A missense variant in SLC39A8 is associated with severe idiopathic scoliosis

Haller, Gabe; McCall, Kevin; Jenkitkasemwong, Supak; Sadler, Brooke; Antunes, Lilian; Nikolov, Momchil A.; Whittle, Julia; Upshaw, Zachary; Shin, Jimann; Baschal, Erin E.; Cruchaga, Carlos; Harms, Matthew B.; Raggio, Cathleen; Morcuende, José A.; Giampietro, Philip F.; Miller, Nancy H.; Wise, Carol A.; Gray, Ryan S.; Solnica‐Krezel, Lila; Knutson, Mitchell D.; Dobbs, Matthew B.; Gurnett, Christina A.

doi:10.1038/s41467-018-06705-0

Cited by 66 publications

(58 citation statements)

References 40 publications

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“…No differences were detected in any of the other trace elements transported through SLC39A8 (Zn, Co, and Cu), though effects on Cd could not be assessed as levels were below our method of detection limit. Fe was not measured in our study, though GWAS on Fe levels and Fe-related traits have not identified any associations with the A391T missense variant, and two recent studies show no difference in Fe concentration in A391T carriers, suggesting that serum Fe is not affected (9,46) Multiple studies demonstrate the importance of SLC39A8 to health and disease. Hypomorphic mice expressing 10-15% of basal SLC39A8 show severe growth stunting, dysmorphogenesis, and anemia (47,48).…”

Section: Discussioncontrasting

confidence: 53%

The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation

Mealer

Jenkins

Chen

et al. 2019

Preprint

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A common missense variant (rs13107325 (C->T), A391T) in SLC39A8, a gene encoding a transporter of divalent cations including manganese (Mn), is convincingly associated with schizophrenia and has pleiotropic effects on several additional brain-related phenotypes.Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum Mn and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified Mn-related changes in human carriers of the SLC39A8 missense allele. Analysis of structural brain MRI scans from the UK Biobank showed a dose-dependent change in the ratio of T2w to T1w signal in several brain regions, presumably from altered transport of paramagnetic cations including Mn. We confirmed a specific reduction of serum Mn and showed through comprehensive profiling reduced complexity and branching of the plasma protein N-glycome in both heterozygous and homozygous minor allele carriers. N-glycome profiling of two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that hypofunction of the common missense variant exists on a spectrum with potential for reversibility.Characterizing the functional impact of this variant may enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers of disease.

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Section: Discussioncontrasting

confidence: 53%

The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation

Mealer

Jenkins

Chen

et al. 2019

Preprint

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“…In silico modeling predicts rs13107325 to be in the top 1.4% of deleterious substitutions in the human genome ( 2 ). The major allele associates with an increased risk of Parkinson’s disease, hypertension ( 3 ), and alcohol misuse disorders ( 4 ), and the minor allele associates with increased risk of schizophrenia ( 5 ), Crohn’s disease ( 6 ), obesity ( 7 ), dyslipidemia ( 8 ), and scoliosis ( 9 ). The minor allele frequency (MAF) is approximately 0.05 in American population and, 0.08 in Northern European populations and increases to 0.14–0.25 in the Ashkenazi Jewish population; the major allele is monomorphic in African and East and South Asian populations ( 10 – 12 ).…”

Section: Introductionmentioning

confidence: 99%

Pleiotropic ZIP8 A391T implicates abnormal manganese homeostasis in complex human disease

et al. 2020

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ZIP8 is a metal transporter with a role in manganese (Mn) homeostasis. A common genetic variant in ZIP8 (rs13107325; A391T) ranks in the top 10 of pleiotropic SNPs identified in GWAS; A391T has associations with an increased risk of schizophrenia, obesity, Crohn’s disease, and reduced blood Mn. Here, we used CRISPR/ Cas9 -mediated knockin (KI) to generate a mouse model of ZIP8 A391T (Zip8 393T-KI mice). Recapitulating the SNP association with blood Mn, blood Mn was reduced in Zip8 393T-KI mice. There was restricted abnormal tissue Mn homeostasis, with decreases in liver and kidney Mn and a reciprocal increase in biliary Mn, providing in vivo evidence of hypomorphic Zip8 function. Upon challenge in a chemically induced colitis model, male Zip8 393T-KI mice exhibited enhanced disease susceptibility. ZIP8 391-Thr associated with reduced triantennary plasma N-glycan species in a population-based cohort to define a genotype-specific glycophenotype hypothesized to be linked to Mn-dependent glycosyltransferase activity. This glycophenotype was maintained in a cohort of patients with Crohn’s disease. These data and the pleiotropic disease associations with ZIP8 391-Thr suggest underappreciated roles of Mn homeostasis in complex human disease.

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“…5 The solute carrier 39 (SLC39) gene family encoding the Zinc IRT-like Proteins (ZIPs) contribute to cellular metal and zinc homeostasis by encoding proteins that mediate cation influx or transport from intracellular compartments. 6 Mutations in the ZIP transporter family have been linked to various genetic disorders, such as acrodermatitis enteropathica, 7,8 schizophrenia, 9 scoliosis, 10 intellectual disability, [11][12][13] Crohn's disease, 14 Ehlers-Danlos syndrome, 15 and parkinsonism-dystonia. 16 Given the wide roles for zinc in many biochemical processes, the genes regulating cellular zinc homeostasis can impact diverse processes of the nervous system.…”

Section: Introductionmentioning

confidence: 99%

Role of zinc transporter ZIP12 in susceptibility‐weighted brain magnetic resonance imaging (MRI) phenotypes and mitochondrial function

et al. 2020

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Brain zinc dysregulation is linked to many neurological disorders. However, the mechanisms regulating brain zinc homeostasis are poorly understood. We performed secondary analyses of brain MRI GWAS and exome sequencing data from adults in the UK Biobank. Coding ZIP12 polymorphisms in zinc transporter ZIP12 (SLC39A12) were associated with altered brain susceptibility weighted MRI (swMRI). Conditional and joint association analyses revealed independent GWAS signals in linkage disequilibrium with 2 missense ZIP12 polymorphisms, rs10764176 and rs72778328, with reduced zinc transport activity. ZIP12 rare coding variants predicted to be deleterious were associated with similar impacts on brain swMRI. In Neuro‐2a cells, ZIP12 deficiency by short hairpin RNA (shRNA) depletion or CRISPR/Cas9 genome editing resulted in impaired mitochondrial function, increased superoxide presence, and detectable protein carbonylation. Inhibition of Complexes I and IV of the electron transport chain reduced neurite outgrowth in ZIP12 deficient cells. Transcriptional coactivator PGC‐1α, mitochondrial superoxide dismutase (SOD2), and chemical antioxidants α‐tocopherol, MitoTEMPO, and MitoQ restored neurite extension impaired by ZIP12 deficiency. Mutant forms of α‐synuclein and tau linked to familial Parkinson’s disease and frontotemporal dementia, respectively, reduced neurite outgrowth in cells deficient in ZIP12. Zinc and ZIP12 may confer resilience against neurological diseases or premature aging of the brain.

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A missense variant in SLC39A8 is associated with severe idiopathic scoliosis

Cited by 66 publications

References 40 publications

The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation

The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation

Pleiotropic ZIP8 A391T implicates abnormal manganese homeostasis in complex human disease

Role of zinc transporter ZIP12 in susceptibility‐weighted brain magnetic resonance imaging (MRI) phenotypes and mitochondrial function

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