title: Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8.
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.
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada. Electronic address: kboycott@cheo.on.ca.
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Chandree L
authors.initials: CL
authors.lastname: Beaulieu
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Kristin D
authors.initials: KD
authors.lastname: Kernohan
authors.affiliation: National Research Centre, El Bohoth Street, Dokki, Giza 12622, Egypt.
authors.forename: Ola H
authors.initials: OH
authors.lastname: Gebril
authors.affiliation: Section of Genetics and Metabolism, Children's Hospital and the Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB R3A 1S1, Canada.
authors.forename: Aziz
authors.initials: A
authors.lastname: Mhanni
authors.affiliation: Section of Genetics and Metabolism, Children's Hospital and the Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB R3A 1S1, Canada.
authors.forename: Albert E
authors.initials: AE
authors.lastname: Chudley
authors.affiliation: Department of Medical Genetics, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Redl
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Wen
authors.initials: W
authors.lastname: Qin
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hampson
authors.affiliation: Department of Medical Genetics, CHU Nantes, Nantes 44093, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Küry
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Tetreault
authors.affiliation: Clinic for Special Children, Strasburg, PA 17579, USA.
authors.forename: Erik G
authors.initials: EG
authors.lastname: Puffenberger
authors.affiliation: Department of Radiology, Foothills Hospital, Calgary, AB T2N 2T9, Canada.
authors.forename: James N
authors.initials: JN
authors.lastname: Scott
authors.affiliation: Department of Medical Genetics, CHU Nantes, Nantes 44093, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bezieau
authors.affiliation: Institute of Human Genetics, FAU Erlangen-Nürnberg, Erlangen 91054, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.affiliation: Institute of Human Genetics, FAU Erlangen-Nürnberg, Erlangen 91054, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Uebe
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn 53012, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schumacher
authors.affiliation: Robarts Research Institute and University of Western Ontario, London, ON N6A 5B7, Canada.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.affiliation: Department of Medical Genetics, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: D Ross
authors.initials: DR
authors.lastname: McLeod
authors.affiliation: Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Gálvez-Peralta
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Department of Paediatric Neurology, Centre Hospitalier Universitaire, Liege 4032, Belgium.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ramaekers
authors.affiliation: 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.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
authors.affiliation: Department of Medical Genetics, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.affiliation: Department of Medical Genetics, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Jillian S
authors.initials: JS
authors.lastname: Parboosingh
authors.affiliation: Institute of Human Genetics, FAU Erlangen-Nürnberg, Erlangen 91054, Germany. Electronic address: rami.aboujamra@medizin.uni-leipzig.de.
authors.forename: Rami
authors.initials: R
authors.lastname: Abou Jamra
mesh_terms: D000293:Adolescent; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002413:Cations, Divalent; D002526:Cerebellar Diseases / Q000097:blood / Q000150:complications / Q000208:ethnology / Q000235:genetics*; D002648:Child; D004392:Dwarfism / Q000097:blood / Q000150:complications / Q000208:ethnology / Q000235:genetics*; D005006:Ethnicity; D059472:Exome; D005260:Female; D015870:Gene Expression; D005808:Genes, Recessive; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008607:Intellectual Disability / Q000097:blood / Q000150:complications / Q000208:ethnology / Q000235:genetics*; D017136:Ion Transport; D008297:Male; D008345:Manganese / Q000097:blood* / Q000652:urine; D044465:White People; D055815:Young Adult; D015032:Zinc / Q000097:blood* / Q000652:urine
chemical_list: D027682:Cation Transport Proteins; D002413:Cations, Divalent; C530151:SLC39A8 protein, human; D008345:Manganese; D015032:Zinc