Functional insight into a neurodevelopmental disorder caused by missense variants in an RNA-binding protein, RBM10

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• RNA-binding motif protein 10 (RBM10) is a crucial RNA splicing regulator for development.
• Loss-of-function RBM10 variants cause TARP syndrome, a severe X-linked condition.
• Understanding RBM10's role in milder phenotypes is essential for comprehensive genotype-phenotype correlation.

Observation:

• A 3-year-old male presented with a mild phenotype including cleft palate, hypotonia, and developmental delay.
• This patient carried a novel missense RBM10 variant (c.943T>C, p.Ser315Pro) in the RRM2 RNA-binding domain.
• The p.Ser315Pro mutant protein showed normal nuclear localization but reduced expression and stability.

Findings:

• While the RRM2 domain's structure and RNA-binding were unaffected by p.Ser315Pro, alternative splicing of downstream genes (NUMB, TNRC6A) was altered.
• The splicing alterations were transcript-dependent, indicating a nuanced impact on gene regulation.
• This novel germline variant results in functional changes in downstream gene expression, leading to a non-lethal phenotype.

Implications:

• This study expands the spectrum of RBM10-associated disorders, linking a missense variant to milder developmental outcomes.
• The findings highlight that the precise functional consequences of RBM10 variants depend on the affected residues and downstream targets.
• Further research into RBM10 genotype-phenotype relationships can improve diagnosis and understanding of its molecular mechanisms.