The TRAPPC6BGene and Protein
The TRAPPC6Bgene (OMIM *610397) is located on chromosome 14q21 and encodes Trafficking Protein Particle Complex Subunit 6B (TRAPPC6B), a core subunit of the TRAPP II (Transport Protein Particle) complex. TRAPPC6B plays a critical role in regulating vesicle trafficking between the endoplasmic reticulum (ER) and the Golgi apparatus.
Type of Mutations
All reported pathogenic variants in TRAPPC6Bare biallelic loss-of-function mutations:
• Homozygous splice-site variants (most common)
• Homozygous nonsense (stop-gain) variants
• Compound heterozygous variants (associated with milder phenotype)
• Homozygous missense variants (rare; pathogenicity uncertain in some cases)
The Egyptian Founder Variant
A recurrent homozygous splice-site founder mutation (c.82-2A>G (NM_177452.3) was first identified by Marin-Valencia, Zaki et al. (2018) in 6 patients from 3 unrelated consanguineous Egyptian families. This variant leads to skipping of exon 2, frameshift, and premature protein truncation (p.Glu28Valfs*11). Haplotype analysis confirmed a founder effect in the Egyptian population.
Other Reported Variants
• c.124C>T, p.(Arg42*)— homozygous nonsense; Pakistani family (Harripaul et al. 2018)
• c.23T>A, p.(Leu8*) — homozygous nonsense; Lebanese family (Nair et al. 2019)
• Multiple additional splice-site and nonsense variants across 18 families (Almousa et al. 2024)
Pathophysiologic Mechanism
Loss-of-function variants in TRAPPC6Bdisrupt the stability of the TRAPP II complex by weakening the interaction between TRAPPC6B and its binding partner TRAPPC3. This leads to:
• Decreased protein expression of TRAPPC6B and TRAPP II members (TRAPPC9, TRAPPC10)
• Reduced rate of ER-to-Golgi protein trafficking
• Golgi fragmentation (rescued by wild-type TRAPPC6B transfection)
In zebrafish models, loss of trappc6b led to decreased head, neuronal hyperexcitability, and lower seizure threshold, closely replicating the human phenotype.
Diagnostic Testing
• Next-generation sequencing (NGS): gene panels for intellectual disability/microcephaly or whole exome sequencing (WES) are the recommended diagnostic approaches
• Sanger sequencing: for confirmation of identified variants and family segregation analysis
• In Egyptian populations: targeted testing for the founder variant c.82-2A>G may be considered as a first-line approach
Figure 3:Schematic of the TRAPP complex showing TRAPPC6Bas a core subunit; effect of the founder splice mutation on TRAPPC6Btranscripts
