Journal of Inherited Metabolic Disease

, Volume 40, Issue 2, pp 261–269 | Cite as

A SLC39A8 variant causes manganese deficiency, and glycosylation and mitochondrial disorders

  • Lisa G. Riley
  • Mark J. Cowley
  • Velimir Gayevskiy
  • Tony Roscioli
  • David R. Thorburn
  • Kristina Prelog
  • Melanie Bahlo
  • Carolyn M. Sue
  • Shanti Balasubramaniam
  • John Christodoulou
Original Article

Summary

SLC39A8 variants have recently been reported to cause a type II congenital disorder of glycosylation (CDG) in patients with intellectual disability and cerebellar atrophy. Here we report a novel SLC39A8 variant in siblings with features of Leigh-like mitochondrial disease. Two sisters born to consanguineous Lebanese parents had profound developmental delay, dystonia, seizures and failure to thrive. Brain MRI of both siblings identified bilateral basal ganglia hyperintensities on T2-weighted imaging and cerebral atrophy. CSF lactate was elevated in patient 1 and normal in patient 2. Respiratory chain enzymology was only performed on patient 1 and revealed complex IV and II + III activity was low in liver, with elevated complex I activity. Complex IV activity was borderline low in patient 1 muscle and pyruvate dehydrogenase activity was reduced. Whole genome sequencing identified a homozygous Chr4(GRCh37):g.103236869C>G; c.338G>C; p.(Cys113Ser) variant in SLC39A8, located in one of eight regions identified by homozygosity mapping. SLC39A8 encodes a manganese and zinc transporter which localises to the cell and mitochondrial membranes. Patient 2 blood and urine manganese levels were undetectably low. Transferrin electrophoresis of patient 2 serum revealed a type II CDG defect. Oral supplementation with galactose and uridine led to improvement of the transferrin isoform pattern within 14 days of treatment initiation. Oral manganese has only recently been added to the treatment. These results suggest SLC39A8 deficiency can cause both a type II CDG and Leigh-like syndrome, possibly via reduced activity of the manganese-dependent enzymes β-galactosyltransferase and mitochondrial manganese superoxide dismutase.

Supplementary material

10545_2016_10_Fig3_ESM.gif (73 kb)
Supplementary Fig. 1

Alignment of the SLC39A8 p.Cys113Ser variant (shown in bold) among vertebrate species. Conserved residues are marked by an asterisk (GIF 73 kb)

10545_2016_10_MOESM1_ESM.tif (22 kb)
High Resolution Image (TIF 21 kb)

References

  1. Abecassis G, Wiggington J (2005) Handling marker-marker linkage disequilibrium: pedigree analysis with clustered markers. Am J Hum Genet 77:754–767CrossRefGoogle Scholar
  2. Bahlo M, Bromhead C (2009) Generating linkage mapping files from Affymetrix SNP chip data. Bioinformatics 25:1961–1962CrossRefPubMedGoogle Scholar
  3. Besecker B, Bao S, Bohacova B, Papp A, Sadee W, Knoell D (2008) The human zinc transporter SLC39A8 (Zip8) is critical in zinc-mediated cytoprotection in lung epithelia. Am J Physiol Lung Cell Mol Physiol 294:L1127–L1136CrossRefPubMedGoogle Scholar
  4. Bouchereau J, Barrot SV, Dupre T et al (2015) Abnormal glycosylation profile and high alpha-fetoprotein in a patient with Twinkle variants. J Inherit Metab Dis. doi:10.1007/8904_2016_526 Google Scholar
  5. Boycott K, Beaulieu C, Kernohan K et al (2015) Autosomal-recessive intellectual disability with cerebellar atrophy syndrome caused by mutation of the manganese and zinc transporter gene SLC39A8. Am J Hum Genet 97:886–893CrossRefPubMedPubMedCentralGoogle Scholar
  6. Calvo S, Clauser K, Mootha V (2015) MitoCarta2.0: an updated inventory of mammalian proteins. Nucleic Acids Res 44:D1251–D1257CrossRefPubMedPubMedCentralGoogle Scholar
  7. Cameron J, Janer A, Levandovskiy V et al (2011) Mutations in iron-sulfur scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes. Am J Hum Genet 89:486–495CrossRefPubMedPubMedCentralGoogle Scholar
  8. Frazier A, Thorburn D (2012) Biochemical analyses of the electron transport chain complexes by spectrophotometry. Methods Mol Biol 837:49–62CrossRefPubMedGoogle Scholar
  9. Haack T, Rolinski B, Haberberger B et al (2013) Homozygous missense mutation in BOLA3 causes multiple dysfunctions syndrome in two siblings. J Inherit Metab Dis 36:55–62CrossRefPubMedGoogle Scholar
  10. He L, Girijashanker K, Dalton T et al (2006) ZIP8, member of the solute-carrier-39 (SLC39) metal-transporter family: characterization of transporter properties. Mol Pharmacol 70:171–180PubMedGoogle Scholar
  11. Herrera C, Pettiglio M, Bartnikas T (2014) Investigating the role of transferrrin in the distribution of iron, manganese, copper and zinc. J Biol Inorg Chem 19:869–877CrossRefPubMedPubMedCentralGoogle Scholar
  12. Holley A, Bakthavatchalu V, Velez-Roman J, Clair DS (2011) Manganese superoxide dismutase: guardian of the powerhouse. Int J Mol Sci 12:7114–7162CrossRefPubMedPubMedCentralGoogle Scholar
  13. Irazusta V, Cabiscol E, Reverter-Branchat G, Ros J, Tamarit J (2006) Manganese is the link between frataxin and iron-sulfur deficiency in the yeast model of Friedrich ataxia. J Biol Chem 281:12227–12232CrossRefPubMedGoogle Scholar
  14. Lake N, Compton A, Rahman S, Thorburn D (2016) Leigh syndrome: one disorder, more than 75 monogenic causes. Ann Neurol 79:190–203CrossRefPubMedGoogle Scholar
  15. Lebovitz R, Zhang H, Vogel H et al (1996) Neurodegeneration, myocardial injury and perinatal death in mitochondrial superoxide dismutase-deficient mice. Proc Natl Acad Sci U S A 93:9782–9787CrossRefPubMedPubMedCentralGoogle Scholar
  16. Legros F, Nuyens V, Minet E et al (2002) Carbohydrate-deficient transferrin isoforms measured by capillary zone elctrophoresis for detection of alcohol abuse. Clin Chem 48:2177–2186PubMedGoogle Scholar
  17. Lek M, Karczewski K, Minikel E, Samocha K, Banks E (2015) Analysis of protein-coding genetic variation in 60,706 humans. bioRxiv. doi:10.1101/030338
  18. Lim S, Friemel M, Marum J et al (2013) Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of mulitple respiratory chain complexes. Hum Mol Genet 22:4460–4473CrossRefPubMedPubMedCentralGoogle Scholar
  19. Montero R, Yubero D, Villaroya J et al (2016) GDF-15 is elevated in children with mitochondrial diseases and is induced by mitochondrial dysfunction. PLoS ONE 11:e0148709CrossRefPubMedPubMedCentralGoogle Scholar
  20. Morava E, van de Heuvel L, Hol F et al (2006) Mitochondrial disease criteria: diagnostic applications in children. Neurology 67:1823–1826CrossRefPubMedGoogle Scholar
  21. Pagliarini D, Calvo S, Chang B et al (2008) A mitochondrial protein compendium elucidates complex I disease biology. Cell 134:112–123CrossRefPubMedPubMedCentralGoogle Scholar
  22. Paila U, Chapman B, Kirchner R, Quinlan A (2013) GEMINI: integrative exploration of genetic variation and genome annotations. PLoS Comput Biol 9:e1003153CrossRefPubMedPubMedCentralGoogle Scholar
  23. Park J, Hogrebe M, Gruneberg M et al (2015) SLC39A8 deficiency: a disorder of manganese transport and glycosylation. Am J Hum Genet 97:894–903CrossRefPubMedPubMedCentralGoogle Scholar
  24. Ramakrishnan B, Ramasamy V, Qasba P (2006) Structural snapshots of b-1,4-galactosyltransferase-I along the kinetic pathway. J Mol Biol 357:1619–1633CrossRefPubMedGoogle Scholar
  25. Sim K, Carpenter K, Hammond J, Christodoulou J, Wilcken B (2002) Acylcarnitine profiles in fibroblasts from patients with respiratory chain defects can resemble those with mitochondrial fatty acid oxidation disorders. Metabolism 51:366–371CrossRefPubMedGoogle Scholar
  26. Tuschl K, Mills P, Clayton P (2013) Manganese and the brain. Int Rev Neurobiol 110:277–312CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM 2016

Authors and Affiliations

  • Lisa G. Riley
    • 1
    • 2
  • Mark J. Cowley
    • 3
  • Velimir Gayevskiy
    • 3
  • Tony Roscioli
    • 3
    • 4
    • 5
  • David R. Thorburn
    • 6
    • 7
  • Kristina Prelog
    • 8
  • Melanie Bahlo
    • 9
    • 10
  • Carolyn M. Sue
    • 3
    • 11
  • Shanti Balasubramaniam
    • 2
    • 12
    • 13
  • John Christodoulou
    • 1
    • 2
    • 6
    • 7
    • 12
    • 13
  1. 1.Genetic Metabolic Disorders Research UnitThe Children’s Hospital at WestmeadWestmeadAustralia
  2. 2.Discipline of Paediatrics & Child Health, Sydney Medical SchoolUniversity of SydneySydneyAustralia
  3. 3.Kinghorn Centre for Clinical GenomicsGarvan Institute of Medical ResearchSydneyAustralia
  4. 4.St Vincent’s Clinical SchoolUniversity of New South WalesSydneyAustralia
  5. 5.Department of Medical GeneticsSydney Children’s HospitalRandwickAustralia
  6. 6.Murdoch Childrens Research Institute and Victorian Clinical Genetics ServicesRoyal Children’s HospitalMelbourneAustralia
  7. 7.Department of PaediatricsUniversity of MelbourneMelbourneAustralia
  8. 8.Medical Imaging DepartmentThe Children’s Hospital at WestmeadSydneyAustralia
  9. 9.Department of Medical BiologyUniversity of MelbourneMelbourneAustralia
  10. 10.Population Health and Immunity DivisionThe Walter and Eliza Hall Institute of Medical ResearchParkvilleAustralia
  11. 11.Department of Neurogenetics, Kolling Institute of Medical ResearchUniversity of Sydney and Royal North Shore HospitalSydneyAustralia
  12. 12.Western Sydney Genetics ProgramThe Children’s Hospital at WestmeadSydneyAustralia
  13. 13.Discipline of Genetic Medicine, Sydney Medical SchoolUniversity of SydneySydneyAustralia

Personalised recommendations