A novel variant in the SLCO2A1 gene in a Chinese patient with chronic gastroenteropathy and primary hypertrophic osteoarthropathy.
Chronic enteropathy associated with SLCO2A1 gene
DNA sequencing
Nonsense-mediated mRNA decay
Primary hypertrophic osteoarthropathy
Journal
Orphanet journal of rare diseases
ISSN: 1750-1172
Titre abrégé: Orphanet J Rare Dis
Pays: England
ID NLM: 101266602
Informations de publication
Date de publication:
11 Jun 2024
11 Jun 2024
Historique:
received:
21
08
2023
accepted:
19
05
2024
medline:
12
6
2024
pubmed:
12
6
2024
entrez:
11
6
2024
Statut:
epublish
Résumé
Chronic enteropathy associated with SLCO2A1 gene (CEAS) results from loss-of-function variants in SLCO2A1, which encodes the prostaglandin transporter (PGT). CEAS follows an autosomal recessive inheritance pattern. To date, approximate 30 pathogenic variants have been reported in CEAS. We performed whole exome sequencing (WES) to screen for potential pathogenic variants in a patient suspected of having CEAS, and confirmed a variant in SLCO2A1 using Sanger sequencing. We established an in vitro minigene model to compare splicing between wild type (WT) and mutant transcripts. Quantitative polymerase chain reaction (qPCR) was used to evaluate SLCO2A1 transcription in the stomach and colon tissues from the patient and a healthy control (HC). The transcripts were further cloned and sequenced. The patient had a novel, homozygous, recessive c.929A > G variant in exon 7 of SLCO2A1, which has not been previously reported in CEAS or PHO. This variant altered splicing, resulting in an exon 7-truncated transcript lacking 16 bases. No normal transcript was detected in the patient's stomach or colon tissue. qPCR also showed significantly decreased SLCO2A1 transcription compared to HC. A previously unreported variant caused defective SLCO2A1 splicing and reduced mRNA levels in a patient with CEAS and PHO. This research enhances understanding of CEAS and PHO pathophysiology and aids genetic counseling and diagnosis.
Sections du résumé
BACKGROUND
BACKGROUND
Chronic enteropathy associated with SLCO2A1 gene (CEAS) results from loss-of-function variants in SLCO2A1, which encodes the prostaglandin transporter (PGT). CEAS follows an autosomal recessive inheritance pattern. To date, approximate 30 pathogenic variants have been reported in CEAS.
METHODS
METHODS
We performed whole exome sequencing (WES) to screen for potential pathogenic variants in a patient suspected of having CEAS, and confirmed a variant in SLCO2A1 using Sanger sequencing. We established an in vitro minigene model to compare splicing between wild type (WT) and mutant transcripts. Quantitative polymerase chain reaction (qPCR) was used to evaluate SLCO2A1 transcription in the stomach and colon tissues from the patient and a healthy control (HC). The transcripts were further cloned and sequenced.
RESULTS
RESULTS
The patient had a novel, homozygous, recessive c.929A > G variant in exon 7 of SLCO2A1, which has not been previously reported in CEAS or PHO. This variant altered splicing, resulting in an exon 7-truncated transcript lacking 16 bases. No normal transcript was detected in the patient's stomach or colon tissue. qPCR also showed significantly decreased SLCO2A1 transcription compared to HC.
CONCLUSION
CONCLUSIONS
A previously unreported variant caused defective SLCO2A1 splicing and reduced mRNA levels in a patient with CEAS and PHO. This research enhances understanding of CEAS and PHO pathophysiology and aids genetic counseling and diagnosis.
Identifiants
pubmed: 38862970
doi: 10.1186/s13023-024-03221-x
pii: 10.1186/s13023-024-03221-x
doi:
Substances chimiques
SLCO2A1 protein, human
0
Organic Anion Transporters
0
Types de publication
Journal Article
Case Reports
Langues
eng
Sous-ensembles de citation
IM
Pagination
229Subventions
Organisme : Natural Science Foundation of Beijing Municipality
ID : 7212078
Organisme : CAMS Innovation Fund for Medical Sciences (CIFMS) from Chinese Academy of Medical Sciences
ID : 2021-I2M-1-062
Informations de copyright
© 2024. The Author(s).
Références
Umeno J, et al. A hereditary enteropathy caused by mutations in the SLCO2A1 gene, encoding a prostaglandin transporter. PLoS Genet. 2015;11(11):e1005581.
doi: 10.1371/journal.pgen.1005581
pubmed: 26539716
pmcid: 4634957
Busch J, et al. Mutations in the prostaglandin transporter SLCO2A1 cause primary hypertrophic osteoarthropathy with digital clubbing. J Invest Dermatol. 2012;132(10):2473–6.
doi: 10.1038/jid.2012.146
pubmed: 22696055
Hong HS, et al. Clinical and genetic characteristics of Korean patients diagnosed with chronic enteropathy associated with SLCO2A1 gene: a KASID multicenter study. Gut Liver. 2022;16:942.
doi: 10.5009/gnl210415
pubmed: 35611666
pmcid: 9668493
Nakanishi T, Nakamura Y, Umeno J. Recent advances in studies of SLCO2A1 as a key regulator of the delivery of prostaglandins to their sites of action. Pharmacol Ther. 2021;223:107803.
doi: 10.1016/j.pharmthera.2021.107803
pubmed: 33465398
Yap FY, et al. Hypertrophic osteoarthropathy: clinical and imaging features. Radiographics. 2017;37(1):157–95.
doi: 10.1148/rg.2017160052
pubmed: 27935768
Uchida K, et al. Pediatric-onset chronic nonspecific multiple ulcers of small intestine: a nationwide survey and genetic study in Japan. J Pediatr Gastroenterol Nutr. 2017;64(4):565–8.
doi: 10.1097/MPG.0000000000001321
pubmed: 27467110
Huang H, et al. Four variants of SLCO2A1 identified in three Chinese patients with chronic enteropathy associated with the SLCO2A1 gene. Dig Dis Sci. 2020;66(9):2992–3001.
doi: 10.1007/s10620-020-06629-0
pubmed: 33000396
Jimbo K, et al. A novel mutation in the SLCO2A1 gene, encoding a prostaglandin transporter, induces chronic enteropathy. PLoS ONE. 2020;15(11):e0241869.
doi: 10.1371/journal.pone.0241869
pubmed: 33166338
pmcid: 7652309
Gaildrat P, et al. Use of splicing reporter minigene assay to evaluate the effect on splicing of unclassified genetic variants. Methods Mol Biol. 2010;653:249–57.
doi: 10.1007/978-1-60761-759-4_15
pubmed: 20721748
Yanai S, et al. Distinction between chronic enteropathy associated with the SLCO2A1 gene and crohn’s disease. Gut Liver. 2019;13(1):62–6.
doi: 10.5009/gnl18261
pubmed: 30400730
pmcid: 6347011
Umeno J, et al. Clinical features of chronic enteropathy associated with SLCO2A1 gene: a new entity clinically distinct from crohn’s disease. J Gastroenterol. 2018;53(8):907–15.
doi: 10.1007/s00535-017-1426-y
pubmed: 29313109
pmcid: 6061663
Sonoda A, et al. Characteristic facial appearance was the key to diagnosing chronic enteropathy associated with SLCO2A1-associated primary hypertrophic osteoarthropathy. Intern Med. 2020;59(4):491–4.
doi: 10.2169/internalmedicine.3369-19
pubmed: 31611528
Hu P, et al. Chronic enteropathy associated with SLCO2A1 gene: A case report and literature review. Clin Res Hepatol Gastroenterol. 2019;43(5):e68–72.
doi: 10.1016/j.clinre.2019.05.003
pubmed: 31196708