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Cold Spring Harb Mol Case Stud. 2018 Feb 1;4(1). pii: a002303. doi: 10.1101/mcs.a002303. Print 2018 Feb.

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.

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Department of Medical Genetics, Haukeland University Hospital, Bergen N-5021, Norway.
Department of Neuroscience, University of Copenhagen, Copenhagen DK-2200, Denmark.
Department of Informatics, University of Bergen, Bergen N-5020, Norway.
KG Jebsen Center for Diabetes Research, Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen N-5020, Norway.
Department of Neurology, Haukeland University Hospital, Bergen N-5021, Norway.
Department of Clinical Medicine (K1), University of Bergen, Bergen N-5020, Norway.


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.


brain atrophy; cerebral ischemia; concentric hypertrophic cardiomyopathy; congenital sensorineural hearing impairment; gait imbalance; intellectual disability, mild; macrocephaly at birth; relative macrocephaly; spastic gait

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