Functional analysis of the neurodevelopmental disorder candidate gene RUFY4 in Drosophila melanogaster
Functional analysis of the neurodevelopmental disorder candidate gene RUFY4 in Drosophila melanogaster
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DissertationPrüfungsdatum
10.04.2025Datum der Veröffentlichung
21.05.2025Erstgutachter
Soba, PeterZweitgutachter
Grunwald Kadow, IlonaMetadaten
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Neurodevelopmental disorders (NDDs) encompass a heterogeneous group of complex conditions, most of which are characterized by intellectual disability (ID). ID arises from both environmental and genetic causes, with most severe forms predominantly attributed to genetic factors. Notably, most genes associated with ID exhibit an autosomal recessive inheritance pattern, particularly prevalent in the ID cases in consanguineous populations. Despite technological advancements in gene discovery, most autosomal recessive ID genes remain unidentified. This is likely due to high genetic heterogeneity and challenges in proving pathogenicity of variants. Drosophila melanogaster offers a cost-effective and efficient model for in vivo functional studies of recessive variants of the identified conserved candidate genes, which are present in approximately 75% of all cases.
The focus of this study was on RUFY4, one of the NDDs candidate genes identified through our collaboration with the Human Genetics apartment at the FAU Erlangen. RUFY proteins are essential in intracellular membrane trafficking and cytoskeleton dynamics, but have not been extensively studied at the organismal level and in the nervous system. I identified a single fly RUFY homolog (CG31064/dRUFY), which I analyzed functionally in Drosophila. Manipulating the Drosophila homolog of human RUFY genes revealed that its disruption resulted in various phenotypes which mirror the common features of NDDs. Loss of dRUFY led to decreased number of autophagosomes, synaptic abnormalities within the nociceptive circuits, as well as aberrant somatosensory functions. In addition, dRUFY-deficient Drosophila displayed memory dysfunction in associative learning test, and reduced social interaction in food competition assays. Importantly, I discovered that reintroducing human RUFY4, but not the patient-derived variant, could rescue some of these deficits, including synaptic alterations and somatosensory hypersensitivity caused by loss of dRUFY in sensory neurons. These findings validate the functional conservation between Drosophila dRUFY and human RUFY4 and confirming the pathogenic nature of the patient-derived variant. This study illuminates the crucial role of RUFY4 in neuronal development and behavior, enhancing our understanding of NDD pathogenesis.
The focus of this study was on RUFY4, one of the NDDs candidate genes identified through our collaboration with the Human Genetics apartment at the FAU Erlangen. RUFY proteins are essential in intracellular membrane trafficking and cytoskeleton dynamics, but have not been extensively studied at the organismal level and in the nervous system. I identified a single fly RUFY homolog (CG31064/dRUFY), which I analyzed functionally in Drosophila. Manipulating the Drosophila homolog of human RUFY genes revealed that its disruption resulted in various phenotypes which mirror the common features of NDDs. Loss of dRUFY led to decreased number of autophagosomes, synaptic abnormalities within the nociceptive circuits, as well as aberrant somatosensory functions. In addition, dRUFY-deficient Drosophila displayed memory dysfunction in associative learning test, and reduced social interaction in food competition assays. Importantly, I discovered that reintroducing human RUFY4, but not the patient-derived variant, could rescue some of these deficits, including synaptic alterations and somatosensory hypersensitivity caused by loss of dRUFY in sensory neurons. These findings validate the functional conservation between Drosophila dRUFY and human RUFY4 and confirming the pathogenic nature of the patient-derived variant. This study illuminates the crucial role of RUFY4 in neuronal development and behavior, enhancing our understanding of NDD pathogenesis.
Klassifikation (DDC)
570 Biowissenschaften, Biologie 610 Medizin, GesundheitYu, Peiyun: Functional analysis of the neurodevelopmental disorder candidate gene RUFY4 in Drosophila melanogaster. - Bonn, 2025. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-82681
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-82681
@phdthesis{handle:20.500.11811/13081,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-82681,
author = {{Peiyun Yu}},
title = {Functional analysis of the neurodevelopmental disorder candidate gene RUFY4 in Drosophila melanogaster},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2025,
month = may,
note = {Neurodevelopmental disorders (NDDs) encompass a heterogeneous group of complex conditions, most of which are characterized by intellectual disability (ID). ID arises from both environmental and genetic causes, with most severe forms predominantly attributed to genetic factors. Notably, most genes associated with ID exhibit an autosomal recessive inheritance pattern, particularly prevalent in the ID cases in consanguineous populations. Despite technological advancements in gene discovery, most autosomal recessive ID genes remain unidentified. This is likely due to high genetic heterogeneity and challenges in proving pathogenicity of variants. Drosophila melanogaster offers a cost-effective and efficient model for in vivo functional studies of recessive variants of the identified conserved candidate genes, which are present in approximately 75% of all cases.
The focus of this study was on RUFY4, one of the NDDs candidate genes identified through our collaboration with the Human Genetics apartment at the FAU Erlangen. RUFY proteins are essential in intracellular membrane trafficking and cytoskeleton dynamics, but have not been extensively studied at the organismal level and in the nervous system. I identified a single fly RUFY homolog (CG31064/dRUFY), which I analyzed functionally in Drosophila. Manipulating the Drosophila homolog of human RUFY genes revealed that its disruption resulted in various phenotypes which mirror the common features of NDDs. Loss of dRUFY led to decreased number of autophagosomes, synaptic abnormalities within the nociceptive circuits, as well as aberrant somatosensory functions. In addition, dRUFY-deficient Drosophila displayed memory dysfunction in associative learning test, and reduced social interaction in food competition assays. Importantly, I discovered that reintroducing human RUFY4, but not the patient-derived variant, could rescue some of these deficits, including synaptic alterations and somatosensory hypersensitivity caused by loss of dRUFY in sensory neurons. These findings validate the functional conservation between Drosophila dRUFY and human RUFY4 and confirming the pathogenic nature of the patient-derived variant. This study illuminates the crucial role of RUFY4 in neuronal development and behavior, enhancing our understanding of NDD pathogenesis.},
url = {https://hdl.handle.net/20.500.11811/13081}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-82681,
author = {{Peiyun Yu}},
title = {Functional analysis of the neurodevelopmental disorder candidate gene RUFY4 in Drosophila melanogaster},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2025,
month = may,
note = {Neurodevelopmental disorders (NDDs) encompass a heterogeneous group of complex conditions, most of which are characterized by intellectual disability (ID). ID arises from both environmental and genetic causes, with most severe forms predominantly attributed to genetic factors. Notably, most genes associated with ID exhibit an autosomal recessive inheritance pattern, particularly prevalent in the ID cases in consanguineous populations. Despite technological advancements in gene discovery, most autosomal recessive ID genes remain unidentified. This is likely due to high genetic heterogeneity and challenges in proving pathogenicity of variants. Drosophila melanogaster offers a cost-effective and efficient model for in vivo functional studies of recessive variants of the identified conserved candidate genes, which are present in approximately 75% of all cases.
The focus of this study was on RUFY4, one of the NDDs candidate genes identified through our collaboration with the Human Genetics apartment at the FAU Erlangen. RUFY proteins are essential in intracellular membrane trafficking and cytoskeleton dynamics, but have not been extensively studied at the organismal level and in the nervous system. I identified a single fly RUFY homolog (CG31064/dRUFY), which I analyzed functionally in Drosophila. Manipulating the Drosophila homolog of human RUFY genes revealed that its disruption resulted in various phenotypes which mirror the common features of NDDs. Loss of dRUFY led to decreased number of autophagosomes, synaptic abnormalities within the nociceptive circuits, as well as aberrant somatosensory functions. In addition, dRUFY-deficient Drosophila displayed memory dysfunction in associative learning test, and reduced social interaction in food competition assays. Importantly, I discovered that reintroducing human RUFY4, but not the patient-derived variant, could rescue some of these deficits, including synaptic alterations and somatosensory hypersensitivity caused by loss of dRUFY in sensory neurons. These findings validate the functional conservation between Drosophila dRUFY and human RUFY4 and confirming the pathogenic nature of the patient-derived variant. This study illuminates the crucial role of RUFY4 in neuronal development and behavior, enhancing our understanding of NDD pathogenesis.},
url = {https://hdl.handle.net/20.500.11811/13081}
}
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