Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans

T Ozcelik, N Akarsu, E Uz, S Caglayan… - Proceedings of the …, 2008 - National Acad Sciences
T Ozcelik, N Akarsu, E Uz, S Caglayan, S Gulsuner, OE Onat, M Tan, U Tan
Proceedings of the National Academy of Sciences, 2008National Acad Sciences
Quadrupedal gait in humans, also known as Unertan syndrome, is a rare phenotype
associated with dysarthric speech, mental retardation, and varying degrees of
cerebrocerebellar hypoplasia. Four large consanguineous kindreds from Turkey manifest
this phenotype. In two families (A and D), shared homozygosity among affected relatives
mapped the trait to a 1.3-Mb region of chromosome 9p24. This genomic region includes the
VLDLR gene, which encodes the very low-density lipoprotein receptor, a component of the …
Quadrupedal gait in humans, also known as Unertan syndrome, is a rare phenotype associated with dysarthric speech, mental retardation, and varying degrees of cerebrocerebellar hypoplasia. Four large consanguineous kindreds from Turkey manifest this phenotype. In two families (A and D), shared homozygosity among affected relatives mapped the trait to a 1.3-Mb region of chromosome 9p24. This genomic region includes the VLDLR gene, which encodes the very low-density lipoprotein receptor, a component of the reelin signaling pathway involved in neuroblast migration in the cerebral cortex and cerebellum. Sequence analysis of VLDLR revealed nonsense mutation R257X in family A and single-nucleotide deletion c2339delT in family D. Both these mutations are predicted to lead to truncated proteins lacking transmembrane and signaling domains. In two other families (B and C), the phenotype is not linked to chromosome 9p. Our data indicate that mutations in VLDLR impair cerebrocerebellar function, conferring in these families a dramatic influence on gait, and that hereditary disorders associated with quadrupedal gait in humans are genetically heterogeneous.
National Acad Sciences