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De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy
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Personen und Körperschaften: | , , , , , , , , , , , , , |
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Titel: |
De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy |
In: | Journal of Medical Genetics, 57, 2020, 4, S. 283-288 |
veröffentlicht: |
BMJ
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Umfang: | 283-288 |
ISSN: |
0022-2593 1468-6244 |
DOI: | 10.1136/jmedgenet-2019-106273 |
Zusammenfassung: | <jats:sec><jats:title>Background</jats:title><jats:p>Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in <jats:italic>SLC12A6</jats:italic> have been associated with autosomal-recessive hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). We identified heterozygous de novo variants in <jats:italic>SLC12A6</jats:italic> in three unrelated patients with intermediate CMT.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in <jats:italic>SLC12A6</jats:italic> identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in <jats:italic>Xenopus</jats:italic> oocytes.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in <jats:italic>SLC12A6</jats:italic> in three unrelated individuals with early-onset progressive CMT. All presented with axonal/demyelinating sensorimotor neuropathy accompanied by spasticity in one patient. Cognition and brain MRI were normal. Modelling of the mutant KCC3 cotransporter in <jats:italic>Xenopus</jats:italic> oocytes showed a significant reduction in potassium influx for both changes.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our findings expand the genotypic and phenotypic spectrum associated with <jats:italic>SLC12A6</jats:italic> variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy.</jats:p></jats:sec> |
Format: | E-Article |
Quelle: | BMJ (CrossRef) |
Sprache: | Englisch |