OBJECTIVE: To explore the prenatal features and genetic etiology of a fetus with Short-rib cage dysplasia (SRTD) due to variants of DYNC2H1 gene. METHODS: A pregnant women presented at Xinxiang Central Hospital in June 2020 for abnormal prenatal ultrasound findings was selected as the study subject. With informed consent obtained, amniotic fluid sample was extracted from the woman, and clinical data of the fetus were collected. Whole exome sequencing (WES) was carried out, and candidate variants were verified by Sanger sequencing. This study was approved by the Medical Ethics Committee of Xinxiang Central Hospital [Ethics No.: 2025-214-01(K)]. RESULTS: At 25⁺⁶ weeks gestation, genetic testing revealed that the fetus has harbored compound heterozygous variants of the DYNC2H1 gene, namely c.10585C>T (p.Arg3529Ter) and c.8954T>G (p.Val2985Gly), which were derived from its father and mother, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.10585C>T (p.Arg3529Ter) and c.8954T>G (p.Val2985Gly) variants were classified as pathogenic (PVS1+PM2_supporting+PM3+PP5) and likely pathogenic (PM1+PM2_supporting+PM3+PP3), respectively. Bioinformatics analysis suggested that both variants may affect the 3D structure of the DYNC2H1 protein. CONCLUSION The compound heterozygous variants of c.10585C>T (p.Arg3529Ter) and c.8954T>G (p.Val2985Gly) of the DYNC2H1 gene probably underlay the pathogenesis of SRTD in the fetus. Above findings had facilitated prenatal diagnosis and genetic counseling for the couple.
Humans ; Female ; Pregnancy ; Cytoplasmic Dyneins/chemistry* ; Prenatal Diagnosis ; Adult ; Short Rib-Polydactyly Syndrome/diagnostic imaging* ; Mutation ; Exome Sequencing ; Fetus/abnormalities* ; Ultrasonography, Prenatal

N-acetylglucosamine kinase (GlcNAc kinase or NAGK) is a ubiquitously expressed enzyme in mammalian cells. Recent studies have shown that NAGK has an essential structural, non-enzymatic role in the upregulation of dendritogenesis. In this study, we conducted yeast two-hybrid screening to search for NAGK-binding proteins and found a specific interaction between NAGK and dynein light-chain roadblock type 1 (DYNLRB1). Immunocytochemistry (ICC) on hippocampal neurons using antibodies against NAGK and DYNLRB1 or dynein heavy chain showed some colocalization, which was increased by treating the live cells with a crosslinker. A proximity ligation assay (PLA) of NAGK-dynein followed by tubulin ICC showed the localization of PLA signals on microtubule fibers at dendritic branch points. NAGK-dynein PLA combined with Golgi ICC showed the colocalization of PLA signals with somal Golgi facing the apical dendrite and with Golgi outposts in dendritic branch points and distensions. NAGK-Golgi PLA followed by tubulin or DYNLRB1 ICC showed that PLA signals colocalize with DYNLRB1 at dendritic branch points and at somal Golgi, indicating a tripartite interaction between NAGK, dynein and Golgi. Finally, the ectopic introduction of a small peptide derived from the C-terminal amino acids 74-96 of DYNLRB1 resulted in the stunting of hippocampal neuron dendrites in culture. Our data indicate that the NAGK-dynein-Golgi tripartite interaction at dendritic branch points functions to regulate dendritic growth and/or branching.
Amino Acid Sequence ; Animals ; Cells, Cultured ; Cytoplasmic Dyneins/chemistry/*metabolism ; Dendrites/metabolism ; Golgi Apparatus/metabolism ; HEK293 Cells ; Hippocampus ; Humans ; Molecular Sequence Data ; Neurons/*metabolism ; Phosphotransferases (Alcohol Group Acceptor)/*metabolism ; Protein Interaction Maps ; Rats, Sprague-Dawley ; Tubulin