Identification of a nonsense mutation in the very low-density lipoprotein receptor gene ( ) in an Iranian family with dysequilibrium syndrome

• Published in: European journal of human genetics : EJHG Vol. 16; no. 2; pp. 270 - 273
• Main Authors: LIA ABBASI MOHEB, TZSCHACH, Andreas, GARSHASBI, Masoud, KAHRIZI, Kimia, DARVISH, Hossein, HESHMATI, Yaser, KORDI, Alireza, NAJMABADI, Hossein, ROPERS, Hans Hilger, KUSS, Andreas Walter
• Format: Journal Article
• Language: English
• Published: Avenel, NJ Nature Publishing 01.02.2008; Nature Publishing Group
• Subjects: Adolescent; Adult; Adult and adolescent clinical studies; Ataxia; Ataxia - genetics; Biological and medical sciences; Cell migration; Cerebellar ataxia; Cerebellum; Cerebellum - abnormalities; Chromosome 9; Clonal deletion; Coding; Codon, Nonsense - genetics; Cortex; Etiology; Families & family life; Female; Fundamental and applied biological sciences. Psychology; Gene deletion; Gene mapping; General aspects. Genetic counseling; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Humans; Hypoplasia; Intellectual deficiency; Intellectual disabilities; Intellectual Disability - genetics; Intellectual Disability - physiopathology; Iran; Leukocyte migration; Low density lipoprotein; Male; Medical genetics; Medical sciences; Molecular and cellular biology; Mutation; Nonsense mutation; Patients; Pedigree; Phenotypes; Planck, Max; Population; Postural Balance; Proteins; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Receptor density; Receptors, LDL - genetics; Reelin protein; Rodents; Signal transduction; Stop codon; Strabismus; Syndrome; Iran; Asia; United States > US; Germany; Nervous system diseases; reelin signalling; Family study; Nonsense mutation; Developmental disorder; Identification; VLDLR; Mental retardation; Syndrome; dysequilibrium syndrome; Cerebral disorder; Lipoprotein LDL; Gene; Central nervous system disease; Intellectual deficiency; Family environment; Ataxia; Genetics; Neurological disorder; Biological receptor
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/sj.ejhg.5201967

We have investigated a consanguineous Iranian family with eight patients who suffer from mental retardation, disturbed equilibrium, walking disability, strabismus and short stature. By autozygosity mapping we identified one region with a significant LOD score on chromosome 9(p24.2-24.3). The interval contains the VLDLR gene, which codes for the very low-density lipoprotein receptor. This protein is part of the reelin signalling pathway, which is involved in neuroblast migration in the cerebral cortex and cerebellum. A homozygous deletion encompassing VLDLR has previously been found to cause a syndrome of cerebellar ataxia and mental retardation associated with cerebellar hypoplasia in the Hutterite population known as dysequilibrium syndrome (DES). The reported deletion however, contains an additional brain expressed gene of unknown function, whose involvement in the aetiology of the phenotype could so far not be excluded. We screened the coding region of VLDLR for mutations in our patients and found a homozygous c.1342C>T nucleotide substitution, which leads to a premature stop codon in exon 10. This is the first report of a mutation in patients with DES that affects VLDLR exclusively, confirming the central role of the very low-density lipoprotein receptor in the aetiology of this condition.