RABGAP1encodes Rab GTPase-activating protein 1, a protein involved in regulation of Rab GTPases and several intracellular cellular processes, including vesicular trafficking, cell migration, mitosis and signaling through the mechanistic target of rapamycin (mTOR) pathway.
RABGAP1 has been reported to interact with several Rab GTPases, including RAB6A, RAB6B, RAB2, RAB4 and RAB36. The protein also has a role in intracellular lysosomal positioning and vesicular trafficking.
Disease-causing variants
The currently established disease mechanism is loss of function. The original report identified three different homozygous variants in five affected individuals from three unrelated families:
• NM_012197.3:c.591-1G>T, a canonical splice-site variant, identified in two siblings.
• NM_012197.3:c.1101+1del, a canonical splice-site variant, identified in one individual.
• NM_012197.3:c.1072C>T (p.Arg358*), a nonsense variant, identified in two siblings.
All three variants are predicted to result in loss of RABGAP1function and are located upstream of the TBC and C-terminal coiled-coil domains.
Functional studies of the c.591-1G>T variant demonstrated abnormal splicing, including loss of 8 base pairs from the 5′ end of exon 5, resulting in a predicted frameshift and premature termination codon. Reduced RABGAP1RNA levels were consistent with nonsense-mediated mRNA decay.
Functional consequences
Studies of patient-derived cells demonstrated reduced mTOR signaling, including decreased levels of phosphorylated AKT and phosphorylated S6. Abnormal intracellular localization of lysosomes and early endosomes was also observed.
These findings support a loss-of-function disease mechanism and suggest that abnormal vesicular trafficking and dysregulation of mTOR signaling contribute to the pathophysiology.
A Rabgap1 knockout mouse model demonstrated several overlapping features, including microcephaly, thinning of the corpus callosum and ventriculomegaly, providing additional evidence for the pathogenicity of loss of RABGAP1 function.
Diagnostic testing
Diagnosis should be considered in individuals with a compatible neurodevelopmental phenotype, particularly when severe global developmental delay/intellectual disability is accompanied by microcephaly, congenital bilateral sensorineural hearing loss, seizures and/or characteristic brain MRI abnormalities.
Molecular diagnosis can be established by identification of biallelic pathogenic or likely pathogenic RABGAP1variants using next-generation sequencing. Exome or genome sequencing is appropriate in the diagnostic evaluation of individuals with an unexplained neurodevelopmental disorder. If only one pathogenic variant is identified, additional analysis for a second variant, including copy-number or other structural variants where appropriate, may be considered.
RABGAP1