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.

Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity

“…We examined N-glycan profiles in the serum of our Slc39a8-knockout mouse models using MALDI/time-of-flight mass spectrometric (MALDI-TOF-MS) analysis ( Figure 5, A-D). Compared with control mice, we observed that ZIP8-iKO mice had a decreased abundance of fully glycosylated N-glycan species (26.6% in WT vs. 16.2% in ZIP8-iKO mice) and an increased abundance of truncated N-glycan species, especially under-galactosylated N-glycan species including monosialo-monogalacto-biantennary glycans (1.0% in WT vs. 3.7% in ZIP8-iKO mice), asialo-monogalacto-biantennary glycans (0 in WT vs 1.7% in ZIP8-iKO mice), and asialo-agalactobiantennary glycans (0 in WT vs 1.4% in ZIP8-iKO mice). Similarly, compared with control mice, ZIP8-LSKO mice had a decreased abundance of fully glycosylated N-glycan species (41.0% in WT vs. 35.5% in ZIP8-LSKO mice) and an increased abundance of truncated N-glycan species, especially under-galactosylated N-glycan species monosialo-monogalacto-biantennary glycans (0.7% vs. 2.6%).…”

“…***P ≤ 0.001, **P ≤ 0.01, and *P ≤0. (16)(17)(18). We examined N-glycan profiles in the serum of our Slc39a8-knockout mouse models using MALDI/time-of-flight mass spectrometric (MALDI-TOF-MS) analysis ( Figure 5, A-D).…”

“…Importantly, this variant associated with lower hepatic SLC39A8 expression and reduced ZIP8 activity is associated with lower whole-blood Mn levels (1). Furthermore, SLC39A8 loss-of-function mutations were recently identified in human patients with neurological and skeletal symptoms (16)(17)(18), and these patients were found to have decreased whole-blood Mn levels and reduced protein N-glycosylation, especially galactosylation. Thus, the human data indicate that reduced expression and function of ZIP8 lead to reduced whole-blood Mn levels and protein N-glycosylation, especially galactosylation, a directionality fully consistent with our findings in Slc39a8 loss-of-function mice and rs13107325 homozygous minor allele carriers.…”

“…Hypomorphic Slc39a8 mice exhibited diminished tissue Zn and Fe levels, stunted growth, multiple-organ hypoplasia, anemia, and perinatal death (15). Patients carrying SLC39A8 mutations had severe Mn deficiency, neurological and skeletal defects, and biomarkers of type II congenital disorders of glycosylation (CDG) (16)(17)(18), a growing family of genetic diseases that affect multiple organs and systems (19). However, there is virtually nothing known about how ZIP8 regulates metal ion metabolism in vivo.…”

Zinc- and bicarbonate-dependent ZIP8 transporter mediates selenite uptake

“…SLC39A8 mutations have also been associated with schizophrenia [42, 43], mental retardation [44], and with cerebellar atrophy [45] or cranial asymmetry [46] with accompanying dysmorphologies. Our reason for choosing those particular mouse tissues for HSeO 3 − uptake studies (Figure 4) reflected this growing list of ZIP8-related clinical disorders.…”