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A de novo Ser111Thr variant in aquaporin-4 in a patient with intellectual disability, transient signs of brain ischemia, transient cardiac hypertrophy, and progressive gait disturbance

Aquaporin-4, encoded by AQP4, is the major water channel in the central nervous system and plays an important role in the brain's water balance, including edema formation and clearance. Using genomic copy-number analysis and trio-exome sequencing, we investigated a male patient with intellectua...

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Autores principales: Berland, Siren, Toft-Bertelsen, Trine L., Aukrust, Ingvild, Byska, Jan, Vaudel, Marc, Bindoff, Laurence A., MacAulay, Nanna, Houge, Gunnar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793774/
https://www.ncbi.nlm.nih.gov/pubmed/29437797
http://dx.doi.org/10.1101/mcs.a002303
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author Berland, Siren
Toft-Bertelsen, Trine L.
Aukrust, Ingvild
Byska, Jan
Vaudel, Marc
Bindoff, Laurence A.
MacAulay, Nanna
Houge, Gunnar
author_facet Berland, Siren
Toft-Bertelsen, Trine L.
Aukrust, Ingvild
Byska, Jan
Vaudel, Marc
Bindoff, Laurence A.
MacAulay, Nanna
Houge, Gunnar
author_sort Berland, Siren
collection PubMed
description Aquaporin-4, encoded by AQP4, is the major water channel in the central nervous system and plays an important role in the brain's water balance, including edema formation and clearance. Using genomic copy-number analysis and trio-exome sequencing, we investigated a male patient with intellectual disability, hearing loss, and progressive gait dysfunction and found a de novo missense change Ser111Thr in AQP4 as the only suspicious finding. Perinatally, signs of brain ischemia were detected in relation to acute collapse 2 h after birth that resolved a few days later. At the age of 3 mo, cardiac hypertrophy was detected that persisted through childhood but was completely resolved by age 16. In theory, this neurodevelopmental disorder with transient cardiomyopathy could be caused by a disturbance of cellular water balance. Ser111 is an extremely conserved residue in the short cytoplasmic loop between AQP4 transmembrane helix 2 and 3, present across all AQP isoforms from plants to mammals, and it does not appear to be a phosphorylation site. We found that the Ser111Thr change does not affect water permeability or protein stability, suggesting another and possibly regulatory role. Although causality remains unproven, this case study draws attention to AQP4 as a candidate gene for a unique developmental disorder and to a specific serine as a residue of possibly great functional importance in many AQPs.
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spelling pubmed-57937742018-02-05 A de novo Ser111Thr variant in aquaporin-4 in a patient with intellectual disability, transient signs of brain ischemia, transient cardiac hypertrophy, and progressive gait disturbance Berland, Siren Toft-Bertelsen, Trine L. Aukrust, Ingvild Byska, Jan Vaudel, Marc Bindoff, Laurence A. MacAulay, Nanna Houge, Gunnar Cold Spring Harb Mol Case Stud Research Article Aquaporin-4, encoded by AQP4, is the major water channel in the central nervous system and plays an important role in the brain's water balance, including edema formation and clearance. Using genomic copy-number analysis and trio-exome sequencing, we investigated a male patient with intellectual disability, hearing loss, and progressive gait dysfunction and found a de novo missense change Ser111Thr in AQP4 as the only suspicious finding. Perinatally, signs of brain ischemia were detected in relation to acute collapse 2 h after birth that resolved a few days later. At the age of 3 mo, cardiac hypertrophy was detected that persisted through childhood but was completely resolved by age 16. In theory, this neurodevelopmental disorder with transient cardiomyopathy could be caused by a disturbance of cellular water balance. Ser111 is an extremely conserved residue in the short cytoplasmic loop between AQP4 transmembrane helix 2 and 3, present across all AQP isoforms from plants to mammals, and it does not appear to be a phosphorylation site. We found that the Ser111Thr change does not affect water permeability or protein stability, suggesting another and possibly regulatory role. Although causality remains unproven, this case study draws attention to AQP4 as a candidate gene for a unique developmental disorder and to a specific serine as a residue of possibly great functional importance in many AQPs. Cold Spring Harbor Laboratory Press 2018-02 /pmc/articles/PMC5793774/ /pubmed/29437797 http://dx.doi.org/10.1101/mcs.a002303 Text en © 2018 Berland et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Research Article
Berland, Siren
Toft-Bertelsen, Trine L.
Aukrust, Ingvild
Byska, Jan
Vaudel, Marc
Bindoff, Laurence A.
MacAulay, Nanna
Houge, Gunnar
A de novo Ser111Thr variant in aquaporin-4 in a patient with intellectual disability, transient signs of brain ischemia, transient cardiac hypertrophy, and progressive gait disturbance
title A de novo Ser111Thr variant in aquaporin-4 in a patient with intellectual disability, transient signs of brain ischemia, transient cardiac hypertrophy, and progressive gait disturbance
title_full A de novo Ser111Thr variant in aquaporin-4 in a patient with intellectual disability, transient signs of brain ischemia, transient cardiac hypertrophy, and progressive gait disturbance
title_fullStr A de novo Ser111Thr variant in aquaporin-4 in a patient with intellectual disability, transient signs of brain ischemia, transient cardiac hypertrophy, and progressive gait disturbance
title_full_unstemmed A de novo Ser111Thr variant in aquaporin-4 in a patient with intellectual disability, transient signs of brain ischemia, transient cardiac hypertrophy, and progressive gait disturbance
title_short A de novo Ser111Thr variant in aquaporin-4 in a patient with intellectual disability, transient signs of brain ischemia, transient cardiac hypertrophy, and progressive gait disturbance
title_sort de novo ser111thr variant in aquaporin-4 in a patient with intellectual disability, transient signs of brain ischemia, transient cardiac hypertrophy, and progressive gait disturbance
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793774/
https://www.ncbi.nlm.nih.gov/pubmed/29437797
http://dx.doi.org/10.1101/mcs.a002303
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