Severe neonatal hypotonia due to <scp><i>SLC30A5</i></scp> variant affecting function of <scp>ZnT5</scp> zinc transporter
Author(s)
Type
Journal Article
Abstract
The tightly-regulated spatial and temporal distribution of zinc ion concentrations within cellular compartments is controlled by two groups of Zn2+ transporters: the 14-member ZIP/SLC39 family, facilitating Zn2+ influx into the cytoplasm from the extracellular space or intracellular organelles; and the 10-member ZnT/SLC30 family, mobilizing Zn2+ in the opposite direction. Genetic aberrations in most zinc transporters cause human syndromes. Notably, previous studies demonstrated osteopenia and male-specific cardiac death in mice lacking the ZnT5/SLC30A5 zinc transporter, and suggested association of two homozygous frameshift SLC30A5 variants with perinatal mortality in humans, due to hydrops fetalis and hypertrophic cardiomyopathy. We set out to decipher the molecular basis of a severe hypotonia syndrome. Combining homozygosity mapping and exome sequencing studies of consanguineous Bedouin kindred, as well as transfection experiments and zinc monitoring in HEK293 cells, we demonstrate that a bi-allelic in-frame 3bp deletion variant in SLC30A5, deleting isoleucine within the highly conserved cation efflux domain of the encoded ZnT5, results in lower cytosolic zinc concentrations, causing a syndrome of severe non-progressive neonatal axial and limb hypotonia with high-arched palate and respiratory failure. There was no evidence of hydrops fetalis, cardiomyopathy or multi-organ involvement. Affected infants required nasogastric tube or gastrostomy feeding, suffered from various degrees of respiratory compromise and failure to thrive and died in infancy. Thus, a biallelic variant in SLC30A5 (ZnT5), affecting cytosolic zinc concentrations, causes a severe hypotonia syndrome with respiratory insufficiency and failure to thrive, lethal by 1 year of age.
Date Issued
2025-01-01
Date Acceptance
2024-11-27
Citation
JIMD Reports, 2025, 66 (1)
ISSN
2192-8312
Publisher
Wiley
Start Page
e12465
Journal / Book Title
JIMD Reports
Volume
66
Issue
1
Copyright Statement
© 2024 The Author(s). JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39790720
PII: JMD212465
Subjects
SLC30A5
ZnT5
hypotonia
mutation
neurological syndrome
Publication Status
Published
Coverage Spatial
United States
Article Number
e12465
Date Publish Online
2025-01-09