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

Date
2008
Authors
Ozcelik, T.
Akarsu, N.
Uz, E.
Caglayan, S.
Gulsuner, S.
Onat, O. E.
Tan, M.
Tan, U.
Advisor
Instructor
Source Title
Proceedings of the National Academy of Sciences of the United States of America
Print ISSN
1091-6490
Electronic ISSN
Publisher
National Academy of Sciences
Volume
105
Issue
11
Pages
4232 - 4236
Language
English
Type
Article
Journal Title
Journal ISSN
Volume Title
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.

Course
Other identifiers
Book Title
Keywords
Genetics, Unertan syndrome, membrane protein, nucleotide, reelin, very low density lipoprotein receptor, adult, aged, article, brain cortex, brain function, cell migration, cerebellum, cerebellum hypoplasia, chromosome 9p, chromosome 9p24, family, female, gait, gait disorder, gene, gene mapping, gene mutation, genetic disorder, genetic trait, genomics, homozygosity, human, male, neuroblast, nonsense mutation, nucleotide sequence, phenotype, prediction, priority journal, protein domain, quadruped gait, relative, sequence analysis, Turkey (republic)
Citation
Published Version (Please cite this version)