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Assorted dysfunctions of endosomal alkali cation/proton exchanger SLC9A6 variants linked to Christianson syndrome

Ilie, Alina, Boucher, Annie, Park, Jaeok, Berghuis, Albert Marinus, McKinney, R. Anne, Orlowski, John·2020·Journal of Biological Chemistry
DOI 10.1074/jbc.ra120.012614
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Abstract

Genetic screening has identified numerous variants of the endosomal solute carrier family 9 member A6 ( SLC9A6 )/(Na + ,K + )/H + exchanger 6 (NHE6 ) gene that cause Christianson syndrome, a debilitating X-linked developmental disorder associated with a range of neurological, somatic, and behavioral symptoms. Many of these variants cause complete loss of NHE6 expression, but how subtler missense substitutions or nonsense mutations that partially truncate its C-terminal cytoplasmic regulatory domain impair NHE6 activity and endosomal function are poorly understood. Here, we describe the molecular and cellular consequences of six unique mutations located in the N-terminal cytoplasmic segment (A9S), the membrane ion translocation domain (L188P and G383D), and the C-terminal regulatory domain (E547*, R568Q, and W570*) of human NHE6 that purportedly cause disease. Using a heterologous NHE6-deficient cell expression system, we show that the biochemical, catalytic, and cellular properties of the A9S and R568Q variants were largely indistinguishable from those of the WT transporter, which obscured their disease significance. By contrast, the L188P, G383D, E547*, and W570* mutants exhibited variable deficiencies in biosynthetic post-translational maturation, membrane sorting, pH homeostasis in recycling endosomes, and cargo trafficking, and they also triggered apoptosis. These findings broaden our understanding of the molecular dysfunctions of distinct NHE6 variants associated with Ch…

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  • Some Slc9a6 mutant variants causing Christianson syndrome do not significantly alter NHE6 ion exchange properties, suggesting Christianson syndrome could be caused by loss of NHE6 scaffolding functions rather than loss of endosomal pH regulation.

    “However, some Slc9a6 mutant variants causing Christianson syndrome in humans do not significantly alter the ion exchange properties of NHE6 (Ilie et al., 2020; Ilie et al., 2019) suggesting that Christianson syndrome could be caused by loss of NHE6 scaffolding functions and not by loss of endosomal pH regulation.”

    From NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load (2021) · cites this paper as Ilie et al., 2020

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Metadata

Authors
Ilie, A., Boucher, A., Park, J., Berghuis, A. M., McKinney, R. A., & Orlowski, J.
ORCID
Orlowski, John
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2020-05
Volume
295
Issue
20
Pages
7075-7095
ISSN
0021-9258
DOI
10.1074/jbc.ra120.012614
Cited by
24
References
7
Language
en
Licence
Funders
Government of Canada | Canadian Institutes of Health Research (PJT-155976, MOP-133611, PJT-162365)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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