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Hum Mol Genet. 2019 Feb 15;28(4):598-614. doi: 10.1093/hmg/ddy371.

A recurrent missense variant in SLC9A7 causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation.

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Department of Physiology, McGill University, Montreal, Quebec, Canada.
Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW, Australia.
Adelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.
Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
GeneDx, Gaithersburg, MD, USA.
Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.
Department of Pediatrics, Division of Medical Genetics, University of Mississippi Medical Center, Jackson, MS, USA.
South Australian Health and Medical Research Institute, Adelaide, SA, Australia.


We report two unrelated families with multigenerational nonsyndromic intellectual disability (ID) segregating with a recurrent de novo missense variant (c.1543C>T:p.Leu515Phe) in the alkali cation/proton exchanger gene SLC9A7 (also commonly referred to as NHE7). SLC9A7 is located on human X chromosome at Xp11.3 and has not yet been associated with a human phenotype. The gene is widely transcribed, but especially abundant in brain, skeletal muscle and various secretory tissues. Within cells, SLC9A7 resides in the Golgi apparatus, with prominent enrichment in the trans-Golgi network (TGN) and post-Golgi vesicles. In transfected Chinese hamster ovary AP-1 cells, the Leu515Phe mutant protein was correctly targeted to the TGN/post-Golgi vesicles, but its N-linked oligosaccharide maturation as well as that of a co-transfected secretory membrane glycoprotein, vesicular stomatitis virus G (VSVG) glycoprotein, was reduced compared to cells co-expressing SLC9A7 wild-type and VSVG. This correlated with alkalinization of the TGN/post-Golgi compartments, suggestive of a gain-of-function. Membrane trafficking of glycosylation-deficient Leu515Phe and co-transfected VSVG to the cell surface, however, was relatively unaffected. Mass spectrometry analysis of patient sera also revealed an abnormal N-glycosylation profile for transferrin, a clinical diagnostic marker for congenital disorders of glycosylation. These data implicate a crucial role for SLC9A7 in the regulation of TGN/post-Golgi pH homeostasis and glycosylation of exported cargo, which may underlie the cellular pathophysiology and neurodevelopmental deficits associated with this particular nonsyndromic form of X-linked ID.

[Available on 2020-02-15]
[Indexed for MEDLINE]

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