Identification of very low density lipoprotein receptor (vldlr) mutations in cerebellar hypoplasia and quadrupedal locomotion (Unertan syndrome) in humans

Cerebellar hypoplasia and quadrupedal locomotion in humans, also known as Unertan syndrome, is a severe neurodevelopmental condition accompanied by dysarthria and impaired cognitive skills. The molecular underpinnings of development of the brain structures required for bipedal gait in humans can be established through identification of the gene(s) associated with this disorder. Four consanguineous families from Turkey exhibiting this autosomal recessive trait were studied. In two families (A and D), affected individuals shared homozygosity in a critical 1.032-Mb region in chromosome 9p24. Sequence analysis linked the disease to two distinct mutations in the very low density lipoprotein receptor (VLDLR) gene; the nonsense change R257X in family A and the single nucleotide deletion leading to frameshift I780TfsX3 in family D. VLDL receptor is a co-receptor of reelin molecule. Reelin signaling pathway is involved in neuronal migration and lamination to form brain cortices during embryonic development. Mutant VLDL receptors are truncated proteins that cannot be inserted into the membrane. Homozygosity mapping linked the disease locus in family B to chromosome 17p13. Family C does not share homozygosity in neither of the loci.