Severe neonatal hypotonia due to SLC30A5 variant affecting function of ZnT5 zinc transporter
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 organel...
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| Format: | Article |
| Language: | English |
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Wiley
2025-01-01
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| Series: | JIMD Reports |
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| Online Access: | https://doi.org/10.1002/jmd2.12465 |
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| author | Vadim Dolgin Pauline Chabosseau Jacob Bistritzer Iris Noyman Orna Staretz‐Chacham Ohad Wormser Noam Hadar Marina Eskin‐Schwartz Bibi Kanengisser‐Pines Ginat Narkis Ramy Abramsky Eilon Shany Guy A. Rutter Kyla Marks Ohad S. Birk |
| author_facet | Vadim Dolgin Pauline Chabosseau Jacob Bistritzer Iris Noyman Orna Staretz‐Chacham Ohad Wormser Noam Hadar Marina Eskin‐Schwartz Bibi Kanengisser‐Pines Ginat Narkis Ramy Abramsky Eilon Shany Guy A. Rutter Kyla Marks Ohad S. Birk |
| author_sort | Vadim Dolgin |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-79f79982e67947069d2cf5b76a0678af |
| institution | Kabale University |
| issn | 2192-8312 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | JIMD Reports |
| spelling | doaj-art-79f79982e67947069d2cf5b76a0678af2025-01-28T07:38:32ZengWileyJIMD Reports2192-83122025-01-01661n/an/a10.1002/jmd2.12465Severe neonatal hypotonia due to SLC30A5 variant affecting function of ZnT5 zinc transporterVadim Dolgin0Pauline Chabosseau1Jacob Bistritzer2Iris Noyman3Orna Staretz‐Chacham4Ohad Wormser5Noam Hadar6Marina Eskin‐Schwartz7Bibi Kanengisser‐Pines8Ginat Narkis9Ramy Abramsky10Eilon Shany11Guy A. Rutter12Kyla Marks13Ohad S. Birk14The Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences Ben Gurion University Beer‐Sheva IsraelCRCHUM and Department of Medicine Université de Montréal Montréal QC CanadaPediatric Neurology Unit, Division of Pediatrics, Soroka University Medical Center, Faculty of Health Sciences Ben‐Gurion University of the Negev Beer Sheva IsraelPediatric Neurology Unit, Division of Pediatrics, Soroka University Medical Center, Faculty of Health Sciences Ben‐Gurion University of the Negev Beer Sheva IsraelDepartment of Neonatology, Soroka University Medical Center, Faculty of Health Sciences Ben‐Gurion University of the Negev Beer Sheva IsraelThe Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences Ben Gurion University Beer‐Sheva IsraelThe Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences Ben Gurion University Beer‐Sheva IsraelThe Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences Ben Gurion University Beer‐Sheva IsraelSoroka Medical Center Genetics Institute Beer‐Sheva IsraelSoroka Medical Center Genetics Institute Beer‐Sheva IsraelDepartment of Neonatology, Soroka University Medical Center, Faculty of Health Sciences Ben‐Gurion University of the Negev Beer Sheva IsraelDepartment of Neonatology, Soroka University Medical Center, Faculty of Health Sciences Ben‐Gurion University of the Negev Beer Sheva IsraelCRCHUM and Department of Medicine Université de Montréal Montréal QC CanadaDepartment of Neonatology, Soroka University Medical Center, Faculty of Health Sciences Ben‐Gurion University of the Negev Beer Sheva IsraelThe Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences Ben Gurion University Beer‐Sheva IsraelAbstract 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.https://doi.org/10.1002/jmd2.12465hypotoniamutationneurological syndromeSLC30A5ZnT5 |
| spellingShingle | Vadim Dolgin Pauline Chabosseau Jacob Bistritzer Iris Noyman Orna Staretz‐Chacham Ohad Wormser Noam Hadar Marina Eskin‐Schwartz Bibi Kanengisser‐Pines Ginat Narkis Ramy Abramsky Eilon Shany Guy A. Rutter Kyla Marks Ohad S. Birk Severe neonatal hypotonia due to SLC30A5 variant affecting function of ZnT5 zinc transporter JIMD Reports hypotonia mutation neurological syndrome SLC30A5 ZnT5 |
| title | Severe neonatal hypotonia due to SLC30A5 variant affecting function of ZnT5 zinc transporter |
| title_full | Severe neonatal hypotonia due to SLC30A5 variant affecting function of ZnT5 zinc transporter |
| title_fullStr | Severe neonatal hypotonia due to SLC30A5 variant affecting function of ZnT5 zinc transporter |
| title_full_unstemmed | Severe neonatal hypotonia due to SLC30A5 variant affecting function of ZnT5 zinc transporter |
| title_short | Severe neonatal hypotonia due to SLC30A5 variant affecting function of ZnT5 zinc transporter |
| title_sort | severe neonatal hypotonia due to slc30a5 variant affecting function of znt5 zinc transporter |
| topic | hypotonia mutation neurological syndrome SLC30A5 ZnT5 |
| url | https://doi.org/10.1002/jmd2.12465 |
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