Berland S et al. (2018), A de novo Ser111Thr variant in aquaporin-4 in a...

XB-ART-55810

Cold Spring Harb Mol Case Stud 2018 Feb 01;41:. doi: 10.1101/mcs.a002303.

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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.

Berland S , Toft-Bertelsen TL , Aukrust I , Byska J , Vaudel M , Bindoff LA , MacAulay N , Houge G .

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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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Species referenced: Xenopus laevis
Genes referenced: aqp4

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References [+] :

Acuna-Hidalgo, New insights into the generation and role of de novo mutations in health and disease. 2016, Pubmed

	Figure 1. Patient pictures. Patient pictures from ages 3 (A), 16 (D–H), 18 (B), and 25 (C) years.
	Figure 2. The relative unit water permeability of AQP4-wt and AQP4-S111T expressed in oocytes. (A) Representative volume traces from an uninjected oocyte (labeled C) and oocytes expressing AQP4-wt or AQP4-S111T challenged with a hyperosmotic gradient of +20 mOsm (indicated by a black bar). (B) The water permeabilities are given for uninjected control oocytes (labeled “C”), AQP4-wt-, and AQP4-S111T-expressing oocytes for one representative experiment (n = 4 oocytes, error bars given as ±SD, statistical significance above the histograms refers to comparison to uninjected oocytes). (C) A representative western blot of biotinylated oocyte plasma membranes from one experiment (n = 4 oocytes in each lane). (D) Quantification of the representative western blot in C. (E) The relative unit water permeability was obtained for each experiment by division of the AQP4-mediated water permeabilities from B with plasma membrane AQP4 abundance (D), normalized to AQP4-wt and summarized across individual experiments (n = 3, error bars given as ±SEM). Water permeabilities were compared using one-way ANOVA with Dunnett's multiple comparison post hoc test and the relative unit water permeabilities were compared using Student's paired t-test. ***, P < 0.001; ns, not significant.
	Figure 3. Conservation of Ser111 in AQP4 and between aquaporins.