A synonymous NPR2 variant causes acromesomelic dysplasia through aberrant pre-mRNA splicing

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Precise pre-mRNA splicing is vital for development; disruptions cause human diseases.
• Loss-of-function variants in the NPR2 gene cause acromesomelic dysplasia, Maroteaux type (AMDM).

Purpose of the Study:

• To identify the pathogenic mechanism of a synonymous NPR2 variant (c.2484C>T) in an individual with AMDM.
• To investigate the role of aberrant splicing in NPR2 function and skeletal development.

Main Methods:

• In silico splice site analysis.
• Functional analysis of patient-derived leukocyte RNA.
• Transcript-level analysis of NPR2 splicing.

Main Results:

• A homozygous synonymous NPR2 variant (c.2484C>T) was identified in an AMDM patient.
• The variant induced aberrant splicing, leading to partial exon truncation, frameshift, and premature termination of NPR2.
• Affected individuals exclusively expressed the aberrant NPR2 transcript, indicating a dosage-dependent loss-of-function.

Conclusions:

• Aberrant splicing caused by a synonymous variant is a disease-causing mechanism affecting skeletal development.
• Transcript-level analysis is crucial for interpreting rare variants.
• Precise RNA processing is central to skeletal development and human disease.