Defining the Contribution of Genetic Variants in MRGPRX4 With Pruritus in Paediatric Cholestasis: Evidence From...

Area of Science:

• Genetics and Genomics
• Hepatology
• Pediatric Gastroenterology

Background:

• Cholestatic pruritus is a significant symptom in pediatric liver diseases, with unclear underlying mechanisms.
• The Mas-related G protein-coupled receptor X4 (MRGPRX4), a bile acid receptor, is implicated in itch signaling.
• The role of single nucleotide variants (SNVs) in MRGPRX4 concerning cholestatic pruritus is not well understood.

Purpose of the Study:

• To investigate the association between MRGPRX4 coding region SNVs and cholestatic pruritus in children with liver disease.
• To identify specific MRGPRX4 variants that may contribute to or protect against pruritus.

Main Methods:

• A case-control study was conducted with pediatric patients diagnosed with Alagille syndrome, PFIC, biliary atresia, or PSC.
• Patients were categorized into cases (with pruritus) and controls (without pruritus).
• Targeted sequencing of the MRGPRX4 gene was performed, and clinical data, including bile acid levels, were collected.

Main Results:

• All 36 participants (17 cases, 19 controls) carried at least one MRGPRX4 SNV; eleven unique SNVs were identified.
• No single SNV showed a significant overall association with pruritus.
• Certain co-occurring variants (Phe8Leu, Asn25Lys, Tyr215Tyr) were less frequent in pruritic patients, while a rare Lys11Glu variant was found only in non-pruritic patients.

Conclusions:

• The functional impact of identified MRGPRX4 variants remains to be determined.
• Specific variants, such as Phe8Leu, Asn25Lys, and Lys11Glu, may influence MRGPRX4 activity and potentially modulate cholestatic pruritus.
• Larger cohort studies are necessary to clarify the mechanistic and clinical significance of these MRGPRX4 variants in pediatric cholestatic pruritus.