<i>Drosophila</i> models of phosphatidylinositol glycan biosynthesis class A congenital disorder of glycosylation (PIGA-CDG) mirror patient phenotypes

Thorpe, Holly J; Owings, Katie G; Aziz, Miriam C; Haller, Madelyn; Coelho, Emily; Chow, Clement Y

doi:10.1093/g3journal/jkad291

Cited by 2 publications

References 25 publications

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Identification ofCNTN2as a genetic modifier of PIGA-CDG through pedigree analysis of a family with incomplete penetrance and functional testing inDrosophila

Thorpe,

Pedersen,

Dietze

et al. 2024

Preprint

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Loss of function mutations in the X-linked PIGA gene lead to PIGA-CDG, an ultra-rare congenital disorder of glycosylation (CDG), typically presenting with seizures, hypotonia, and neurodevelopmental delay. We identified two brothers (probands) with PIGA-CDG, presenting with epilepsy and mild developmental delay. Both probands carry PIGAS132C, an ultra-rare variant predicted to be damaging. Strikingly, the maternal grandfather and a great-uncle also carry PIGAS132C, but neither presents with symptoms associated with PIGA-CDG. We hypothesized genetic modifiers may contribute to this reduced penetrance. Using whole genome sequencing and pedigree analysis, we identified possible susceptibility variants found in the probands and not in carriers and possible protective variants found in the carriers and not in the probands. Candidate variants included heterozygous, damaging variants in three genes also involved directly in GPI-anchor biosynthesis and a few genes involved in other glycosylation pathways or encoding GPI-anchored proteins. We functionally tested the predicted modifiers using a Drosophila eye-based model of PIGA-CDG. We found that loss of CNTN2, a predicted protective modifier, rescues loss of PIGA in Drosophila eye-based model, like what we predict in the family. Further testing found that loss of CNTN2 also rescues patient-relevant phenotypes, including seizures and climbing defects in Drosophila neurological models of PIGA-CDG. By using pedigree information, genome sequencing, and in vivo testing, we identified CNTN2 as a strong candidate modifier that could explain the incomplete penetrance in this family. Identifying and studying rare disease modifier genes in human pedigrees may lead to pathways and targets that may be developed into therapies.

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Identification ofCNTN2as a genetic modifier of PIGA-CDG through pedigree analysis of a family with incomplete penetrance and functional testing inDrosophila

Thorpe,

Pedersen,

Dietze

et al. 2024

Preprint

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Drosophila as a Model for Human Disease: Insights into Rare and Ultra-Rare Diseases

Casas-Tintó

2024

Insects

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Rare and ultra-rare diseases constitute a significant medical challenge due to their low prevalence and the limited understanding of their origin and underlying mechanisms. These disorders often exhibit phenotypic diversity and molecular complexity that represent a challenge to biomedical research. There are more than 6000 different rare diseases that affect nearly 300 million people worldwide. However, the prevalence of each rare disease is low, and in consequence, the biomedical resources dedicated to each rare disease are limited and insufficient to effectively achieve progress in the research. The use of animal models to investigate the mechanisms underlying pathogenesis has become an invaluable tool. Among the animal models commonly used in research, Drosophila melanogaster has emerged as an efficient and reliable experimental model for investigating a wide range of genetic disorders, and to develop therapeutic strategies for rare and ultra-rare diseases. It offers several advantages as a research model including short life cycle, ease of laboratory maintenance, rapid life cycle, and fully sequenced genome that make it highly suitable for studying genetic disorders. Additionally, there is a high degree of genetic conservation from Drosophila melanogaster to humans, which allows the extrapolation of findings at the molecular and cellular levels. Here, I examine the role of Drosophila melanogaster as a model for studying rare and ultra-rare diseases and highlight its significant contributions and potential to biomedical research. High-throughput next-generation sequencing (NGS) technologies, such as whole-exome sequencing and whole-genome sequencing (WGS), are providing massive amounts of information on the genomic modifications present in rare diseases and common complex traits. The sequencing of exomes or genomes of individuals affected by rare diseases has enabled human geneticists to identify rare variants and identify potential loci associated with novel gene–disease relationships. Despite these advances, the average rare disease patient still experiences significant delay until receiving a diagnosis. Furthermore, the vast majority (95%) of patients with rare conditions lack effective treatment or a cure. This scenario is enhanced by frequent misdiagnoses leading to inadequate support. In consequence, there is an urgent need to develop model organisms to explore the molecular mechanisms underlying these diseases and to establish the genetic origin of these maladies. The aim of this review is to discuss the advantages and limitations of Drosophila melanogaster, hereafter referred as Drosophila, as an experimental model for biomedical research, and the applications to study human disease. The main question to address is whether Drosophila is a valid research model to study human disease, and in particular, rare and ultra-rare diseases.

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Drosophila models of phosphatidylinositol glycan biosynthesis class A congenital disorder of glycosylation (PIGA-CDG) mirror patient phenotypes

Cited by 2 publications

References 25 publications

Identification ofCNTN2as a genetic modifier of PIGA-CDG through pedigree analysis of a family with incomplete penetrance and functional testing inDrosophila

Identification ofCNTN2as a genetic modifier of PIGA-CDG through pedigree analysis of a family with incomplete penetrance and functional testing inDrosophila

Drosophila as a Model for Human Disease: Insights into Rare and Ultra-Rare Diseases

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