X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F16%3A10325228" target="_blank" >RIV/00216208:11110/16:10325228 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1242/dmm.022780" target="_blank" >http://dx.doi.org/10.1242/dmm.022780</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1242/dmm.022780" target="_blank" >10.1242/dmm.022780</a>

Result language

angličtina

Original language name

X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities

Original language description

Christianson syndrome 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 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, have not yet been systematically characterized. Slc9a6 knockout mice were generated by insertion of the bacterial lacZ/Beta-galactosidase 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. In heterozygous female Slc9a6 KO mice, Beta-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 Beta-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.

Czech name

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Czech description

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Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

FH - Neurology, neuro-surgery, nuero-sciences

OECD FORD branch

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Project

<a href="/en/project/NT14015" target="_blank" >NT14015: Progress in methods of laboratory diagnostics of inherited lysosomal neurodegenerative disorders</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2016

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

DMM Disease Models and Mechanisms

ISSN

1754-8403

e-ISSN

—

Volume of the periodical

9

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

11

Pages from-to

13-23

UT code for WoS article

000371437500002

EID of the result in the Scopus database

2-s2.0-84954507960