PUBLICATION

Personalized genome sequencing coupled with iPSC technology identifies GTDC1 as a gene involved in neurodevelopmental disorders

Authors

Aksoy, I., Utami, K.H., Winata, C.L., Hillmer, A.M., Rouam, S.L., Briault, S., Davila, S., Stanton, L.W., Cacheux, V.

ID

ZDB-PUB-170404-16

Date

2017

Source

Human molecular genetics 26: 367-382 (Journal)

Registered Authors

Winata, Cecilia Lanny

Keywords

phenotype, nervous system disorder, chromosome rearrangements, stem cells, dna, genes, genome, neurons, technology, zebrafish, stem cells, pluripotent, autism spectrum disorder, genome sequencing, neurodevelopmental disorders, individualized medicine, transluminal attenuation gradient, central nervous system development

MeSH Terms

Animals
Autism Spectrum Disorder/genetics*
Autism Spectrum Disorder/metabolism
Autism Spectrum Disorder/pathology
Cell Differentiation/genetics
Central Nervous System/growth & development
Central Nervous System/pathology
Disease Models, Animal
Gene Expression Regulation, Developmental
Genome, Human
Glycosyltransferases/biosynthesis
Glycosyltransferases/genetics*
High-Throughput Nucleotide Sequencing
Humans
Induced Pluripotent Stem Cells/metabolism*
Induced Pluripotent Stem Cells/pathology
Neural Stem Cells/metabolism*
Neural Stem Cells/pathology
Neurons/metabolism
Neurons/pathology
Precision Medicine
Zebrafish/genetics
Zebrafish/growth & development

(all 23)

PubMed

28365779 Full text @ Hum. Mol. Genet.

Abstract

The cellular and molecular mechanisms underlying neurodevelopmental conditions such as autism spectrum disorders have been studied intensively for decades. The ability to generate patient-specific induced pluripotent stem cells (iPSCs) now offers a novel strategy for modelling human diseases. Recent studies have reported the derivation of iPSCs from patients with neurological disorders. The key challenge remains the demonstration of disease-related phenotypes and the ability to model the disease. Here we report a case study with signs of neurodevelopmental disorders (NDDs) harbouring chromosomal rearrangements that were sequenced using long-insert DNA paired-end tag (DNA-PET) sequencing approach. We identified the disruption of a specific gene, GTDC1. By deriving iPSCs from this patient and differentiating them into neural progenitor cells (NPCs) and neurons we dissected the disease process at the cellular level and observed defects in both NPCs and neuronal cells. We also showed that disruption of GTDC1 expression in wild type human NPCs and neurons showed a similar phenotype as patient's iPSCs. Finally, we utilized a zebrafish model to demonstrate a role for GTDC1 in the development of the central nervous system. Our findings highlight the importance of combining sequencing technologies with the iPSC technology for NDDs modelling that could be applied for personalized medicine.

Genes / Markers

Marker	Marker Type	Name
fgfr3	GENE	fibroblast growth factor receptor 3
gtdc1	GENE	glycosyltransferase-like domain containing 1
isl1a	GENE	ISL LIM homeobox 1a

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
fgfr3	AB	standard conditions	Long-pec	hindbrain	ISH	Fig. 5
fgfr3	AB	standard conditions	Long-pec	midbrain	ISH	Fig. 5
fgfr3	AB	standard conditions	Long-pec	telencephalon	ISH	Fig. 5
fgfr3	AB + MO1-gtdc1	standard conditions	Long-pec	hindbrain	ISH	Fig. 5
fgfr3	AB + MO1-gtdc1	standard conditions	Long-pec	midbrain	ISH	Fig. 5
fgfr3	AB + MO1-gtdc1	standard conditions	Long-pec	telencephalon	ISH	Fig. 5
isl1a	AB	standard conditions	Long-pec	forebrain	ISH	Fig. 5
isl1a	AB	standard conditions	Long-pec	hypothalamus	ISH	Fig. 5
isl1a	AB	standard conditions	Long-pec	retinal ganglion cell	ISH	Fig. 5
isl1a	AB + MO1-gtdc1	standard conditions	Long-pec	forebrain	ISH	Fig. 5

1 - 10 of 12

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB + MO1-gtdc1	standard conditions	Long-pec	embryo development disrupted, abnormal	Fig. 5
AB + MO1-gtdc1	standard conditions	Long-pec	eye decreased size, abnormal	Fig. 5
AB + MO1-gtdc1	standard conditions	Long-pec	forebrain isl1a expression decreased amount, abnormal	Fig. 5
AB + MO1-gtdc1	standard conditions	Long-pec	head decreased size, abnormal	Fig. 5
AB + MO1-gtdc1	standard conditions	Long-pec	hypothalamus isl1a expression decreased amount, abnormal	Fig. 5
AB + MO1-gtdc1	standard conditions	Long-pec	retinal ganglion cell isl1a expression absent, abnormal	Fig. 5
AB + MO1-gtdc1	standard conditions	Long-pec	trunk curved, abnormal	Fig. 5
knu3Tg + MO1-gtdc1	standard conditions	Long-pec	optic tectum neuron increased amount, abnormal	Fig. 5

1 - 8 of 8

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
knu3Tg	Tg(elavl3:EGFP)	Transgenic Insertion

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
cognitive disorder			TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
gtdc1	MO1-gtdc1	MRPHLNO

Fish

Fish
AB
AB + MO1-gtdc1
knu3Tg + MO1-gtdc1

Antibodies

Orthology

Gene

Orthology

gtdc1

Species	Symbol	Chromosome	Accession #	Evidence
Human	GTDC1	2	Ensembl:ENSG00000121964 Gene:79712 OMIM:610165 HGNC:20887	Amino acid sequence comparison (1) Conserved genome location (synteny) (1) Functional complementation (1)
Mouse	Gtdc1	2	Ensembl:ENSMUSG00000036890 MGI:2444269 Gene:227835	Conserved genome location (synteny) (1) Amino acid sequence comparison (1)

1 - 1 of 1

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Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP

Mapping

Aksoy et al., 2017 ZDB-PUB-170404-16 PMID:28365779

Personalized genome sequencing coupled with iPSC technology identifies GTDC1 as a gene involved in neurodevelopmental disorders

Aksoy et al., 2017

ZDB-PUB-170404-16
PMID:28365779