Bem et al. (2011) reported 6 consanguineous families, 5 Pakistani and 1 Turkish, segregating Warburg Micro syndrome. All of the affected children had microcephaly, brachycephaly, microphthalmia, microcornea, low anterior hairline, large protruding pinnae, and downturned mouth corners. The ... Bem et al. (2011) reported 6 consanguineous families, 5 Pakistani and 1 Turkish, segregating Warburg Micro syndrome. All of the affected children had microcephaly, brachycephaly, microphthalmia, microcornea, low anterior hairline, large protruding pinnae, and downturned mouth corners. The older children were wheelchair bound and had kyphoscoliosis, severe spastic quadriplegia with contractures, and diminished muscle bulk. The clinical features were indistinguishable from those in patients with WARBM1 (600118) with RAB3GAP1 (602356) mutations and from those in patients with WARBM2 (614225) with RAB3GAP2 (609275) mutations, but mutations in these genes were excluded by linkage and direct sequencing.
In affected members of 5 large consanguineous families, 4 Pakistani and 1 Turkish, segregating Warburg Micro syndrome, Bem et al. (2011) identified homozygous loss-of-function mutations in the RAB18 gene (602207.0001 and 602207.0002, respectively). The mutation in the Pakistani ... In affected members of 5 large consanguineous families, 4 Pakistani and 1 Turkish, segregating Warburg Micro syndrome, Bem et al. (2011) identified homozygous loss-of-function mutations in the RAB18 gene (602207.0001 and 602207.0002, respectively). The mutation in the Pakistani families was a founder mutation. Direct sequencing for RAB18 mutations in 58 additional families segregating Warburg Micro syndrome detected compound heterozygous mutations (602207.0003-602207.0004) in affected sibs of 1 family. Bem et al. (2011) performed nucleotide-binding assays and showed that although RAB18 bound GDP and GTP comparably to other RABs (RAB5A, 179512; RAB35, 604199), the RAB18 L24Q (602207.0001) and R93del (602207.0003) mutant proteins did not bind detectable levels of either GDP or GTP and are therefore functionally null. Bem et al. (2011) noted that the pathogenicity of these mutations could be explained by their lack of guanosine nucleotide binding because, as for other RAB proteins, this is a prerequisite for correct subcellular localization and function.