Background The genetic heterogeneity of developmental delay and cognitive impairment is vast. The endocytic network is essential for neural development and synaptic plasticity by regulating the sorting of numerous transmembrane proteins. Disruption of the pathway can lead to neuronal pathology. Endosomal biogenesis relies on two Rab proteins, Rab5 and Rab7, which bind to two hexameric tethering complexes, the endosomal class C core vacuole/endosome tethering complex (CORVET) and the late endosomal/lysosomal homotypic fusion and protein sorting complex (HOPS). Both complexes consist of four core proteins and differ by their specific Rab-binding proteins.
Objectives To identify the molecular basis of a neurological disease, which consists of global developmental stagnation at 3–8 months, increasing appendicular spasticity, truncal hypotonia and acquired microcephaly, with variable seizure disorder, accompanied by thin corpus callosum, paucity of white matter and delayed myelination in eight patients from four unrelated Ashkenazi-Jewish (AJ) families.
Methods Exome analysis, homozygosity mapping and Mup1-GFP transport assay in mutant yeast.
Results Homozygosity for a missense mutation, p.Cys846Gly, in one of the endosomal biogenesis core proteins, VPS11, was identified in all the patients. This was shown to be a founder mutation with a carrier frequency of 0.6% in the AJ population. The homologous yeast mutant had moderate impairment of fusion of the late endosome to the vacuole in Mup1-GFP transport assay.
Conclusions We speculate that in neuronal cells, impairment of fusion of the late endosome to the vacuole would attenuate the degradation of plasma membrane receptors, thereby underlying the progressive neuronal phenotype in our patients. The VPS11 p.Cys846Gly mutation should be added to the AJ carrier screening panel.
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