PUBLICATION

CTNND2-a candidate gene for reading problems and mild intellectual disability

Authors
Hofmeister, W., Nilsson, D., Topa, A., Anderlid, B.M., Darki, F., Matsson, H., Tapia Páez, I., Klingberg, T., Samuelsson, L., Wirta, V., Vezzi, F., Kere, J., Nordenskjöld, M., Syk Lundberg, E., Lindstrand, A.
ID
ZDB-PUB-141205-3
Date
2015
Source
Journal of Medical Genetics   52(2): 111-22 (Journal)
Registered Authors
Keywords
Cell biology, Chromosomal, Copy-number, Memory Disorders, Molecular genetics
MeSH Terms
  • Cognition
  • Sequence Analysis, DNA
  • Base Sequence
  • Zebrafish Proteins/genetics
  • Genetic Predisposition to Disease*
  • White Matter/pathology
  • Pedigree
  • Child
  • Polymorphism, Single Nucleotide/genetics
  • Introns/genetics
  • Molecular Sequence Data
  • Catenins/genetics*
  • Genetic Association Studies*
  • Humans
  • Chromosome Breakpoints
  • Adult
  • Intellectual Disability/genetics*
  • Exons/genetics
  • Green Fluorescent Proteins/metabolism
  • Translocation, Genetic
  • Female
  • Mutation/genetics
  • Young Adult
  • Male
  • Reading*
  • Adolescent
  • Genetic Loci
(all 27)
PubMed
25473103 Full text @ J. Med. Genet.
Abstract
Cytogenetically visible chromosomal translocations are highly informative as they can pinpoint strong effect genes even in complex genetic disorders.
Here, we report a mother and daughter, both with borderline intelligence and learning problems within the dyslexia spectrum, and two apparently balanced reciprocal translocations: t(1;8)(p22;q24) and t(5;18)(p15;q11). By low coverage mate-pair whole-genome sequencing, we were able to pinpoint the genomic breakpoints to 2 kb intervals. By direct sequencing, we then located the chromosome 5p breakpoint to intron 9 of CTNND2. An additional case with a 163 kb microdeletion exclusively involving CTNND2 was identified with genome-wide array comparative genomic hybridisation. This microdeletion at 5p15.2 is also present in mosaic state in the patient's mother but absent from the healthy siblings. We then investigated the effect of CTNND2 polymorphisms on normal variability and identified a polymorphism (rs2561622) with significant effect on phonological ability and white matter volume in the left frontal lobe, close to cortical regions previously associated with phonological processing. Finally, given the potential role of CTNND2 in neuron motility, we used morpholino knockdown in zebrafish embryos to assess its effects on neuronal migration in vivo. Analysis of the zebrafish forebrain revealed a subpopulation of neurons misplaced between the diencephalon and telencephalon.
Taken together, our human genetic and in vivo data suggest that defective migration of subpopulations of neuronal cells due to haploinsufficiency of CTNND2 contribute to the cognitive dysfunction in our patients.
Genes / Markers
Figures
No images available
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Expression
No data available
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
rw0TgTransgenic Insertion
    1 - 1 of 1
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    Human Disease / Model
    No data available
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    ctnnd2aMO1-ctnnd2aMRPHLNO
    ctnnd2aMO2-ctnnd2aMRPHLNO
    ctnnd2bMO1-ctnnd2bMRPHLNO
    ctnnd2bMO2-ctnnd2bMRPHLNO
    1 - 4 of 4
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    Fish
    Antibodies
    Orthology
    Engineered Foreign Genes
    Marker Marker Type Name
    GFPEFGGFP
    1 - 1 of 1
    Show
    Mapping