Submission Details

Autosomal dominant

08/27/2019

The MAPK8IP3 gene was first reported in relation to autosomal dominant MAPK8IP3-related neurodevelopmental disorder with or without variable brain abnormalities in 2019 (30612693: Platzer et al. 2019). At least six unique variants (including five missense variants and one stop-gained) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least six probands in two publications (30612693: Platzer et al. 2019; 30945334: Iwasawa et al. 2019). The mechanism of the disease is not yet established. However, it is known that the protein encoded by MAPK8IP3 acts as a regulator of vesicle transport and promotes neuronal axon elongation in a kinesin- and JNK-dependent manner and that both missense variants in important functional domains and null variants are implicated in disease. This gene-disease relationship is supported by evidence from model organisms where the effect of five missense and one null variant on axonal lysosomal accumulation in C.elegans was evaluated with at least three of the variants resulting in higher axonal lysosomal density and reduced swimming rates (30612693: Platzer et al. 2019). In addition, a heterozygous knockout mouse for the MAPK8IP3 gene was shown to present with axonal lysosome accumulations demonstrating a role for the protein in axonal lysosome transport (28784610: Gowrishankar et al. 2017). In summary, there is strong evidence to support the relationship between the MAPK8IP3 gene and MAPK8IP3-related neurodevelopmental disorder with or without variable brain abnormalities (autosomal dominant). Additional reports in humans are needed over time from the first proposal of the association to reach a definitive classification.

30612693 30945334 28784610