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.

Figure 1

MRI Findings in Individuals with Mutation in SLC39A8 MRI findings from individual 1 at 6 years of age (A), individual 2 at 12 years of age (B), individual 4 at 3 years of age (C), individual 7 at 8 years of age (D), and individual 6 at 9 years of age (E) demonstrate a small cerebellum with wide interfoliate sulci and major fissures demonstrating diffuse cerebellar vermian and hemispheric atrophy. The posterior fossa is normal in size. MRS over the left basal ganglia in individual 6 (E) demonstrates an elevated lactate peak.

Figure 2

SLC39A8 Mutation Causes a Zinc and Manganese Deficiency Syndrome (A) Evolutionary alignment of SLC39A8 amino acid sequence shows strict conservation of Gly38. Conservation plot was generated with Alamut software. (B and C) Western blot (lymphoblasts) (B) and immunofluorescence (fibroblasts) (C) analyses demonstrate normal levels and localization of SLC39A8 in cells derived from individual 2 compared to controls. GAPDH was used as immunoblot loading control.