Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 97, Issue 6, Pages 886-893Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2015.11.002
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Funding
- Care4Rare Canada Consortium (Enhanced Care for Rare Genetic Diseases in Canada) - Genome Canada
- Canadian Institutes of Health Research
- Ontario Genomics Institute
- Ontario Research Fund
- Genome Quebec
- Children's Hospital of Eastern Ontario Foundation
- Alberta Children's Hospital Research Institute
- Alberta Innovates Health Solutions
- DFG [AB393/2-2, AB393/4-1]
- Alberta Children's Hospital Foundation
- CIHR Training Program in Genetics, Child Development, and Health at the University of Calgary
- NIH [R01 ES010416, T32 ES016646, P30 ES006096]
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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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