SLC9A6 – Christianson Syndrome

Christianson syndrome is a rare X-linked neurodevelopmental disorder caused by mutations in the SLC9A6 gene, characterized by severe intellectual disability, progressive microcephaly, truncal ataxia, early-onset seizures, absent speech, and autistic behavior (PMID:20949524). Patients often present in infancy with developmental regression and MRI-demonstrated cerebellar atrophy reminiscent of Angelman syndrome.

Genetic analyses have identified over 30 affected males from more than 20 unrelated pedigrees harboring truncating, splicing, or missense SLC9A6 variants. In the largest cohort of 12 independent families (14 boys), all 12 mutations were protein-truncating or splicing variants, including recurrent c.1342C>T (p.Arg448Ter) and c.1710G>A (p.Trp570Ter) (PMID:25044251). Additional case reports describe de novo nonsense (c.1548_1549insT), splice-site (IVS10-1G>A), and interstitial deletions encompassing SLC9A6 (PMID:21932316, PMID:24630051).

Segregation in multiplex pedigrees, including a large extended family with three affected males cosegregating a c.190G>T (p.Glu64Ter) variant and recurrence in siblings, confirms X-linked recessive inheritance with high penetrance in hemizygous males (PMID:27142213).

Functional studies demonstrate that SLC9A6 loss-of-function disrupts endosomal-lysosomal homeostasis and leads to neurodegeneration. Slc9a6 knockout mice display Purkinje cell loss, motor hyperactivity, and cerebellar atrophy, mirroring patient ataxia (PMID:21964919, PMID:26515654). In vitro assays in patient lymphoblastoid cells and heterologous systems reveal aberrant endosomal acidification, impaired cargo trafficking, and apoptosis for truncating and regulatory-domain mutants (PMID:32277048, PMID:37381736).

Some missense variants such as c.-57+50G>T (p.Ala9Ser) appear hypomorphic; in vivo mouse studies show no significant neurodegeneration or pH defects, underscoring the need for functional assessment of individual variants (PMID:31676550).

Collectively, genetic, segregation, and functional data establish a definitive association between SLC9A6 and Christianson syndrome, with haploinsufficiency causing endosomal-lysosomal dysfunction. Sequencing of SLC9A6 is essential for diagnosis and genetic counseling.

Key Take-home: Recognition of SLC9A6 variants enables accurate diagnosis, informs family counseling, and guides the development of targeted therapeutic strategies.

References

• American journal of medical genetics. Part A • 2010 • Natural history of Christianson syndrome PMID:20949524
• Annals of neurology • 2014 • Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome PMID:25044251
• American journal of medical genetics. Part A • 2011 • Christianson syndrome in a patient with an interstitial Xq26.3 deletion PMID:21932316
• Epilepsy research • 2014 • A novel mutation in the endosomal Na+/H+ exchanger NHE6 causes Christianson syndrome with electrical status epilepticus during slow-wave sleep PMID:24630051
• Human genetics • 2016 • The expanding phenotypic spectrum of female SLC9A6 mutation carriers PMID:27142213
• Brain: a journal of neurology • 2011 • X-linked Angelman-like syndrome caused by Slc9a6 knockout in mice PMID:21964919
• Disease models & mechanisms • 2016 • X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities PMID:26515654
• The Journal of biological chemistry • 2020 • Assorted dysfunctions of endosomal alkali cation/proton exchanger SLC9A6 variants linked to Christianson syndrome PMID:32277048
• CNS neuroscience & therapeutics • 2023 • Functional analysis of two SLC9A6 frameshift variants in lymphoblastoid cells from patients with Christianson syndrome PMID:37381736
• eNeuro • 2019 • Functional Assessment In Vivo of the Mouse Homolog of the Human Ala-9-Ser NHE6 Variant PMID:31676550

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