PMID- 37479888
OWN - NLM
STAT- MEDLINE
DCOM- 20240206
LR  - 20240206
IS  - 1434-9949 (Electronic)
IS  - 0770-3198 (Linking)
VI  - 42
IP  - 11
DP  - 2023 Nov
TI  - A novel missense compound heterozygous variant in TLR1 gene is associated with 
      susceptibility to rheumatoid arthritis - structural perspective and functional 
      annotations.
PG  - 3097-3111
LID - 10.1007/s10067-023-06702-9 [doi]
AB  - INTRODUCTION: Besides human leukocyte antigen (HLA-DRB1) locus, more than 100 
      loci across the genome have been identified and linked with the onset, expression 
      and/or progression of rheumatoid arthritis (RA). However, there are still grey 
      areas in our understanding of the key genetic contributors of the disease, 
      particularly in familial cases. METHODS: In the present study, we have performed 
      the whole exome sequencing (WES) of RA patients from two consanguineous families 
      of Pakistan in a quest to identify novel, high-impact, RA-susceptibility genetic 
      variants. RESULTS: Through stepwise filtering, around 17,000 variants (common in 
      the affected members) were recognized, out of which 2651 were predicted to be 
      deleterious. Of these, 196 had direct relevance to RA. When selected for 
      homozygous recessive mode of inheritance, two novel pathogenic variants 
      (c.1324T>C, p.Cys(442)-->Arg(442); c.2036T>C, p.Ile(679)-->Thr(679)) in the TLR1 gene 
      displayed the role of compound heterozygosity in modulating the phenotypic 
      expression and penetrance of RA. The structural and functional consequences of 
      the TLR1 missense single nucleotide mutations (Cys(442)-->Arg(442); 
      Ile(679)-->Thr(679)) were evaluated through molecular dynamic simulation (MDS) 
      studies. Analysis showed domain's rigidification, conferring stability to mutant 
      TLR1-TIR/TIRAP-TIR complex with concomitant increase in molecular interactions 
      with pro-inflammatory cytokines, compared to the wild-type conformation. Gene 
      co-expression network analysis highlighted interlinked partnering genes along 
      with interleukin-6 production of TLR1 (corrected p-value 2.98e-4) and 
      acetylcholine receptor activity of CHRNG (corrected p-value 6.12e-2) as highly 
      enriched associated functions. CONCLUSION: The results, validated through 
      case-control study subjects, suggested that the variants identified through WES 
      and confirmed through Sanger sequencing and MDS are the novel disease variants 
      and are likely to confer RA-susceptibility, independently and/or in a 
      family-specific context. Key Points * Exploration of population 
      based/ethno-specific big data is imperative to identify novel causal variants of 
      RA. * Two new deleterious missense mutations in mutational hotspot exon 4 of TLR1 
      gene have been identified in Pakistani RA patients. * MD simulation data provides 
      evidence for domain's rigidification, conferring stability to mutant 
      TLR1-TIR/TIRAP-TIR complex, with concomitant increase in production of 
      pro-inflammatory cytokines, thus adding to the onset/erosive outcome of RA.
CI  - (c) 2023. The Author(s), under exclusive licence to International League of 
      Associations for Rheumatology (ILAR).
FAU - Pasha, Usman
AU  - Pasha U
AD  - School of Biochemistry and Biotechnology, University of the Punjab, Lahore, 
      54590, Pakistan.
FAU - Hanif, Kiran
AU  - Hanif K
AD  - School of Biochemistry and Biotechnology, University of the Punjab, Lahore, 
      54590, Pakistan.
FAU - Nisar, Haseeb
AU  - Nisar H
AD  - School of Biochemistry and Biotechnology, University of the Punjab, Lahore, 
      54590, Pakistan.
AD  - Department of Life Sciences, University of Management and Technology, Lahore, 
      Pakistan.
FAU - Abid, Rizwan
AU  - Abid R
AD  - School of Biochemistry and Biotechnology, University of the Punjab, Lahore, 
      54590, Pakistan.
FAU - Mirza, Muhammad Usman
AU  - Mirza MU
AD  - Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for 
      Medical Research, Medicinal Chemistry, University of Leuven, Leuven, Belgium.
FAU - Wajid, Bilal
AU  - Wajid B
AD  - Department of Computer Engineering, University of Engineering and Technology, 
      Lahore, Pakistan.
FAU - Sadaf, Saima
AU  - Sadaf S
AUID- ORCID: 0000-0002-5680-7976
AD  - School of Biochemistry and Biotechnology, University of the Punjab, Lahore, 
      54590, Pakistan. saima.sbb@pu.edu.pk.
LA  - eng
GR  - 8488/2017/Higher Education Commision, Pakistan/
PT  - Journal Article
DEP - 20230721
PL  - Germany
TA  - Clin Rheumatol
JT  - Clinical rheumatology
JID - 8211469
RN  - 0 (Cytokines)
RN  - 0 (Toll-Like Receptor 1)
RN  - 0 (TLR1 protein, human)
SB  - IM
MH  - Humans
MH  - *Arthritis, Rheumatoid/genetics
MH  - Case-Control Studies
MH  - Cytokines
MH  - Genetic Predisposition to Disease
MH  - *Mutation, Missense
MH  - Toll-Like Receptor 1/genetics
OTO - NOTNLM
OT  - Autoimmunity
OT  - Consanguineous
OT  - Exome sequencing
OT  - Rheumatoid arthritis
OT  - Single nucleotide mutation
OT  - Toll-like receptor
EDAT- 2023/07/22 10:42
MHDA- 2024/01/29 06:43
CRDT- 2023/07/21 23:29
PHST- 2023/01/12 00:00 [received]
PHST- 2023/07/13 00:00 [accepted]
PHST- 2023/07/07 00:00 [revised]
PHST- 2024/01/29 06:43 [medline]
PHST- 2023/07/22 10:42 [pubmed]
PHST- 2023/07/21 23:29 [entrez]
AID - 10.1007/s10067-023-06702-9 [pii]
AID - 10.1007/s10067-023-06702-9 [doi]
PST - ppublish
SO  - Clin Rheumatol. 2023 Nov;42(11):3097-3111. doi: 10.1007/s10067-023-06702-9. Epub 
      2023 Jul 21.