Novel autosomal recessive syndrome characterized by manganese deficiency, cerebellar atrophy, skeletal dysplasia, and cognitive impairment caused by mutation in SLC39A8. CL. Beaulieu1, M. Galvez-Peralta2, D. Redl3, L. Huang1, EG. Puffenberger4, SC. Hampson1, AE. Chudley5, JN. Scott6, RA. Hegele7, DR. McLeod3, AE. MacKenzie1, DE. Bulman1, JS. Parboosingh3, DW. Nebert2, AM. Innes3, KM. Boycott1, FORGE Canada Consortium 1) Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada; 2) Department of Environmental Health and the Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, USA; 3) Department of Medical Genetics and Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, AB, Canada; 4) Clinic for Special Children, Stratsburg, and Franklin and Marshall College, Lancaster, PA, USA; 5) Section of Genetics and Metabolism, Children's Hospital and the Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada; 6) Department of Radiology, Foothills Hospital, Calgary, AB, Canada; 7) Robarts Research Institute and University of Western Ontario, London, ON, Canada.

   Manganese (Mn) is an essential trace element acting as a cofactor for enzymes including mitochondrial superoxide dismutase. Mn deficiency in animal models is known to cause impaired growth, skeletal abnormalities, and ataxia. Recently, mutations in SLC30A10 have been found to cause hypermanganesemia resulting in dystonia, parkinsonism, polycythemia, and liver disease. We have identified a homozygous mutation in SLC39A8 (ZIP8) associated with manganese deficiency and cerebellar atrophy, hypotonia, strabismus, developmental delay, short stature, mild skeletal dysplasia, and connective tissue abnormalities. This novel autosomal recessive disorder was identified in three patients from three Hutterite families. An identity-by-descent mapping approach identified an associated 11.7 Mb region on chromosome 4q22-25 and a mutation, p.Gly38Arg, was identified in a conserved residue of SLC39A8. As a member of the solute carrier gene (SLC) superfamily, SLC39A8 transports Mn, Zn, and Cd across the plasma membrane with very high-affinity binding constants. Evaluation of trace element levels in affected patients revealed a severe biochemical defect with very low blood Mn levels (20 nM, compared to normal range of 273-278 nM) and high Mn levels excreted in the urine; the Zn deficiency was milder, likely due to redundancy (presence of other Zn transporters). To our knowledge, this is the first gene associated with a human Mn deficiency syndrome and provides insight into the role of Mn homeostasis in development and health.

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