2. Academic Validation
  3. Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8

Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8

  • Am J Hum Genet. 2015 Dec 3;97(6):886-93. doi: 10.1016/j.ajhg.2015.11.002.
Kym M Boycott 1,  Chandree L Beaulieu 2,  Kristin D Kernohan 2,  Ola H Gebril 3,  Aziz Mhanni 4,  Albert E Chudley 4,  David Redl 5,  Wen Qin 2,  Sarah Hampson 2,  Sébastien Küry 6,  Martine Tetreault 7,  Erik G Puffenberger 8,  James N Scott 9,  Stéphane Bezieau 6,  André Reis 10,  Steffen Uebe 10,  Johannes Schumacher 11,  Robert A Hegele 12,  D Ross McLeod 5,  Marina Gálvez-Peralta 13,  Jacek Majewski 7,  Vincent T Ramaekers 14,  Care4Rare Canada Consortium,  Daniel W Nebert 15,  A Micheil Innes 5,  Jillian S Parboosingh 5,  Rami Abou Jamra 16
Affiliations

Affiliations

  • 1 Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada. Electronic address: [email protected].
  • 2 Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
  • 3 National Research Centre, El Bohoth Street, Dokki, Giza 12622, Egypt.
  • 4 Section of Genetics and Metabolism, Children's Hospital and the Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB R3A 1S1, Canada.
  • 5 Department of Medical Genetics, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 6 Department of Medical Genetics, CHU Nantes, Nantes 44093, France.
  • 7 Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
  • 8 Clinic for Special Children, Strasburg, PA 17579, USA.
  • 9 Department of Radiology, Foothills Hospital, Calgary, AB T2N 2T9, Canada.
  • 10 Institute of Human Genetics, FAU Erlangen-Nürnberg, Erlangen 91054, Germany.
  • 11 Institute of Human Genetics, University of Bonn, Bonn 53012, Germany.
  • 12 Robarts Research Institute and University of Western Ontario, London, ON N6A 5B7, Canada.
  • 13 Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
  • 14 Department of Paediatric Neurology, Centre Hospitalier Universitaire, Liege 4032, Belgium.
  • 15 Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Department of Pediatrics & Molecular Developmental Biology, Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.
  • 16 Institute of Human Genetics, FAU Erlangen-Nürnberg, Erlangen 91054, Germany. Electronic address: [email protected].
PMID: 26637978 DOI: 10.1016/j.ajhg.2015.11.002
Abstract

Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.112G>C (p.Gly38Arg), affecting a conserved residue of SLC39A8. The affected Hutterite and Egyptian individuals did not share an extended common haplotype, suggesting that the mutation arose independently. SLC39A8 is a member of the solute carrier gene family known to import Mn, Zn, and other divalent cations across the plasma membrane. Evaluation of these two metal ions in the affected individuals revealed variably low levels of Mn and Zn in blood and elevated levels in urine, indicating renal wasting. Our findings identify a human Mn and Zn transporter deficiency syndrome linked to SLC39A8, providing insight into the roles of Mn and Zn homeostasis in human health and development.

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