PUBLICATION
Biallelic loss-of-function variants in GON4L cause microcephaly and brain structure abnormalities
- Authors
- Li, S., Takada, S., Abdel-Salam, G.M.H., Abdel-Hamid, M.S., Zaki, M.S., Issa, M.Y., Salem, A.M.S., Koshimizu, E., Fujita, A., Fukai, R., Ohshima, T., Matsumoto, N., Miyake, N.
- ID
- ZDB-PUB-241106-8
- Date
- 2024
- Source
- NPJ genomic medicine 9: 5555 (Journal)
- Registered Authors
- Ohshima, Toshio
- Keywords
- none
- MeSH Terms
- none
- PubMed
- 39500882 Full text @ NPJ Genom Med
Citation
Li, S., Takada, S., Abdel-Salam, G.M.H., Abdel-Hamid, M.S., Zaki, M.S., Issa, M.Y., Salem, A.M.S., Koshimizu, E., Fujita, A., Fukai, R., Ohshima, T., Matsumoto, N., Miyake, N. (2024) Biallelic loss-of-function variants in GON4L cause microcephaly and brain structure abnormalities. NPJ genomic medicine. 9:5555.
Abstract
We identified two homozygous truncating variants in GON4L [NM_001282860.2:c.62_63del, p.(Gln21Argfs*12) and c.5517+1G>A] in two unrelated families who presented prenatal-onset growth impairment, microcephaly, characteristic face, situs inversus, and developmental delay. The frameshift variant is predicted to invoke nonsense-mediated mRNA decay of all five known GON4L isoforms resulting in the complete loss of GON4L function. The splice site variant located at a region specific to the longer isoforms; therefore, defects of long GON4L isoforms may explain the phenotypes observed in the three patients. Knockdown of Gon4l in rat PC12 cells suppressed neurite outgrowth in vitro. gon4lb knockdown and knockout zebrafish successfully recapitulated the patients' phenotypes including craniofacial abnormalities. We also observed situs inversus in gon4lb-knockout zebrafish embryo. To our knowledge, the relationship between craniofacial abnormalities or situs inversus and gon4lb has not been reported before. Thus, our data provide evidence that GON4L is involved in craniofacial and left-right patterning during development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping