ClinVar

In an unrelated Japanese girl and boy who died at ages 24 months and 34 months with MIRAGE syndrome (MIRAGE; 617053), Narumi et al. (2016) identified heterozygosity for an arg1293-to-trp (R1293W) substitution at a highly conserved residue in the SAMD9 gene. The girl died suddenly after a hospital-to-hospital transfer, whereas the boy developed monosomy 7-related myelodysplastic syndrome and died from acute respiratory distress triggered by respiratory syncytial virus infection. The mutation arose de novo in both patients, and was not found in 400 in-house Japanese control samples, the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, Human Genetic Variation, or ExAC databases. Functional analysis in HEK293 cells demonstrated that expression of wildtype SAMD9 resulted in mild growth restriction, whereas expression of the R1293W mutant caused profound growth inhibition, consistent with an 'activating' effect. Patient fibroblasts grew more slowly than control cells and showed lower levels of phosphorylated ERK and lower EGFR expression on the plasma membrane. Confocal microscopy with endosome markers revealed that the cytoplasm of patient fibroblasts was filled with giant RAB7A (see 602298)-positive vesicles, and RAB5A (179512) vesicles also skewed larger in patients than controls. Narumi et al. (2016) suggested that the R1293W mutant caused functional as well as structural alterations of the endosome system, because the decrease in membrane EFGR was likely due to defective recycling of the receptor.