte lumbar subsegment of spinal cord pancreas islet of Langerhans liver More reference expression data BioGPS n/a
Orthologs Species Human Mouse Entrez 145497 627607 Ensembl ENSG00000100565 ENSMUSG00000059114 UniProt Q0VAA2 F6QBN8 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 Mb Chr 12: 86.78 – 86.81 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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]

Gene

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

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

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

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

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

Expression pattern

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

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

Paralogs

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

Orthologs

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

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

Disease association

COVID-19

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

1. GRCh38: Ensembl release 89: ENSG00000100565 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000059114 – Ensembl, 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. "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. "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.