RAB3GAP1 – Warburg micro syndrome 1

Warburg micro syndrome 1 is a rare autosomal recessive neurodevelopmental disorder characterized by severe intellectual disability, postnatal microcephaly, congenital cataracts, microcornea, microphthalmia, hypogenitalism and corpus callosum hypoplasia. Biallelic loss‐of‐function mutations in RAB3GAP1 disrupt the RAB3 GTPase‐activating complex, leading to deficient RAB3 cycle regulation in neuronal and ocular tissues. A recurrent splice donor variant, c.748+1G>A, and multiple nonsense and frameshift mutations (e.g., c.2011C>T (p.Arg671Ter)) have been reported in homozygosity across diverse populations (PMID:22768674; PMID:18286824; PMID:32740904).

Genetic evidence includes 33 unrelated probands with biallelic RAB3GAP1 mutations and segregation of disease alleles in seven affected relatives across consanguineous pedigrees (PMID:22768674; PMID:32740904). The variant spectrum comprises 14 splice or canonical ±1,2 variants, 12 nonsense/frameshift alleles and novel missense changes in conserved domains, with recurrent founder alleles in Turkish and Pakistani cohorts (PMID:36876345; PMID:37186309).

Functional studies demonstrate that RAB3GAP1 deficiency leads to aberrant lipid droplet formation and impaired exocytic vesicle cycling in fibroblasts, and reduced neurite outgrowth in human stem cell–derived neurons. Splice site mutations (e.g., c.2607-1G>C) cause exon skipping and transcript decay, confirmed by RT-PCR and qRT-PCR (PMID:33910511). Downregulation of RAB3GAP1 alters subcellular localization of ER–Golgi trafficking factors and activates cellular stress pathways (ATF6, MAPK, PI3-AKT) in neuronal models (PMID:37385458).

No studies to date have refuted the RAB3GAP1–Warburg micro syndrome 1 association. The constellation of genetic, segregation and functional data yield a definitive gene–disease relationship with consistent phenotypic correlation and mechanistic insight.

Key take-home: RAB3GAP1 sequencing should be prioritized in patients with microcephaly, ocular anomalies and hypogenitalism to enable precise diagnosis, family planning and potential inclusion in future therapy trials.

References

• Journal of pediatric endocrinology & metabolism : JPEM • 2012 • Warburg Micro syndrome. PMID:22768674
• Genetic counseling (Geneva, Switzerland) • 2007 • Phenotypic variability in Micro syndrome: report of new cases. PMID:18286824
• Clinical genetics • 2020 • Micro and Martsolf syndromes in 34 new patients: Refining the phenotypic spectrum and further molecular insights. PMID:32740904
• BMC neurology • 2021 • Novel manifestations of Warburg micro syndrome type 1 caused by a new splicing variant of RAB3GAP1: a case report. PMID:33910511
• Neurobiology of disease • 2023 • The Warburg micro syndrome protein RAB3GAP1 modulates neuronal morphogenesis and interacts with axon elongation end ER-Golgi trafficking factors. PMID:37385458
• International journal of developmental neuroscience • 2023 • Exome sequencing identifies a novel pathogenic variant in RAB3GAP1 causing Warburg Micro syndrome in a Pakistani family. PMID:37186309

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