LRRC74A

Leucine-rich repeat-containing protein 74A, is a protein encoded by the LRRC74A gene. The protein LRRC74A is localized in the cytoplasm. It has a calculated molecular weight of approximately 55 kDa. The LRRC74A protein is nominally expressed in the testis, salivary gland, and pancreas.

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. LRRC74A spans from 76,826,408 to 76,870,304 for a total length of 43.9 kpb.

Transcripts

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

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. It has higher than normal levels of methionine and asparagine.

Domains and structure

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

Isoforms

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

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. Within the cell, LRRC74A is localized to the cytosol.

Transcript level regulation

The 5' UTR of LRRC74A transcript variant 1 is 91 bp in length. Analysis of potential folding structures identifies two possible stemloop structures.
The 3' UTR is 158 bp in length and contains one polyadenylation signal. 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

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.

	Genus species	Common name	Taxonomic order	Estimated date of divergence	Accession number	Sequence length	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. 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.