Biallelic loss-of-function variants in GON4L cause microcephaly and brain structure abnormalities
Simo Li1, Sanami Takada2, Ghada M H Abdel-Salam3
1Department of Life Science and Medical Bioscience, Waseda University, Tokyo, Japan.
NPJ Genomic Medicine
|November 5, 2024
Summary
Genetic variants in the GON4L gene cause developmental disorders including growth impairment and microcephaly. This study links GON4L to craniofacial and left-right patterning, revealing new insights into developmental biology.
Area of Science:
- Genetics
- Developmental Biology
- Human Disease
Background:
- Genetic variations can lead to complex developmental disorders.
- The GON4L gene's role in human development is not fully understood.
- Previous research has not established a link between GON4L and craniofacial or situs inversus abnormalities.
Purpose of the Study:
- To investigate the role of GON4L gene variants in patients with prenatal-onset growth impairment and developmental delay.
- To explore the function of GON4L in craniofacial and left-right patterning using cellular and zebrafish models.
Main Methods:
- Identified homozygous truncating variants in GON4L in two unrelated families.
- Utilized rat PC12 cells for in vitro knockdown experiments of Gon4l.
- Generated gon4lb knockdown and knockout zebrafish models to study developmental phenotypes.
Main Results:
- Two novel homozygous truncating variants in GON4L were identified in affected individuals.
- Gon4l knockdown in rat cells suppressed neurite outgrowth.
- Zebrafish models recapitulated patient phenotypes, including craniofacial abnormalities and situs inversus.
Conclusions:
- Discovered that GON4L variants are associated with prenatal growth impairment, microcephaly, and developmental delay.
- Provided evidence that GON4L plays a crucial role in craniofacial development and left-right patterning.
- Highlighted the potential impact of GON4L defects on embryonic development, including organ positioning.
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