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

Khayat, Wujood; Hackett, Anna; Shaw, Marie; Ilie, Alina; Dudding‐Byth, Tracy; Kalscheuer, Vera M.; Christie, Louise; Corbett, Mark; Juusola, Jane; Friend, Kathryn; Kirmse, Brian; Gécz, Jozef; Field, Michael; Orlowski, John

doi:10.1093/hmg/ddy371

Cited by 28 publications

(20 citation statements)

References 128 publications

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“…Khayat et al (2019) recently described a new pH homeostasis-associated disease with multigenerational non-syndromic intellectual disability (ID). The disease is caused by missense mutations in the alkali cation/proton exchanger NHE7 (SLC9A7).…”

Section: Altered Golgi Homeostasis In Golgi Dysfunction and Diseasementioning

confidence: 99%

Golgi pH, Ion and Redox Homeostasis: How Much Do They Really Matter?

Kellokumpu

2019

Front. Cell Dev. Biol.

111

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Exocytic and endocytic compartments each have their own unique luminal ion and pH environment that is important for their normal functioning. A failure to maintain this environment – the loss of homeostasis – is not uncommon. In the worst case, all the main Golgi functions, including glycosylation, membrane trafficking and protein sorting, can be perturbed. Several factors contribute to Golgi homeostasis. These include not only ions such as H + , Ca 2+ , Mg 2+ , Mn 2+ , but also Golgi redox state and nitric oxide (NO) levels, both of which are dependent on the oxygen levels in the cells. Changes to any one of these factors have consequences on Golgi functions, the nature of which can be dissimilar or similar depending upon the defects themselves. For example, altered Golgi pH homeostasis gives rise to Cutis laxa disease, in which glycosylation and membrane trafficking are both affected, while altered Ca 2+ homeostasis due to the mutated SCPA1 gene in Hailey–Hailey disease, perturbs various protein sorting, proteolytic cleavage and membrane trafficking events in the Golgi. This review gives an overview of the molecular machineries involved in the maintenance of Golgi ion, pH and redox homeostasis, followed by a discussion of the organelle dysfunction and disease that frequently result from their breakdown. Congenital disorders of glycosylation (CDGs) are discussed only when they contribute directly to Golgi pH, ion or redox homeostasis. Current evidence emphasizes that, rather than being mere supporting factors, Golgi pH, ion and redox homeostasis are in fact key players that orchestrate and maintain all Golgi functions.

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Section: Altered Golgi Homeostasis In Golgi Dysfunction and Diseasementioning

confidence: 99%

Golgi pH, Ion and Redox Homeostasis: How Much Do They Really Matter?

Kellokumpu

2019

Front. Cell Dev. Biol.

111

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“…Two other recent clinical studies investigating two unrelated ion transport mutations are relevant to our hypothesis, as they have been linked to changes in Golgi pH and glycosylation. Khayat et al reported a multigenerational nonsyndromic intellectual disability that is the result of mutation in the alkali cation/proton exchanger gene SLC9A7 (also commonly referred to as NHE7) located on human X chromosome [9]. The gene is widely transcribed in various secretory tissues with prominent enrichment in the trans-Golgi network and post-Golgi vesicles.…”

Section: The Gs and Bs Phenotypic Overlappingmentioning

confidence: 99%

Are the Clinical Presentations (Phenotypes) of Gitelman’s and Bartter’s Syndromes Gene Mutations Driven by Their Effects on Intracellular pH, Their “pH” Enotype?

Calò

Davis

2020

IJMS

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Gitelman’s syndrome (GS) and Bartter’s syndrome (BS) are rare inherited salt-losing tubulopathies whose variations in genotype do not correlate well with either clinical course or electrolyte requirements. Using GS/BS patients as nature’s experiments, we found them to be a human model of endogenous Ang II antagonism with activated Renin-Angiotensin System (RAS), resulting in high Ang II levels with blunted cardiovascular effects. These patients are also characterized by increased and directly correlated levels of both Angiotensin Converting Enzyme 2 (ACE2) and Ang 1-7. Understanding the myriad of distinctive and frequently overlapping clinical presentations of GS/BS arises remains challenging. Efforts to find a treatment for COVID-19 has fueled a recent surge in interest in chloroquine/hydroxychloroquine and its effects. Of specific interest are chloroquine/hydroxychloroquine’s ability to inhibit SARS-CoV infection by impairing ACE2, the SARS-CoV2 entry point, through terminal glycosylation via effects on TGN/post-Golgi pH homeostasis. Several different studies with a GS or a BS phenotype, along with a nonsyndromic form of X-linked intellectual disability linked to a mutated SLC9A7, provide additional evidence that specific gene defects can act via misregulation of TGN/post-Golgi pH homeostasis, which leads to a common mechanistic basis resulting in overlapping phenotypes. We suggest that linkage between the specific gene defects identified in GS and BS and the myriad of distinctive and frequently overlapping clinical findings may be the result of aberrant glycosylation of ACE2 driven by altered TGN/endosome system acidification caused by the metabolic alkalosis brought about by these salt-losing tubulopathies in addition to their altered intracellular calcium signaling due to a blunted second messenger induced intracellular calcium release that is, in turn, amplified by the RAS system.

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“…The last XLID update published, estimated that 141 genes are associated with XLID. Since then, more genes have been associated to XLID such as CXorf56 , HS6ST2 , NAA15 , POLA1 and SLC9A7 (Figure ). However, the link of some of these genes to XLID is still questionable .…”

Section: Introductionmentioning

confidence: 99%

Non‐syndromic X linked intellectual disability: Current knowledge in light of the recent advances in molecular and functional studies

Tejada

Ibarluzea

2020

Clinical Genetics

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Since the discovery of the FMR1 gene and the clinical and molecular characterization of Fragile X Syndrome in 1991, more than 141 genes have been identified in the Xchromosome in these 28 years thanks to applying continuously evolving molecular techniques to X-linked intellectual disability (XLID) families. In the past decade, array comparative genomic hybridization and next generation sequencing technologies have accelerated gene discovery exponentially. Classically, XLID has been subdivided in syndromic intellectual disability (S-XLID)-where intellectual disability (ID) is always associated with other recognizable physical and/or neurological features-and non-specific or non-syndromic intellectual disability (NS-XLID) where the only common feature is ID. Nevertheless, new advances on the study of these entities have showed that this classification is not always clear-cut because distinct variants in several of these XLID genes can result in S-XLID as well as in NS-XLID. This review focuses on the current knowledge on the XLID genes involved in non-syndromic forms, with the emphasis on their pathogenic mechanism, thus allowing the possibility to elucidate why some of them can give both syndromic and non-syndromic phenotypes.

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A recurrent missense variant inSLC9A7causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation

Cited by 28 publications

References 128 publications

Golgi pH, Ion and Redox Homeostasis: How Much Do They Really Matter?

Golgi pH, Ion and Redox Homeostasis: How Much Do They Really Matter?

Are the Clinical Presentations (Phenotypes) of Gitelman’s and Bartter’s Syndromes Gene Mutations Driven by Their Effects on Intracellular pH, Their “pH” Enotype?

Non‐syndromic X linked intellectual disability: Current knowledge in light of the recent advances in molecular and functional studies

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