title: A missense founder mutation in VLDLR is associated with Dysequilibrium Syndrome without quadrupedal locomotion.
abstract: BACKGROUND
  Dysequilibrium syndrome is a genetically heterogeneous condition that combines autosomal recessive, nonprogressive cerebellar ataxia with mental retardation. The condition has been classified into cerebellar ataxia, mental retardation and disequilibrium syndrome types 1 (CAMRQ1), 2 (CAMRQ2) and 3 (CAMRQ3) and attributed to mutations in VLDLR, CA8 and WDR81 genes, respectively. Quadrupedal locomotion in this syndrome has been reported in association with mutations in all three genes.
  
  
  METHODS
  SNP mapping and candidate gene sequencing in one consanguineous Omani family from the United Arab Emirates with cerebellar hypoplasia, moderate mental retardation, delayed ambulation and truncal ataxia was used to identify the mutation. In a second unrelated consanguineous Omani family, massively parallel exonic sequencing was used.
  
  
  RESULTS
  We identified a homozygous missense mutation (c.2117 G > T, p.C706F) in the VLDLR gene in both families on a shared affected haplotype block.This is the first reported homozygous missense mutation in VLDLR and it occurs in a highly conserved residue and predicted to be damaging to protein function.
  
  
  CONCLUSIONS
  We have delineated the phenotype associated with dysequilibrium syndrome in two Omani families and identified the first homozygous missense pathogenic mutation in VLDLR gene with likely founder effect in the southeastern part of the Arabian Peninsula.
authors.affiliation: Department of Pathology, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
authors.forename: Bassam R
authors.initials: BR
authors.lastname: Ali
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Silhavy
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Gleeson
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
mesh_terms: D000293:Adolescent; D001921:Brain / Q000000981:diagnostic imaging; D002524:Cerebellar Ataxia / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008124:Locomotion / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011877:Radionuclide Imaging; D011973:Receptors, LDL / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D011973:Receptors, LDL; C036053:VLDL receptor