title: Molecular genetic studies of DMT1 on 12q in French-Canadian restless legs syndrome patients and families.
abstract: Converging evidence from clinical observations, brain imaging and pathological findings strongly indicate impaired brain iron regulation in restless legs syndrome (RLS). Animal models with mutation in (DMT1) divalent metal transporter 1 gene, an important brain iron transporter, demonstrate a similar iron deficiency profile as found in RLS brain. The human DMT1 gene, mapped to chromosome 12q near the RLS1 locus, qualifies as an excellent functional and possible positional candidate for RLS. DMT1 protein levels were assessed in lymphoblastoid cell lines from RLS patients and controls. Linkage analyses were carried out with markers flanking and within the DMT1 gene. Selected patient samples from RLS families with compatible linkage to the RLS1 locus on 12q were fully sequenced in both the coding regions and the long stretches of UTR sequences. Finally, selected sequence variants were further studied in case/control and family-based association tests. A clinical association of anemia and RLS was further confirmed in this study. There was no detectable difference in DMT1 protein levels between RLS patient lymphoblastoid cell lines and normal controls. Non-parametric linkage analyses failed to identify any significant linkage signals within the DMT1 gene region. Sequencing of selected patients did not detect any sequence variant(s) compatible with DMT1 harboring RLS causative mutation(s). Further studies did not find any association between ten SNPs, spanning the whole DMT1 gene region, and RLS affection status. Finally, two DMT1 intronic SNPs showed positive association with RLS in patients with a history of anemia, when compared to RLS patients without anemia.
authors.affiliation: Laboratoire d'étude des maladies du cerveau, Centre de recherche du CHUM, Hôpital Notre-Dame, Université de Montréal, 1560 rue Sherbrooke Est, Montréal, Québec, Canada.
authors.forename: Lan
authors.initials: L
authors.lastname: Xiong
authors.forename: Patrick
authors.initials: P
authors.lastname: Dion
authors.forename: Jacques
authors.initials: J
authors.lastname: Montplaisir
authors.forename: Anastasia
authors.initials: A
authors.lastname: Levchenko
authors.forename: Pascale
authors.initials: P
authors.lastname: Thibodeau
authors.forename: Liliane
authors.initials: L
authors.lastname: Karemera
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Rivière
authors.forename: Judith
authors.initials: J
authors.lastname: St-Onge
authors.forename: Claudia
authors.initials: C
authors.lastname: Gaspar
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.forename: Alex
authors.initials: A
authors.lastname: Desautels
authors.forename: Gustavo
authors.initials: G
authors.lastname: Turecki
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D002170:Canada; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12; D005190:Family; D005260:Female; D005602:France / Q000208:ethnology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008297:Male; D008967:Molecular Biology; D020641:Polymorphism, Single Nucleotide; D012148:Restless Legs Syndrome / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D000099236:Solute Carrier Family 11, Member 2