Dataset Information

Clinical and molecular characterization of a novel LMX1A frameshift mutation near the C-terminus lead to familial non-syndromic sensorineural hearing loss

ABSTRACT: Clinical and molecular characterization of a novel LMX1A frameshift mutation near the C-terminus lead to familial non-syndromic sensorineural hearing loss

PROVIDER: PRJNA825501 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18713659_1.fastq.gz	Fastqsanger.gz
	SRR18713659_2.fastq.gz	Fastqsanger.gz
	SRR18713660_1.fastq.gz	Fastqsanger.gz
	SRR18713660_2.fastq.gz	Fastqsanger.gz
	SRR18713661_1.fastq.gz	Fastqsanger.gz

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Project description:Rahman syndrome (RMNS) is a rare genetic disorder characterized by mild to severe intellectual disability, hypotonia, anxiety, autism spectrum disorder, vision problems, bone abnormalities, and dysmorphic facies. De novo heterozygous mutations in H1-4 encoding the linker histone H1.4 are found in individuals with RMNS; however, the underlying mechanisms causing significantly impaired neurodevelopment are not understood. So far, all neurodevelopmental associated mutations in H1-4 are small insertions or deletions that create a shared frameshift, resulting in a H1.4 protein that is both truncated and possessing an abnormal C-terminus frameshifted tail (H1.4 CFT). To expand understanding of mutations and phenotypes associated with mutant H1-4, we identified additional and new DNA variants at both the C- and N-terminus of H1.4. The clinical features of mutations identified at the C-terminus are consistent with other reports that strengthen the support of pathogenicity of H1.4 CFT. However, the pathogenicity of disrupting variants at the N-terminus could not be determined. To understand how H1.4 CFT may disrupt brain function, we exogenously expressed wildtype or H1.4 CFT protein in primary rat hippocampal neurons and assessed neuronal structure and function. Genome-wide transcriptome analysis revealed ~400 genes altered specifically in the presence of H1.4 CFT. Neuronal genes downregulated by H1.4 CFT were enriched for functional categories involved in synaptic communication and neuropeptide signaling. Neurons expressing H1.4 CFT showed reduced activity on extracellular electrode arrays, indicating that these transcriptional changes were sufficient to disrupt physiological neuronal function. These data are the first to characterize the consequence of H1.4 CFT in neurons. Our data provide initial insights into causes of neurodevelopmental impairments associated with these frameshift mutations in the C-terminus of H1.4 and highlight the need for future studies on the function of normal histone H1.4 in neurons.

Dataset Information

Clinical and molecular characterization of a novel LMX1A frameshift mutation near the C-terminus lead to familial non-syndromic sensorineural hearing loss

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