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

被引:12
作者
Ilie, Alina [1 ]
Boucher, Annie [1 ]
Park, Jaeok [2 ]
Berghuis, Albert Marinus [2 ]
McKinney, R. Anne [3 ]
Orlowski, John [1 ]
机构
[1] McGill Univ, Dept Physiol, Bellini Pavil,Rm 166, Montreal, PQ H3G 0B1, Canada
[2] McGill Univ, Dept Biochem, Montreal, PQ H3G 0B1, Canada
[3] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H3G 0B1, Canada
关键词
apoptosis; endosome; endocytosis; membrane transport; neurological disease; pH regulation; protein sorting; sodium-proton exchange; structure?function; ENDOPLASMIC-RETICULUM STRESS; MENTAL-RETARDATION; TRANSMEMBRANE SEGMENT; QUALITY-CONTROL; FUNCTIONAL-CHARACTERIZATION; INTELLECTUAL DISABILITY; SODIUM/PROTON EXCHANGER; PHENOTYPIC SPECTRUM; HIPPOCAMPAL-NEURONS; RAT HEPATOCYTES;
D O I
10.1074/jbc.RA120.012614
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 Christianson syndrome.
引用
收藏
页码:7075 / 7095
页数:21
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