Dataset Information

Giant Axonal Neuropathy (GAN): Cross-sectional data on phenotypes, genotypes and proteomics signature from a German-Austrian-Swiss cohort

ABSTRACT: Giant Axon Neuropathy (GAN) is a progressive neurodegenerative disease characterised by involvement of peripheral and central nervous system frequently associated with frizzy hair. The phenotype is caused by bi-allelic variants in the GAN gene, leading to loss of functional gigaxonin proteins.. Thus, far the disease cannot be cured, but a first clinical gene therapy trial in the US was currently completed. So far, there has been no systematic reporting of GAN patients in German-speaking countries. Therefore, we conducted a survey using an e-mail list of German-speaking child neurologists of the so-called DACH region reflecting Germany, Austria and Switzerland. Based on their feedback, clinical, genetic and epidemiological data were collected using a standardised data collection form in turn enabling the collection of comprehensive and detailed epidemiological, clinical and genetic information from a total of 15 patients representing one of the largest cohorts systematically described thus far. Average age of patients was 11.7 years at the time of data collection. In line with the frequency of homozygous variants, the majority were of Syrian origin and of consanguineous relationships. In 14 patients, diagnosis was confirmed by molecular genetics, revealing eight different GAN variants, four being reported as pathogenic in literature. 13 patients had a classical GAN phenotype, one was classified as mild whereas another one was too young to draw final clinical conclusions. Proteomics of white blood cells derived from four patients revealed was conducted to obtain unbiased insights into the underlying pathophysiology and revealed dysregulation of 111 proteins implicated in diverse biological processes. Of note diverse of these proteins are known to be crucial for proper synaptic function and transmission and affection of intermediate filament organization and proteolysis is in line with the known functions of gigaxonin. In view of a potential genetic treatment option, these data on the natural course of the disease are important for study design in preparation for gene therapy trials in Europe and moreover provide a catalogue of proteins serving as minimal invasive but cellular biomarkers.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Leukocyte

SUBMITTER: Andreas Hentschel

LAB HEAD: Andreas Hentschel

PROVIDER: PXD053070 | Pride | 2025-05-07

REPOSITORIES: Pride

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Giant axonal neuropathy (GAN): cross-sectional data on phenotypes, genotypes, and proteomic signature from a German cohort.

Gangfuß Andrea A Goj Guido G Polz Silke S Della Marina Adela A Hentschel Andreas A Ahlbory Katja K Deba Timo T Kotzaeridou Urania U Schuler Elisabeth E Pechmann Astrid A Diebold Uta U Kurlemann Gerhard G Heinzkyll Lucas L Schmitt Dirk D Rostasy Kevin K Ruck Tobias T Böhm Johann J Roos Andreas A Schara-Schmidt Ulrike U

Journal of neurology 20241216 1

Giant axonal neuropathy (GAN) is a progressive neurodegenerative disease affecting the peripheral and central nervous system and is caused by bi-allelic variants in the GAN gene, leading to loss of functional gigaxonin protein. A treatment does not exist, but a first clinical trial using a gene therapy approach has recently been completed. Here, we conducted the first systematic study of GAN patients treated by German-speaking child neurologists. We collected clinical, genetic, and epidemiologic ...[more]

PMID: 39680150

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Project description:Immunoglobulin A Nephropathy (IgAN) is a complex multifactorial disease whose genetic bases remain unknown. Distinct linkage and genome-wide association studies in both familial and sporadic IgAN suggest that there is a strong genetic component in IgAN. In this context, an intriguing role could be ascribed to copy number variants (CNVs) that have been recognized as an important source of genetic variation in humans. Here, we performed a whole-genome screening of CNVs in IgAN patients, their healthy relatives and healthy subjects (HS). A total of 217 individuals consisting of 51 IgAN cases and 166 healthy relatives were included in the initial screening. The high-throughput analysis of structural genetic variations, to find concordant aberrations across classes of samples, identified 178 IgAN-specific aberrations, specifically 114 loss and 64 gain. Several CNVs overlapped with regions evidenced by previous genome-wide genetic studies. Moreover, we found that IgAN patients characterized by deteriorated renal function carried low copy numbers of a CNV in chromosome 3 (chr3_loss:52031010-52260722). This CNV contained the TLR9 gene whose expression significantly correlated with the loss aberration in patients with progressive renal damage. Conversely, IgAN patients with normal renal function had no chr3_loss:52031010-52260722 and the TLR9 mRNA was expressed at the same level as in HS, still maintaining a strong correlation with the CNV. In conclusion, here we performed the first genome-wide CNV study in IgAN identifying some structural variants specific to IgAN patients and providing a collection of new candidate genes and loci that could help to dissect the complex genomic setting of the disease. Moreover, we identified a specific CNV, spanning the TLR9 gene, which could explain the disease severity in IgAN patients. To perform a genome-wide CNV study in IgAN identifying some structural variants specific to IgAN patients and providing a collection of new candidate genes and loci that could help to dissect the complex genomic setting of the disease.

			Action	DRS
	20240613_074542_AH_WBF_52_22_GAN_Ctrl.sne	Other
	Lumos12486.raw	Raw
	Lumos12487.raw	Raw
	Lumos12488.raw	Raw
	Lumos12491.raw	Raw