Biallelic loss-of-function variants in GON4L cause microcephaly and brain structure abnormalities

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.

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Publication Details

Journal
npj Genomic Medicine
Published
2024-11-05
DOI
https://doi.org/10.1038/s41525-024-00437-5
Citations
2
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
1.10

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article

Biallelic loss-of-function variants in GON4L cause microcephaly and brain structure abnormalities

Simo Li, Maha Saad Zaki, Mahmoud Y. Issa, Ryoko Fukai et al.
2 citations
npj Genomic Medicine
Genomics and Rare Diseases
1.10
article

Biallelic loss-of-function variants in GON4L cause microcephaly and brain structure abnormalities

Simo Li, Maha Saad Zaki, Mahmoud Y. Issa, Ryoko Fukai, Toshio Ohshima, Ghada M. H. Abdel‐Salam, Eriko Koshimizu, Sanami Takada, Mohamed S. Abdel‐Hamid, Naomichi Matsumoto, Atsushi Fujita, Noriko Miyake, Aida M. S. Salem
article en
2 citations

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.

npj Genomic MedicineVol. 9(1)
Beni-Suef University (EG), Waseda University (JP), IQVIA (United Kingdom) (GB), National Center for Global Health and Medicine (JP), National Research Centre (EG), Yokohama City University (JP)
Takeda Science Foundation, Japan Agency for Medical Research and Development, National Center for Global Health and Medicine, Science and Technology Development Fund, Japan Society for the Promotion of Science
Zero hunger
Openalex Percentile: Top 18%
Genomics and Rare Diseases
1.10
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