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Case Report: Christianson Syndrome Caused by SLC9A6 Mutation: From Case to Genotype-Phenotype Analysis.

ABSTRACT: Christianson syndrome (CS) is an X-linked neurodevelopmental syndrome characterized by microcephaly, epilepsy, ataxia, and severe generalized developmental delay. Pathogenic mutations in the SLC9A6 gene, which encodes the Na⁺/H⁺ exchanger protein member 6 (NHE6), are associated with CS and autism spectrum disorder in males. In this study, whole exome sequencing (WES) and Sanger sequencing revealed a novel de novo frameshift variant c.1548_1549insT of SLC9A6 in a 14-month-old boy with early-onset seizures. According to The American College of Medical Genetics and Genomics (ACMG)/the Association for Molecular Pathology (AMP) guidelines, the variant was classified as pathogenic. The proband presented with several core symptoms of typical epilepsy, including microcephaly, motor delay, distal muscle weakness, micrognathia, occasional unprovoked laughter, swallowing and speech difficulties. Electroencephalography (EEG) showed spikes-slow waves in frontal pole, frontal, anterior temporal and frontal midline point areas. Gesell development schedules (GDS) indicated generalized developmental delay. We also summarized all the reported variants and analyzed the correlation of genotype and phenotype of CS. Our study extends the mutation spectrum of the SLC9A6 gene, and it might imply that the phenotypes of CS are not correlated with SLC9A6 genotypes.

SUBMITTER: Lan Y

PROVIDER: S-EPMC8721738 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Case Report: Christianson Syndrome Caused by SLC9A6 Mutation: From Case to Genotype-Phenotype Analysis.

Lan Yueyun Y Yi Sheng S Li Mengting M Wang Jinqiu J Yang Qi Q Yi Shang S Chen Fei F Huang Limei L Ruan Yiyan Y Shen Yiping Y Luo Jingsi J Qin Zailong Z

Frontiers in genetics 20211220

Christianson syndrome (CS) is an X-linked neurodevelopmental syndrome characterized by microcephaly, epilepsy, ataxia, and severe generalized developmental delay. Pathogenic mutations in the SLC9A6 gene, which encodes the Na+/H+ exchanger protein member 6 (NHE6), are associated with CS and autism spectrum disorder in males. In this study, whole exome sequencing (WES) and Sanger sequencing revealed a novel de novo frameshift variant c.1548_1549insT of SLC9A6 ...[more]

PMID: 34987551

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Project description:BackgroundChristianson syndrome (CS) is caused by mutations in SLC9A6 and is characterized by global developmental delay, epilepsy, hyperkinesis, ataxia, microcephaly, and behavioral disorder. However, the molecular mechanism by which these SLC9A6 mutations cause CS in humans is not entirely understood, and there is no objective method to determine the pathogenicity of single SLC9A6 variants.MethodsTrio-based whole exome sequencing (WES) was carried out on two individuals with suspicion of CS. qRT-PCR, western blot analysis, filipin staining, lysosomal enzymatic assays, and electron microscopy examination, using EBV-LCLs established from the two patients, were performed.ResultsTrio-based WES identified a hemizygous SLC9A6 c.1560dupT, p.T521Yfs*23 variant in proband 1 and a hemizygous SLC9A6 c.608delA, p.H203Lfs*10 variant in proband 2. Both children exhibited typical phenotypes associated with CS. Expression analysis in EBV-LCLs derived from the two patients showed a significant decrease in mRNA levels and no detectable normal NHE6 protein. EBV-LCLs showed a statistically significant increase in unesterified cholesterol in patient 1, but only non-significant increase in patient 2 when stained with filipin. Activities of lysosomal enzymes (β-hexosaminidase A, β-hexosaminidase A + B, β-galactosidase, galactocerebrosidase, arylsulfatase A) of EBV-LCLs did not significantly differ between the two patients and six controls. Importantly, by electron microscopy we detected an accumulation of lamellated membrane structures, deformed mitochondria, and lipid droplets in the patients' EBV-LCLs.ConclusionsThe SLC9A6 p.T521Yfs*23 and p.H203Lfs*10 variants in our patients result in loss of NHE6. Alterations of mitochondria and lipid metabolism may play a role in the pathogenesis of CS. Moreover, the combination of filipin staining with electron microscopy examination of patient lymphoblastoid cells can serve as a useful complementary diagnostic method for CS.

Project description:BackgroundChristianson Syndrome, a recently identified X-linked neurodevelopmental disorder, is caused by mutations in the human gene SLC9A6 encoding the recycling endosomal alkali cation/proton exchanger NHE6. The patients have pronounced limitations in cognitive ability, motor skills and adaptive behaviour. However, the mechanistic basis for this disorder is poorly understood as few of the more than 20 mutations identified thus far have been studied in detail.MethodsHere, we examined the molecular and cellular consequences of a 6 base-pair deletion of amino acids Glu(287) and Ser(288) (∆ES) in the predicted seventh transmembrane helix of human NHE6 expressed in established cell lines (CHO/AP-1, HeLa and neuroblastoma SH-SY5Y) and primary cultures of mouse hippocampal neurons by measuring levels of protein expression, stability, membrane trafficking, endosomal function and cell viability.ResultsIn the cell lines, immunoblot analyses showed that the nascent mutant protein was properly synthesized and assembled as a homodimer, but its oligosaccharide maturation and half-life were markedly reduced compared to wild-type (WT) and correlated with enhanced ubiquitination leading to both proteasomal and lysosomal degradation. Despite this instability, a measurable fraction of the transporter was correctly sorted to the plasma membrane. However, the rates of clathrin-mediated endocytosis of the ∆ES mutant as well as uptake of companion vesicular cargo, such as the ligand-bound transferrin receptor, were significantly reduced and correlated with excessive endosomal acidification. Notably, ectopic expression of ∆ES but not WT induced apoptosis when examined in AP-1 cells. Similarly, in transfected primary cultures of mouse hippocampal neurons, membrane trafficking of the ∆ES mutant was impaired and elicited marked reductions in total dendritic length, area and arborization, and triggered apoptotic cell death.ConclusionsThese results suggest that loss-of-function mutations in NHE6 disrupt recycling endosomal function and trafficking of cargo which ultimately leads to neuronal degeneration and cell death in Christianson Syndrome.

Project description:Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) were generated by insertion of the bacterial lacZ/β-galactosidase (β-Gal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations and patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, β-Gal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Using β-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group.

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Case Report: Christianson Syndrome Caused by SLC9A6 Mutation: From Case to Genotype-Phenotype Analysis.

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Case Report: Christianson Syndrome Caused by <i>SLC9A6</i> Mutation: From Case to Genotype-Phenotype Analysis.

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