A Novel Missense Mutation in SLC12A6 Impairs Ion Transport Function of the Protein to Cause Agenesis of the Corpus Callosum With Peripheral Neuropathy.
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引用次数: 0
Abstract
Agenesis of the corpus callosum with peripheral neuropathy (ACCPN) is a rare autosomal recessive disorder characterized by malformation or absence of the corpus callosum, accompanied by progressive peripheral nerve degeneration. ACCPN is associated with mutations in the SLC12A6 gene, encoding the potassium-chloride cotransporter (also termed KCC3), which plays a crucial role in neuronal ion homeostasis. In this study, we report a novel homozygous missense variant (c.1634A>G, p.H371R) in SLC12A6, identified through exome sequencing in a male proband presenting with ACCPN symptoms, including developmental delay, hypotonia, epileptic seizures, and corpus callosal dysgenesis. The proband's MRI findings revealed additional neurodevelopmental abnormalities such as hippocampal malformation. Functional analysis showed that while the mutant SLC12A6 transcript and protein levels were comparable to wild type, the mutant protein was mislocalized to the cytoplasm, disrupting its ion transport function. This mislocalization caused an imbalance in potassium and chloride ion levels in the proband's cells. Bioinformatics tools predicted the pathogenicity of the p.H371R mutation, and structural modeling revealed a destabilization effect. Elevated levels of cellular senescence markers, p16 and p21, were detected, indicating that ion dysregulation due to SLC12A6-p.H371R mislocalization contributed to cellular stress. This study provides novel insights into the pathogenic mechanism of ACCPN, highlighting the importance of mutant SLC12A6 mislocalization and ion homeostasis in disease progression. The identification of the p.H371R mutation adds to the spectrum of SLC12A6 mutations linked to ACCPN and underscores the potential for targeted therapeutic strategies.
期刊介绍:
Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice.
Topics of particular interest are:
• Linking genetic variations to disease
• Genome rearrangements and disease
• Epigenetics and disease
• The translation of genotype to phenotype
• Genetics of complex disease
• Management/intervention of genetic diseases
• Novel therapies for genetic diseases
• Developmental biology, as it relates to clinical genetics
• Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease