title: Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans.
abstract: 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.
authors.affiliation: Department of Molecular Biology and Genetics, Faculty of Science and Institute of Materials Science and Nanotechnology, Bilkent University, Ankara 06800, Turkey. tozcelik@fen.bilkent.edu.tr
authors.forename: Tayfun
authors.initials: T
authors.lastname: Ozcelik
authors.forename: Nurten
authors.initials: N
authors.lastname: Akarsu
authors.forename: Elif
authors.initials: E
authors.lastname: Uz
authors.forename: Safak
authors.initials: S
authors.lastname: Caglayan
authors.forename: Suleyman
authors.initials: S
authors.lastname: Gulsuner
authors.forename: Onur Emre
authors.initials: OE
authors.lastname: Onat
authors.forename: Meliha
authors.initials: M
authors.lastname: Tan
authors.forename: Uner
authors.initials: U
authors.lastname: Tan
mesh_terms: D000328:Adult; D000368:Aged; D001132:Arm; D001483:Base Sequence; D002526:Cerebellar Diseases / Q000151:congenital / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D005260:Female; D005684:Gait; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007866:Leg; D008124:Locomotion / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism*; D000091042:Reelin Protein; D013577:Syndrome
chemical_list: D011973:Receptors, LDL; D000091042:Reelin Protein; C036053:VLDL receptor; C000717127:RELN protein, human