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