SF3B4 – Rodriguez Acrofacial Dysostosis

SF3B4 encodes a core U2 snRNP component critical for pre-mRNA splicing. Heterozygous loss-of-function variants in SF3B4 underlie autosomal dominant Rodriguez acrofacial dysostosis (Rodriguez acrofacial dysostosis) by disrupting craniofacial and limb development (PMID:27642715).

Exome sequencing in affected families identified six unrelated probands with de novo frameshift or splice-site variants in SF3B4, including two distinct heterozygous frameshift alleles in three of four fetuses and one splicing variant c.35-2A>G in a 22-week fetus (PMID:27642715). Three affected siblings in one kindred arose via parental gonadal mosaicism, confirming segregation in multiple relatives (PMID:27642715). The consistent truncating and splice-site variant spectrum implicates haploinsufficiency as the primary mechanism.

Functional analyses in patient cells and model organisms corroborate SF3B4 haploinsufficiency. In PLoS Genetics, heterozygous SF3B4 mutations caused aberrant exon skipping, reduced growth-plate chondrocyte expression of DLX5, DLX6, SOX9, and SOX6, and abnormal skeletal development in vitro (PMID:27622494). Sf3b4+/- mice exhibited homeotic posteriorization of vertebrae, flattened calvaria, microcephaly, and reduced forebrain proliferation, mirroring human craniofacial and axial defects (PMID:31900962). In zebrafish, sf3b4 deficiency led to craniofacial and segmentation anomalies that were rescued by exogenous Fgf8, confirming dosage sensitivity and non-splicing roles in NCC survival (PMID:39288852).

No conflicting data disputing the SF3B4–Rodriguez association have been reported. Collectively, genetic and experimental evidence establish a strong, autosomal dominant gene-disease relationship driven by SF3B4 haploinsufficiency. Key take-home: truncating or splice SF3B4 variants should be considered diagnostic for Rodriguez acrofacial dysostosis and guide genetic counseling and potential FGF8-based therapeutic strategies.

References

• American Journal of Medical Genetics Part A • 2016 • Rodriguez acrofacial dysostosis is caused by apparently de novo heterozygous mutations in the SF3B4 gene. PMID:27642715
• PLoS Genetics • 2016 • Altered mRNA Splicing, Chondrocyte Gene Expression and Abnormal Skeletal Development due to SF3B4 Mutations in Rodriguez Acrofacial Dysostosis. PMID:27622494
• Developmental Dynamics • 2020 • Heterozygous mutation of the splicing factor Sf3b4 affects development of the axial skeleton and forebrain in mouse. PMID:31900962
• International Journal of Biological Macromolecules • 2024 • Fgf8 contributes to the pathogenesis of Nager syndrome. PMID:39288852

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