PUBLICATION
Hemifacial microsomia is linked a rare homozygous variant V162I in FRK and validated in zebrafish
- Authors
- Xiong, J., Wang, X., Fan, C., Yan, J., Zhu, J., Cai, T.
- ID
- ZDB-PUB-220908-8
- Date
- 2022
- Source
- Oral diseases 29(8): 3472-3480 (Journal)
- Registered Authors
- Cai, Tao, Fan, Chunxin, Yan, Jizhou
- Keywords
- FRK, Hemifacial microsomia, homozygous missense mutation, patient, zebrafish
- MeSH Terms
-
- Adolescent
- Animals
- Cartilage
- Female
- Goldenhar Syndrome*/genetics
- Humans
- Mandible/abnormalities
- Mice
- Neoplasm Proteins
- Protein-Tyrosine Kinases
- Temporomandibular Joint
- Zebrafish/genetics
- PubMed
- 36070195 Full text @ Oral Dis
Citation
Xiong, J., Wang, X., Fan, C., Yan, J., Zhu, J., Cai, T. (2022) Hemifacial microsomia is linked a rare homozygous variant V162I in FRK and validated in zebrafish. Oral diseases. 29(8):3472-3480.
Abstract
Objectives Hemifacial microsomia (HFM) is a common birth defect involving the first and second branchial arch derivatives. Although several chromosomal abnormalities and causal gene variants have been identified, genetic etiologies in a majority of cases with HFM remain unknown. This study aimed to identify genetic mutations in affected individuals with HFM.
Methods Whole exome sequencing and bioinformatics analysis were performed for 16 affected individuals and their family members. Sanger sequencing was applied for confirmation of selected mutations. Zebrafish embryos were used for in situ hybridization of candidate gene, microinjection with antisense morpholino and cartilage staining.
Results A homozygous missense mutation (c.484G>A; p.V162I) in the FRK gene was identified in an 18-year-old girl with HFM and dental abnormalities. Heterozygous mutation of this mutation was identified in her parents, who are first-cousins in a consanguineous family. FRK is highly expressed in the Meckel's cartilage during embryonic development in mouse and zebrafish. Knockdown of frk in zebrafish showed a lower length and width ratio of Meckel's cartilage, abnormal mandibular jaw joint and disorganized ceratobranchial cartilage and bone.
Conclusions We identified a recessive variant in the FRK gene as a novel candidate gene for a patient with HFM and mandibular hypoplasia and revealed its effects on craniofacial and embryonic development in zebrafish.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping