A homozygous founder splice-site variant in the TRAPPC6B gene was identified in six individuals from three unrelated Egyptian families presenting with a neurodevelopmental disorder characterized by autistic features (poor social interaction and motor stereotypies such as hand flapping), motor delay, delayed or absent speech, epilepsy, and microcephaly (Marin-Valencia et al., 2017). In the same report, zebrafish trappc6b morphants were found to exhibit reduced head size and lowered seizure threshold, thereby replicating the human phenotype. A homozygous nonsense variant in the TRAPPC6B gene had previously been identified in a consanguineous family with two individuals presenting with autosomal-recessive intellectual disability (Harripaul et al., 2017).
Molecular Function
TRAPPC6B is a component of TRAPP complexes, which are tethering complexes involved in vesicle transport. It may play a role in vesicular transport from endoplasmic reticulum to Golgi.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features.
Zebrafish trappc6b morphants replicated the human phenotype, displaying decreased head size and neuronal hyperexcitability, leading to a lower seizure threshold.
References
Type
Title
Author, Year
Primary
A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features.
Model Type:
Genetic
Model Genotype:
Wild type
Mutation:
Zebrafish with trappc6b knocked down using 10ng translation blocking morpholinos.
Allele Type: Knockdown
Strain of Origin: Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Wild type
Mutation:
Zebrafish with trappc6b knocked down using 10ng translation blocking morpholinos and treated with 5mM PTZ after baseline recording for neuronal activity. Seizure threshold was assessed using pentylenetetrazol (PTZ).
Allele Type: Knockdown
Strain of Origin: Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Wild type
Mutation:
Zebrafish with trappc6b knocked down using 1ng translation blocking morpholinos.
Allele Type: Knockdown
Strain of Origin: Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Wild type
Mutation:
Zebrafish with trappc6b knocked down using 2.5ng translation blocking morpholinos.
Allele Type: Knockdown
Strain of Origin: Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Wild type
Mutation:
Zebrafish with trappc6b knocked down using 5ng translation blocking morpholinos.
Allele Type: Knockdown
Strain of Origin: Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Wild type
Mutation:
Transgenic fish with GCaMP expressed under the elavl3 regulator treated with a transkation blocking morpholino against trappc6b. GCaMP is a genetically encoded calcium indicator (ZFIN ID: ZDB-EFG-120320-3). Elavl3 is a neuron-specific regulator (ZFIN ID: ZDB-GENE-980526-76).
Allele Type: Knockdown
Strain of Origin: Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Wild type
Mutation:
Transgenic fish with GCaMP expressed under the elavl3 regulator treated with a translation blocking morpholino against trappc6b. Fish were treated with 5mM pentylenetetrazol (PTZ) after baseline recording of neuronal activity. GCaMP is a genetically encoded calcium indicator (ZFIN ID: ZDB-EFG-120320-3). Elavl3 is a neuron-specific regulator (ZFIN ID: ZDB-GENE-980526-76). Seizure threshold was assessed using pentylenetetrazol (PTZ).
Allele Type: Knockdown
Strain of Origin: Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Wild type
Mutation:
Zebrafish with trappc6b knocked down using a splice blocking blocking morpholinos. The trappc6b-splice MO was designed to mask the splice-donor site of exon 2, the same exon which is abnormally spliced in patients carrying the TRAPPC6B mutation.
Allele Type: Knockdown
Strain of Origin: Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Description: Morphants show increased duration of events, increased peak intensity of events, increased decay time and increased time to reach peak intensity compared to controls.
Description: Morphants show more frequent, longer and more intensity calcium transients. Increase in calcium transient length correlated with a slower calcium transient ramp-up and decay time.
Description: Morphants show increased duration of events, increased peak intensity of events, increased decay time and increased time to reach peak intensity compared to controls.
Description: Morphants show increased spontaneous neuronal activity compared to controls.
Exp Paradigm: Neuronal activity was measuredby quantification of calcium transients in the telencephalon, tectum and hindbrain of 5 dpf Tg(elavl3:GCaMP5G) fish injected with scramble or trappc6b-atg morpholinos.
Description: Morphants treated with PTZ show increased spontaneous neuronal activity compared to controls.
Exp Paradigm: At the end of the baseline recording, pentylenetetrazol (PTZ) was added at the final concentration of 5 mM and activity was recorded for additional 15 min.
Description: Morphants showed abnormal behaviour in all tested conditions indicating a lower PTZ-induced seizure threshold compared to controls.
Exp Paradigm: At the end of the baseline recording, pentylenetetrazol (PTZ) was added at the final concentration of 5 mM and activity was recorded for additional 15 min.
