PUBLICATION

A missense variant in SLC39A8 is associated with severe idiopathic scoliosis

Authors
Haller, G., McCall, K., Jenkitkasemwong, S., Sadler, B., Antunes, L., Nikolov, M., Whittle, J., Upshaw, Z., Shin, J., Baschal, E., Cruchaga, C., Harms, M., Raggio, C., Morcuende, J.A., Giampietro, P., Miller, N.H., Wise, C., Gray, R.S., Solnica-Krezel, L., Knutson, M., Dobbs, M.B., Gurnett, C.A.
ID
ZDB-PUB-181012-5
Date
2018
Source
Nature communications   9: 4171 (Journal)
Registered Authors
Antunes, Lilian, Gray, Ryan, Gurnett, Christina, McCall, Kevin, Nikolov, Momchil, Sadler, Brooke, Shin, Jimann, Solnica-Krezel, Lilianna, Whittle, Julia
Keywords
none
MeSH Terms
  • Humans
  • HEK293 Cells
  • Genetic Predisposition to Disease*
  • Scoliosis/genetics*
  • Polymorphism, Single Nucleotide/genetics
  • Animals
  • Bone and Bones/pathology
  • Mutation, Missense/genetics*
  • Ions
  • Zebrafish/genetics
  • Cation Transport Proteins/deficiency
  • Cation Transport Proteins/genetics*
  • Movement
  • Exome/genetics
  • Genetic Association Studies
(all 15)
PubMed
30301978 Full text @ Nat. Commun.
Abstract
Genetic factors predictive of severe adolescent idiopathic scoliosis (AIS) are largely unknown. To identify genetic variation associated with severe AIS, we performed an exome-wide association study of 457 severe AIS cases and 987 controls. We find a missense SNP in SLC39A8 (p.Ala391Thr, rs13107325) associated with severe AIS (P = 1.60 × 10-7, OR = 2.01, CI = 1.54-2.62). This pleiotropic SNP was previously associated with BMI, blood pressure, cholesterol, and blood manganese level. We replicate the association in a second cohort (841 cases and 1095 controls) resulting in a combined P = 7.02 × 10-14, OR = 1.94, CI = 1.63-2.34. Clinically, the minor allele of rs13107325 is associated with greater spinal curvature, decreased height, increased BMI and lower plasma manganese in our AIS cohort. Functional studies demonstrate reduced manganese influx mediated by the SLC39A8 p.Ala391Thr variant and vertebral abnormalities, impaired growth, and decreased motor activity in slc39a8 mutant zebrafish. Our results suggest the possibility that scoliosis may be amenable to dietary intervention.
Genes / Markers
Figures
Figure Gallery (5 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
ABchemical treatment: manganese(II) chlorideDay 4
slc39a8stl583/+ (AB)standard conditionsDay 4
slc39a8stl583/+ (AB)chemical treatment: manganese(II) chlorideDay 4
slc39a8stl583/stl583 (AB)standard conditionsDay 4
slc39a8stl583/stl583 (AB)standard conditionsDay 4
slc39a8stl583/stl583 (AB)standard conditionsDay 4
slc39a8stl583/stl583 (AB)standard conditionsDays 7-13
slc39a8stl583/stl583 (AB)standard conditionsAdult
slc39a8stl583/stl583 (AB)standard conditionsAdult
slc39a8stl583/stl583 (AB)standard conditionsAdult
1 - 10 of 17
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
stl583
    		Indel
    1 - 1 of 1
    Show
    Human Disease / Model
    Human Disease Fish Conditions Evidence
    idiopathic scoliosisslc39a8stl583/stl583 (AB)standard conditionsTAS
    1 - 1 of 1
    Show
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    slc39a8CRISPR1-slc39a8CRISPR
    1 - 1 of 1
    Show
    Fish
    Fish
    AB
    slc39a8stl583/stl583 (AB)
    slc39a8stl583/+ (AB)
    WT
    1 - 4 of 4
    Show
    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    No data available
    Mapping
    No data available
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    Citation
    Haller, G., McCall, K., Jenkitkasemwong, S., Sadler, B., Antunes, L., Nikolov, M., Whittle, J., Upshaw, Z., Shin, J., Baschal, E., Cruchaga, C., Harms, M., Raggio, C., Morcuende, J.A., Giampietro, P., Miller, N.H., Wise, C., Gray, R.S., Solnica-Krezel, L., Knutson, M., Dobbs, M.B., Gurnett, C.A. (2018) A missense variant in SLC39A8 is associated with severe idiopathic scoliosis. Nature communications. 9:4171.