RAB23 – RAB23-related Carpenter syndrome

RAB23-related Carpenter syndrome is an autosomal recessive acrocephalopolysyndactyly disorder characterized by multisuture craniosynostosis, polysyndactyly, obesity, and other malformations. The phenotype arises from biallelic loss-of-function mutations in RAB23 affecting vesicular transport and Hedgehog signaling (PMID:34748996).

Two unrelated consanguineous Egyptian families presented with Carpenter syndrome features: Patient 1 harbored a novel homozygous missense variant c.416T>C (p.Leu139Pro) and Patient 2 a novel homozygous splice-site variant c.398+1G>A, expanding clinical variability to include overgrowth, advanced bone age, epileptiform EEG changes, and autistic features (PMID:34748996). An additional Emirati consanguineous family exhibited a homozygous intronic mutation c.482-1G>A activating a cryptic splice site, resulting in an eight–nucleotide deletion and frameshift (p.Val161Ter), abolishing the C-terminal prenylation motif (PMID:23599695).

Segregation of these variants with disease in three families and absence in unaffected relatives supports recessive inheritance. No other affected relatives beyond sib-pair segregation were reported.

Functional analyses demonstrate that the c.482-1G>A splice mutation disrupts authentic mRNA splicing and yields a truncated protein unable to prenylate and associate with membranes (PMID:23599695). High-resolution crystal structures of human Rab23 and the clinical Y79del mutant reveal switch II distortions that abrogate GTP-dependent partner binding, consistent with a loss-of-function mechanism in Carpenter syndrome (PMID:39615683).

Collectively, the genetic and functional findings demonstrate that RAB23 mutations cause loss-of-function leading to Carpenter syndrome through defective vesicular transport and Hedgehog pathway dysregulation.

Key Take-home: Biallelic RAB23 variants confer autosomal recessive Carpenter syndrome; molecular diagnosis can guide early craniofacial and metabolic management.

References

• European Journal of Medical Genetics • 2022 • Expansion of the phenotypic and mutational spectrum of Carpenter syndrome. PMID:34748996
• Molecular Syndromology • 2013 • A Novel Aberrant Splice Site Mutation in RAB23 Leads to an Eight Nucleotide Deletion in the mRNA and Is Responsible for Carpenter Syndrome in a Consanguineous Emirati Family. PMID:23599695
• The Journal of Biological Chemistry • 2025 • Structural basis for Rab23 activation and a loss-of-function mutation in Carpenter syndrome. PMID:39615683

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