View source for LRRC74A

{{Short description|Protein-coding gene}}
{{infobox gene}}
'''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 [[Dalton (unit)|kDa]].<ref>{{cite web |title=Protein LRRC74A isoform 1 Homo sapiens |access-date=7 December 2022 |website=National Center for Biotechnology Information |publisher=U.S. National Library of Medicine |url=https://www.ncbi.nlm.nih.gov/protein/NP_919263.2}}</ref> The LRRC74A protein is nominally expressed in the testis, salivary gland, and pancreas.<ref>{{cite web |title=LRRC74A |url=https://www.proteinatlas.org/ENSG00000100565-LRRC74A/tissue |access-date=7 December 2022 |website=The Human Protein Atlas |publisher=Knut and Alice Wallenberg Foundation}}</ref>
== Gene ==
The LRRC74A gene, also known as C14orf166B, is located on the [[Sense (molecular biology)|positive-sense]] strand of locus 14q24.3. The full unspliced gene contains 17 [[exon]]s.<ref name=":0">{{cite web |title=LRRC74A Leucine-rich Repeat-containing Protein 74A [Homo sapiens (human)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene/145497 |website=www.ncbi.nlm.nih.gov}}</ref> LRRC74A spans from 76,826,408 to 76,870,304 for a total length of 43.9 kpb.<ref>{{cite web |title=Genome Data Viewer - NCBI |url=https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=145497 |access-date=7 December 2022 |website=www.ncbi.nlm.nih.gov}}</ref>
=== Transcripts ===
LRRC74A has four [[Alternative splicing|transcript variants]]. The most abundant variant is LRRC74A transcript variant 1, which is 1710 [[Nucleotide|nucleotides]] in length.<ref name=":0" />
{| class="wikitable"
|+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 mass|molecular weight]] of 55 kDA and an [[isoelectric point]] of 5.22.<ref>{{cite web |title="ExPASy - Compute pI/Mw tool" |url=https://web.expasy.org/compute_pi/ |website=Expasy}}</ref> It has higher than normal levels of [[methionine]] and [[asparagine]].<ref>{{cite web |title=SAPS < Sequence Statistics < EMBL-EBI |url=https://www.ebi.ac.uk/Tools/seqstats/saps/ |website=www.ebi.ac.uk}}</ref>
=== Domains and structure ===
The LRRC74A protein contains eight leucine-rich repeat domains in its sequence.<ref>{{Cite web |title=protein LRRC74A isoform 1 [''Homo sapiens''] - Protein - NCBI |url=https://www.ncbi.nlm.nih.gov/protein/NP_919263.2 |access-date=2022-12-13 |website=www.ncbi.nlm.nih.gov}}</ref> LRRC74A isoform 1 [[Protein secondary structure|secondary structure]] is made up of alternating [[Alpha helix|alpha helices]] and [[beta sheet]]s.<ref>{{Cite web |title=A Protein Secondary Structure Prediction Server |url=https://www.compbio.dundee.ac.uk/jpred/ |website=JPred4}}</ref>  [[Protein tertiary structure|Tertiary structure]] predictions show a horseshoe-shaped protein with high similarity to [[ribonuclease inhibitor]]<ref>{{Cite web |title=AlphaFold Protein Structure Database |url=https://alphafold.ebi.ac.uk/entry/Q0VAA2 |access-date=2022-12-13 |website=alphafold.ebi.ac.uk}}</ref>
[[File:Lrrc74aITASSER.gif|thumb|LRRC74A Tertiary Structure prediction by I-TASSER]]<ref>{{Cite web |title=I-TASSER |url=https://zhanggroup.org/I-TASSER/ |website=ZhangGroup}}</ref>
=== Isoforms ===
LRRC74A has four [[Alternative splicing|splice isoforms]]. The most abundant isoform is LRRC74A protein isoform 1 which is 488 amino acids in length.<ref name=":0" />
{| class="wikitable"
|+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.<ref name=":0" /> Within the [[Cell (biology)|cell]], LRRC74A is localized to the [[cytosol]].<ref>{{cite web |title=PSORT II Prediction |url=https://psort.hgc.jp/form2.html |access-date=16 December 2022 |website=psort.hgc.jp}}</ref>
=== Transcript level regulation ===
[[File:Lrrc74a5UTR.png|thumb|Predicted 5' UTR folding structure of LRRC74A]]
The [[5' UTR]] of LRRC74A transcript variant 1 is 91 bp in length.<ref name=":2">{{Cite web |title=Homo sapiens leucine rich repeat containing 74A (LRRC74A), transcript variant 1, mRNA |access-date=2022-12-13 |url=https://www.ncbi.nlm.nih.gov/nuccore/NM_194287.3 |language=en-US}}</ref> Analysis of potential folding structures identifies two possible stemloop structures.<ref>{{Cite web |title=RNA Folding Form |url=http://www.unafold.org/mfold/applications/rna-folding-form.php |website=UNAFold}}</ref>
[[File:Lrrc74a3utr.png|thumb|Predicted folding structure of the 3' UTR of LRRC74A]]
The 3' UTR is 158 bp in length and contains one polyadenylation signal.<ref name=":2" /> 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 [[Sequence homology|paralog]] called LRRC74B. It is located at 22q11.21<ref>{{cite web |title=LRRC74B leucine rich repeat containing 74B [Homo sapiens (human)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene/400891 |access-date=13 December 2022 |website=www.ncbi.nlm.nih.gov}}</ref>
=== Orthologs ===
LRRC74A has [[Sequence homology|orthologs]] in species as distant as [[tunicate]]s. 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.
[[File:Lrrc74atree.png|thumb|Unrooted phylogenetic tree depicting the evolution of LRRC74A]]
{| class="wikitable"
!
! Genus species
! Common name
! Taxonomic order
! Estimated date of divergence (MYA)
! Accession number
! Sequence length (aa)
! Sequence identity (%)
! Sequence similarity (%)
|-
|[[Mammal|Mammalia]]
|[[Human|''Homo sapiens'']]
|Human
|[[Primate|Primates]]
|0
|NP_919263.2
|488
|100
|100
|-
|
|[[House mouse|''Mus musculus'']]
|Mouse
|[[Rodent|Rodentia]]
|87
|NP_001182696.1
|487
|65.7
|77.4
|-
|
|[[Wolverine|''Gulo gulo'']]
|Wolverine
|[[Carnivora]]
|94
|KAI5767761.1
|488
|74.6
|86.3
|-
|
|[[Polar bear|''Ursus maritimus'']]
|Polar bear
|[[Carnivora]]
|94
|XP_040497188.1
|548
|60.6
|70.6
|-
|
|[[Blue whale|''Balaenoptera musculus'']]
|Blue whale
|[[Even-toed ungulate|Artiodactyla]]
|94
|XP_036697954.1
|482
|68.9
|80.1
|-
|
|[[Agile gracile opossum|''Gracilinanus agilia'']]
|Agile gracile opossum
|[[Marsupialia]]
|106
|XP_044518037.1
|468
|52.5
|71.5
|-
|[[Bird|Aves]]
|[[Chicken|''Gallus gallus'']]
|Chicken
|[[Galliformes]]
|319
|XP_040528719.1
|476
|42.8
|60.9
|-
|
|[[Budgerigar|''Melopsittacus undulatus'']]
|Budgerigar
|[[Psittaciformes]]
|319
|XP_005149032.1
|494
|46.4
|64.6
|-
|
|[[Golden eagle|''Aquila chrysaetos'']]
|Golden eagle
|[[Accipitriformes]]
|319
|XP_029863093.1
|492
|46
|62.1
|-
|
|[[White-tailed tropicbird|''Phaethon lepturus'']]
|White-tailed tropicbird
|[[Phaethontiformes]]
|319
|XP_010285698.1
|478
|44.3
|61.5
|-
|[[Reptile|Reptilia]]
|[[Chinese softshell turtle|''Pelodiscus sinensis'']]
|Chinese softshell turtle
|[[Turtle|Testudines]]
|319
|XP_025037771.1
|486
|49.5
|68
|-
|
|[[Central bearded dragon|''Pogona vitticeps'']]
|Central bearded dragon
|[[Squamata]]
|319
|XP_020649579.1
|483
|48
|64.5
|-
|
|[[Tiger snake|''Notechis scutatus'']]
|Tiger snake
|[[Squamata]]
|319
|XP_026520078.1
|491
|45.2
|61.9
|-
|[[Amphibian|Amphibia]]
|''[[Geotrypetes seraphini]]''
|Gaboon caecilian
|[[Caecilian|Gymnophiona]]
|353
|XP_033809167.1
|540
|35.6
|50.3
|-
|
|''[[Bufo bufo]]''
|Common toad
|[[Frog|Anura]]
|353
|XP_040268304.1
|536
|34.5
|51.4
|-
|[[Fish]]
|[[West Indian Ocean coelacanth|''Latimeria chalumnae'']]
|West Indian Ocean coelacanth
|[[Latimeriidae]]
|414
|XP_014341482.1
|456
|47.5
|66.2
|-
|
|[[Spotted gar|''Lepisosteus oculatus'']]
|Spotted gar
|[[Lepisosteiformes]]
|431
|XP_015205589.1
|450
|42
|62.5
|-
|
|[[Atlantic salmon|''Salmo salar'']]
|Atlantic salmon
|[[Salmoniformes]]
|431
|XP_045549789.1
|648
|32.3
|45.1
|-
|
|[[Great white shark|''Carcharodon carcharias'']]
|Great white shark
|[[Chondrichthyes]]
|464
|XP_041070161.1
|727
|24
|37.4
|-
|
|[[Sea lamprey|''Petromyzon marinus'']]
|Sea lamprey
|[[Agnatha]]
|510
|XP_032820627.1
|510
|32.1
|49.6
|-
|[[Invertebrate|Invertebrata]]
|''[[Ciona intestinalis]]''
|Vase tunicate
|[[Ascidiacea|Enterogona]]
|603
|XP_002120047.1
|661
|24.5
|40.6
|}
=== Evolution ===
[[File:Lrrc74aevorate.png|thumb|]]
The LRRC74A gene appears most distantly in tunicates which diverged from humans approximately 603 million years ago.<ref>{{cite web |vauthors=Kumar S, Stecher G, Suleski M |title=TimeTree: The Timescale of Life |url=http://www.timetree.org/ |access-date=15 December 2022 |website=www.timetree.org}}</ref> 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 chain|fibrinogen alpha]].
== Clinical significance ==
=== Disease association ===
==== COVID-19 ====
A [[Genome-wide association study|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.<ref>{{cite journal |display-authors=6 |vauthors=Pandit R, Singh I, Ansari A, Raval J, Patel Z, Dixit R, Shah P, Upadhyay K, Chauhan N, Desai K, Shah M, Modi B, Joshi M, Joshi C |date=June 2022 |title=First report on genome wide association study in western Indian population reveals host genetic factors for COVID-19 severity and outcome |journal=Genomics |volume=114 |issue=4 |doi=10.1016/j.ygeno.2022.110399|pmc=9169419 |pmid=35680011}}</ref>
==References==
{{Reflist}}